Chronic Granulomatous Disease Yoavanit Srivaro M.D.
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Chronic Granulomatous Disease
Yoavanit Srivaro MD
Outlines
bull Introduction
bull History
bull Epidemiology
bull Pathogenesis and Etiology
bull Clinical features
bull Evaluation and Diagnosis
bull Treatment
Introduction
Phagocytic cells
bull Neutrophil
bull Macrophage
bull Monocyte
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Neutrophil
bull Circulate as spherical cells about 12-15 μm in diameter
bull Nucleus of a neutrophil is segmented
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Neutrophil
bull Granule ( large lysosome)1 Azurophilic granule (1deg)
Defensins (gt50 of contents)CathelicidinsMPO (myelopeoxidase)
2 Specific granule (2deg)- only in neutrophil LactoferrinLysozyme
MPO ndash green color in pus
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Outlines
bull Introduction
bull History
bull Epidemiology
bull Pathogenesis and Etiology
bull Clinical features
bull Evaluation and Diagnosis
bull Treatment
Introduction
Phagocytic cells
bull Neutrophil
bull Macrophage
bull Monocyte
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Neutrophil
bull Circulate as spherical cells about 12-15 μm in diameter
bull Nucleus of a neutrophil is segmented
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Neutrophil
bull Granule ( large lysosome)1 Azurophilic granule (1deg)
Defensins (gt50 of contents)CathelicidinsMPO (myelopeoxidase)
2 Specific granule (2deg)- only in neutrophil LactoferrinLysozyme
MPO ndash green color in pus
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Introduction
Phagocytic cells
bull Neutrophil
bull Macrophage
bull Monocyte
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Neutrophil
bull Circulate as spherical cells about 12-15 μm in diameter
bull Nucleus of a neutrophil is segmented
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Neutrophil
bull Granule ( large lysosome)1 Azurophilic granule (1deg)
Defensins (gt50 of contents)CathelicidinsMPO (myelopeoxidase)
2 Specific granule (2deg)- only in neutrophil LactoferrinLysozyme
MPO ndash green color in pus
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Phagocytic cells
bull Neutrophil
bull Macrophage
bull Monocyte
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Neutrophil
bull Circulate as spherical cells about 12-15 μm in diameter
bull Nucleus of a neutrophil is segmented
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Neutrophil
bull Granule ( large lysosome)1 Azurophilic granule (1deg)
Defensins (gt50 of contents)CathelicidinsMPO (myelopeoxidase)
2 Specific granule (2deg)- only in neutrophil LactoferrinLysozyme
MPO ndash green color in pus
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Neutrophil
bull Circulate as spherical cells about 12-15 μm in diameter
bull Nucleus of a neutrophil is segmented
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Neutrophil
bull Granule ( large lysosome)1 Azurophilic granule (1deg)
Defensins (gt50 of contents)CathelicidinsMPO (myelopeoxidase)
2 Specific granule (2deg)- only in neutrophil LactoferrinLysozyme
MPO ndash green color in pus
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Neutrophil
bull Granule ( large lysosome)1 Azurophilic granule (1deg)
Defensins (gt50 of contents)CathelicidinsMPO (myelopeoxidase)
2 Specific granule (2deg)- only in neutrophil LactoferrinLysozyme
MPO ndash green color in pus
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
History
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Janeway amp colleagues 1st reported 5 children with serum gamma globulin levels with recurrent infections
1954 1957
Bridges et al described 4 boys with hypergammaglobulinemia suffering recurrent infections of the lungs lymph nodes and skin with granulomatous lesions
fatal granulomatous disease of childhood was first described
1960
Studies on patient blood confirmed CGD to be a disease of impaired phagocytes
1967
Tx using erythromycin amp novobiocin antibioticsamp regular sx drainage survival rate 4yrs to 12yrs
Chronic granulomatous disease
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Speculation that a b-type cytochrome may also be involved in this O2-
generating activity
1979 1980
Saw the formation of a disease-gene relationship
1986
The gp91phox subunit was first cloned encoded from the CYBB gene
Assari T Chronic Granulomatous Disease fundamental stages in our understanding of CGD Med Immunol 200654
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Epidemiology
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Epidemiology
bull Based on 2 large retrospective studies in the United States and Europe
-gt incidence= 1200000
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Epidemiology
bull Sweden -gt 1 450000
bull Japan -gt 1 300000
bull Israeli Arabs -gt 1 111000
