ESCMID PGEC Nice, 28-31 mars 2017
IS THERE A CONSENSUS ABOUT PATHOGEN
DETECTION TARGETS AND METHODS IN CULTURE-NEGATIVE ENDOCARDITIS?
Pierre-Edouard Fournier
Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes Institut Hospitalo-Universitaire Méditerranée-Infection ESCMID Online Lectu
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Of course not!
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Infective endocarditis
Stable incidence worldwide
15 to 60 cases/million inhabitants/year in the USA and Europe.
0.16 to 5.4 per 1,000 hospital admissions
Heart surgery required: 25 to 50% of cases
Mortality: 20 to 26% during initial hospitalization, 30% overall Duval et al. J. Am. Col. Cardiol. Dis. 2012;59:1968-76
Sandre and Shafran. Clin Infect Dis. 1996:22:276-86; Martin et al. Clin Infect Dis 1997;24:669-75
Bashore et al. Curr Probl Cardiol. 2006:31:274-352
Jault et al. Ann Thorac Surg. 1997:63:1737-41; Larbalestier et al. Circulation. 1992;86:1168-74; Murdoch et al. Arch. Intern. Med. 2009;169:463-473 ESCMID Online Lectu
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Evolving trend of infective endocarditis
Increase in coagulase-negative staphylococci over 50 years (intracardiac devices, prosthetic valves, hemodialysis)
Increase in Staphylococcus aureus (North America, IVDA) and Enterococcus spp. in the past decade
Increase in patient age and male/female ratio
Decrease in Streptococcus viridans and BCNE (1980s 23% 2000s 14%)
(Slipczuk et al. PLoS One. 2013;8:e82665; Dayer et al. Lancet. 2015;385:1219-28; Thanavaro & Nixon. Heart & Lung. 2014;43:334-7)
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Heterogenous incidence of BCNE
North-to-South gradient
France 9%, UK 13%, Spain 14%, USA 14%, Japan 20%, Sweden 24%, Italy 25%, Germany 33%
Brazil 23%, India 31%, Pakistan 48%, Turkey 50%, Tunisia 54%, South Africa 55%, Algeria 56%, Morocco 58%, Lao PDR 61%, Thailand 69%, Egypt 69.7% Differences in the distribution of causative agents (zoonoses), differences in antibiotic use or study design (microbiological techniques used or studied populations)
Bennis A. et al. Ann Cardiol Angeiol (Paris) 1995;44:339-44. Cecchi E. et al. Ital Heart J 2004;5:249 56. Benslimani A. et al. Emerg Infect Dis 2005;11:216-24. Cetinkaya Y. et al. Int J Antimicrob Agents 2001;18:1-7. Ferrera C. et al. Rev Esp Cardiol 2012;65:891-900. Garg N. et al. Int J Cardiol 2005;98:253-60. Koegelenberg C.F. et al. QJM 2003;96:217-25. Lamas C.C. et al. Heart 2003;89:258-62. Letaief A et al. Int J Infect Dis 2007;11:430-3. Mirabel M. et al. Int J Cardiol 2015;180:270-3. Nakatani S. et al. Circ J 2003;67:901-5. Selton-Suty C. et al. Clin Infect Dis 2012;54:1230-9. Siciliano R.F. et al. Int J Infect Dis 2014;25:191-5. Tariq M. et al. Int J Infect Dis 2004;8:163-70. Watt G. et al. Am J Trop Med Hyg 2015;epub. Werner M. et al. Scand J Infect Dis 2008;40:279-85.
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Main etiologies of BCNE
Empirical administration of antibiotics prior to blood cultures (50 – 70%) (Munoz et al. J. Clin. Microbiol. 2008:46:2897-901; Katsouli & Massad. Ann Thorac Surg. 2013;95:1467-74)
Fastidious microorganisms (5 – 30%, ~5% of IE)
Requiring specific media and/or prolonged incubation: Brucella spp., defective streptococci (Abiotrophia spp., Gemella spp., Granulicatella spp.), anaerobes (Finegoldia magna), HACEK bacteria, Legionella spp., Listeria spp., mycobacteria, Mycoplasma spp., Propionibacterium acnes, fungi (Aspergillus spp., Candida spp.)