Ahlin A De Boer M Roos D Leusen J Smith CI Sundin U et al Prevalence genetics and clinical presentation of chronic granulomatous disease in Sweden Acta Paediatr 1995841386-94
Hasui M Japa SGPD Chronic granulomatous disease in Japan Incidence and natural history Pediatrics International 199941589-93
Wolach B Gavrieli R de Boer M Gottesman G Ben-Ari J Rottem M et al Chronic granulomatous disease in Israel clinical functional and molecular studies of 38 patients Clin Immunol 2008129103-14
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Pathogenesis and Etiology
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Abbas AK Lichtman AH Pillai Shiv Cellular and molecular immunology 8th edPhiladelphia WB Saunders Company2015
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
NADPH Oxygen complex
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
httpswwwroswellparkeduoico
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
httpswwwroswellparkeduoico
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
NADPH Oxygen derive reductant
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Catalase positive Bacteria
S-Staph aureusSerratia marcesens
P-Pseudomonas
A-Aspergillus
C-CandidaCryptococcusCorynebacterium
E-EcoliEnterobacter
L-Listeria
M-Mycobacterium
N-Norcardia
LMN SPACE
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Relation among the Components of NADPH Oxidase That Are Affected in Patients with Chronic Granulomatous Disease
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
X-linked CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
X-linked CGD
wwwcgdorguk
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
X-linked CGD
wwwcgdorguk
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
X-linked CGD
In affected women lyonization (ie the inactivation of one or the other X chromosome in every cell) leads to two populations of phagocytes one with normal respiratory burst function and the other with impaired respiratory burst activity
Repine JE Clawson CC White JG Holmes B Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease J Pediatr 197587901-7
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
X-linked CGD
Carriers with less than 20 percent of normal oxidase activity due to skewed X-chromosome lyonization may present with the phenotype of mild to severe CGD
Anderson-Cohen M Holland SM Kuhns DB Fleisher TA Ding L Brenner S et al Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial extremely skewed
X chromosome inactivation Clin Immunol 2003109308-17
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
AR-CGD
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Clinical features
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Clinical features
bull Infection
bull Inflammation
bull Autoimmune disease
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Inflammation
bull Enhanced amp persistent inflammatory response
bull Reflected by hypergammaglobulinaemia
amp anaemia
bull Granuloma formation
-gt Occlusion of hollow viscera
bull Inflammatory cystitis
bull Granulomatous colitis mimicking Crohnrsquosdisease
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Inflammation
bull Persistent inflammation can occur independently of infection
bull Inflammatory sites are frequently sterile
bull One possible explanation for failure to resolve inflammation
-gtInability of CGD phagocytes to degrade
chemotactic factors
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Autoimmune disease
bull CYBB ampother CGD-related genes could be lupus-susceptibility genes
bull Abnormal apoptosis coupled to abnormal clearance of apoptotic cells
bull Complement deficiencies
Carneiro-Sampaio M Liphaus BL Jesus AA Silva CA Oliveira JB Kiss MH Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies J Clin Immunol 200828 Suppl
1S34-41
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Battersby AC Cale AM Goldblatt D Gennery AR Clinical manifestations of disease in X-linked carriers of chronic granulomatous disease J ClinImmunol 2013331276-84
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Common site of infection
wwwcgdorguk
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
H
Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI et al Chronic granulomatous disease Report on a national registry of 368 patients Medicine (Baltimore) 200079155-69
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L et al Chronic granulomatous disease the European experience PLoS One 20094e5234
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
26 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
106 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
098 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
081 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
144 cases per 100 patient-years
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Total 268
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Spalding C Fitzgerald A Mann D Brown T Osgood S et al Common severe infections in chronic granulomatous disease Clin Infect Dis 2015601176-83
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Panel A shows painful inflammation of the nares
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Fig 1 Left fundus demonstrating typical punched out chorioretinal lesion with retinal vessel bowing in the base and pigmented
margins
David Goldblatt Jeremy Butcher Adrian J Thrasher Isabelle Russell-Eggitt
Chorioretinal lesions in patients and carriers of chronic granulomatous disease
The Journal of Pediatrics Volume 134 Issue 6 1999 780 - 783
httpdxdoiorg101016S0022-3476(99)70299-4
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Panel B shows a large granuloma in the neck (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Panel C shows severe gingivitis (arrow)
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Massive lymphadenopathy in the cervical axillary and preauricularareas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Massive lymphadenopathy in the inguinal areas
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Chest radiographr evealed multiple bilateral abscesses in both lungs
Esfandbod M Kabootari M Images in clinical medicine Chronic granulomatous disease N Engl J Med 2012367753
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-OBrien S et al Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004114462-8
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Panel D a barium swallow shows an esophageal stricture (arrow) causedby a granuloma
Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 20003431703-14
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Lublin M Bartlett DL Danforth DN et al Hepatic abscess in patients with chronic granulomatous disease Ann Surg 2002235383-91
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Evaluation and Diagnosis
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Song E Jaishankar GB Saleh H Jithpratuck W Sahni R Krishnaswamy G Chronic granulomatous disease a review of the infectious and inflammatory complications Clin Mol Allergy 2011910
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Diagnostic method of CGD
bull Nitroblue tetrazolium (NBT) dye test
bull Ferricytochrome C reduction
bull Chemiluminescence
bull Dihydrorhodamine and other fluoresceneassay
bull H2O2 reduction(scopoletin oxidation)
Segal BH Leto TL Gallin JI Malech HL Holland SM Genetic biochemical and clinical features of chronic granulomatous disease Medicine (Baltimore) 200079170-200
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Nitroblue tetrazolium (NBT) dye test
bull Measures the ability of phagocytic cells to ingest
bull Reduce a soluble yellow dye to an intracellular blue crystal
bull Screening to rule out CGD
Boxer LA Neutrophil abnormalities Pediatr Rev 2003 Feb24(2)52-62
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Nitroblue tetrazolium (NBT) dye test
NegativeNBT
PositiveNBT
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Dihydrorhodamine reduction test
bull DHR Uncharged amp nonfluorescent reactive oxygen species
bull Activation of granulocyte loaded with DHR
-gtgenerates reactive oxygen intermediate that react with DHR
bull Results in increase green fluorescence
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Dihydrorhodamine reduction test
Leukocytes were loaded with DHR At 37degC for 5 minutes in the presence of catalase
Cells were stimulated with phorbol myristate acetate (PMA) for 14 minutes
Immediately analyzed by flow cytometry
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin
Immunol 2003111374-9
Number of cell react with DHR
Fluorescence intensity
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Harris JB Michelow IC Westra SJ Kradin RL Case records of the Massachusetts General Hospital Case 21-2008 An 11-month-old boy with fever and pulmonary infiltrates N Engl J Med 2008359178-87
Figure 3 Dihydrorhodamine-123 Fluorescence Assay of Peripheral-Blood Neutrophils Unrelated Healthy Control
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Dihydrorhodamine reduction test
Stimulation index=
mean channel fluorescence ofstimulated neutrophils
mean channel fluorescence ofunstimulated neutrophils
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Dihydrorhodamine reduction test
Subjects Stimulation index
Normal subjects 1279 (852-2646)
gp91-phox-deficient 132 (09 -22)
p47-phox-deficient 132 (35-521)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Dihydrorhodamine reduction test
CV of each fluorescent histogram =
Standard deviation
Mean
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
x 100
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Dihydrorhodamine reduction test
Subjects Coefficient of variation of histogram
Normal subjects 189 (114- 411)
gp91-phox-deficient 246 (181-488)
p47-phox-deficient 755 (493 - 100)
Vowells SJ Fleisher TA Sekhsaria S Alling DW Maguire TE Malech HL Genotype-dependent variability in flow cytometric evaluation of reduced nicotinamide adenine dinucleotide phosphate oxidase function in
patients with chronic granulomatous disease J Pediatr 1996128104-7
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Western immunoblot analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
CYBB mutation analysis
Jirapongsananuruk O Malech HL Kuhns DB Niemela JE Brown MR Anderson-Cohen M et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003111374-9
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Treatment
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Treatment
bull General health care
bull Antibiotic prophylaxis
bull Antimycotic prophylaxis
bull Interferon gamma prophylaxis
bull Treatment of acute infection
bull Treatment of inflammatory complications
bull Haematopoietic stem cell transplantation
bull Stem cell gene therapy
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
General health care
wwwcgdorguk
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
General health care
wwwcgdorguk
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
General health care
bull CGD pts should receive all routine immunizations(avoidance of BCG vaccination)
bull Dental hygiene is very important
bull Avoiding sources of Aspergillus spores
bull Risk of perirectal abscesses can be diminished by avoiding constipation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic prophylaxis
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Antibiotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antimycotic prophylaxis
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Antimycotic prophylaxis
wwwprimaryimmuneorg
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Interferon-gamma prophylaxis
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Interferon gamma prophylaxis
wwwprimaryimmuneorg
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease The International Chronic Granulomatous Disease Cooperative Study Group N Engl J Med 1991324509-16
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Treatment of acute infection
bull Antibiotic therapy
bull Antifungal therapy
bull Surgical intervention
bull White cell transfusion
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Antibiotic therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Burkholderia spp S aureus and Nocardia spp
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Antifungal therapy
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Surgical intervention
bull Drainage of abscesses
bull Relief of obstruction
bull Excision of consolidated suppurative amp granulomatous lesions
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
White cell transfusion
bull Complication
1 Leucoagglutinin
2 Rapid decrease of neutrophil
3 Leukastasis
4Alloimmunization to HLA Ag
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Treatment of inflammatory complications
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Haematopoietic stem cell transplantation
Seger RA Modern management of chronic granulomatous disease Br J Haematol 2008140255-66
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Myeloablative bone marrow conditioning with busulfan based regimen
Human leukocyte antigen (HLA)ndashidentical sibling donors bone marrow transplantation
N = 27 gt
Survival rate 85 Cure rate 81
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience 1985-2000 Blood 20021004344-50
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Seger RA Gungor T Belohradsky BH Blanche S Bordigoni P Di Bartolomeo P et al Treatment of chronic granulomatousdisease with myeloablative conditioning and an unmodified hemopoietic allograft a survey of the European experience
1985-2000 Blood 20021004344-50
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Stem cell gene therapy
wwwcgdorguk
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al Correction of X-linked chronic granulomatous disease by gene therapy augmented by insertional activation of MDS1-EVI1 PRDM16 or SETBP1 Nat Med 200612401-9
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Take Home Message
bull CGD is a genetically heterogeneous condition characterized by
Recurrent life-threatening bacterial amp fungal
infections
Granuloma formation
bull Most patients are diagnosed before the age of five years
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Take Home Message
bull CGD is caused by defects in phagocyte NADPH oxidase
Respiratory burst
bull Mutations in all four genes (gp91phoxp47phox p22phox amp p67phox)
Most common mutations are X linked gp91phox
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Take Home Message
bull A neutrophil function test is the initial diagnostic test performed
NBT
DHR
bull Current prophylaxis with trimethoprim-sulfamethoxazole itraconazole amp in selected cases additional interferon gamma is efficient
Thank You
Thank You
Related Documents