Strictly (Coxiella burnetii, Tropheryma whipplei) or facultative (Bartonella spp.) intracellular bacteria
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Variable role of zoonoses in BCNE
0 in South Africa (Koegelenberg et al. QJM 2003;96:217-25)
6.7% in the Lao PDR (two cases of B. henselae IE) (Mirabel et al. Int J Cardiol
2015;180:270-3)
9% in Turkey (Brucella sp. only but neither Q fever nor Bartonella sp. were investigated) (Cetinkaya et al. Int J Antimicrob Agents 2001;18:1-7)
10.3% in Brazil (2 Bartonella and 1 C. burnetii IE) (Lamas et al. Int J Infect Dis 2013
17:e65-e66)
11.9% in Egypt (Q fever, Bartonella sp. and Brucella sp.) (El-Kholy et al. Infection
2015;epub)
12.5% in Italy (3 cases of brucellosis) (Cecchi et al. Ital Heart J 2004;5:249-56)
13% in southern France (Q fever and Bartonella sp. but no Brucella sp.) (Fournier et al. Clin Infect Dis 2010;51:131-40)
17% in Thailand (Q fever, Bartonella sp., Streptococcus suis, Erysipelothrix rusiopathiae, Campylobacter fetus) (Watt et al. Am J Trop Med Hyg
2015;epub)
20% in the UK (mainly Q fever and Bartonella sp. but broad range PCR from valves was not performed) (Lamas et al. Heart 2003;89:258-62)
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Non-infective etiologies of BCNE
Nonbacterial thrombotic endocarditis
Systemic lupus erythematosus (Libman-Sacks endocarditis)
Neoplasia (marantic endocarditis)
Rheumatoid arthritis
Behçet’s disease
Eosinophilic myocarditis & myocardial fibrosis (Loeffler’s endocarditis)
Allergy to pork ESCMID Online Lecture Library
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Outcome of BCNE
Negative culture => etiological diagnosis delayed => increased risk of valve destruction, septic emboli and death
(Hoen et al. Clin Infect Dis. 1995; 20:501-6; Katsouli & Massad. Ann Thorac Surg. 2013;95:1467-74; Murashita et al. Eur J Cardiothorac Surg. 2005;26:1104-11; Zamorano et al. Am J Cardiol. 2001;87:1423-5)
But:
106 BCNE vs 643 BCPE (1996-2011): no statistical difference in diagnostic delay, surgery and mortality
(Ferrera et al. Rev Esp Cardiol. 2012;65:891-900) ESCMID Online Lecture Library
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Is the empirical treatment of IE sufficient for BCNE?
Current guidelines = intravenous -lactam + aminoglycoside (Baddour et al. Circulation; 111:e394-434; Habib et al. Eur Heart J 2009;30:2369-413; Que and Moreillon. Nature Rev. Cardiol. 2011;8:322-36)
May not treat up to 20% of patients: fastidious bacteria (Q fever, Brucella spp., Legionella sp., Mycoplasma sp., Tropheryma whipplei), fungi A precise microbiological diagnosis is mandatory to optimize therapy
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Diagnosis of infective endocarditis
A precise microbiological diagnosis mandatory to guide therapy
Culture long considered the most important diagnostic tool
Highlighted by the weight given to culture in the Duke criteria
Li et al. Clin. Infect. Dis. 2000:30:633-8
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The diagnosis of BCNE: a challenge
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Patient interview
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Homeless, alcoholic and/or patients coming from Maghreb => B. quintana, contact with kittens => B. henselae
Patients > 50 y-o with chronic arthralgias => Tropheryma whipplei
Patients > 40 y-o with bicuspid aortic valve, contact with parturient farm animals => Coxiella burnetii
Patients coming from South America and Turkey, contact with farm animals => Brucella spp.
Young women with a history of thrombosis and/or fetal loss => systemic lupus erythematosus
Older women with arthralgias => rheumatoid arthritis
Patients > 40 y-o with embolic phenomena => marantic endocarditis
Patients with a relapsing BCNE and a porcine bioprosthesis => allergy to pork
Epidemio-clinical clues
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Development of another Diagnostic score for IE
Use of a combination of aspecific clinical symptoms and biological results
Criteria independently associated to IE
Richet et al. J. Antimicrob. Chemother. 2008;62:1434-40
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Blood testing
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Serology
A single serum may identify the causative agent in up to 50% of culture-negative cases
Bartonella sp.: IFA: IgG > 1:800
(sensitivity 89.5%, specificity 99.6%) (Fournier et al. Clin Diagn Lab Immunol. 2002:9:795-801)
Coxiella burnetii : IFA: IgG to phase 1 > 1:800 (Se 100%, Sp 99.5%) Major Duke criterion (Rolain et al. Clin Diagn Lab Immunol. 2003:10:1147-8; Li et al. Clin Infect Dis 2000:30:633-8)
Does an IFA profile of acute QF rule out the diagnosis of endocarditis?
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Endocarditis in acute Q fever ?
• 2012, 45-y-o male, no history of valvular disease • Abrupt fever and elevated transaminases • Discovery of a 10-mm aortic vegetation
(Million M. et al. Clin. Infect. Dis. 2016;62:537-44)
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Endocarditis in acute Q fever
• Anticardiolipin IgG 742 GPLU (N < 20) => diagnosis
of Libman-Sacks endocarditis
• Serology => Acute Q fever (IgG2 1:200, IgM2 1:200)
• Doxycycline + hydroxychloroquine for 12 months
• Normalization of anticardiolipin Abs and TEE
• Asymptomatic on follow-up (27 months)
• Is endocarditis only a late complication of Q fever?
(Million M. et al. 2015, submitted)
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Bartonella endocarditis Western blot
Cross reactions among Bartonella sp. and with Coxiella burnetii or Chlamydia => cross adsorption + WB
Sensitivity 100%, specificity 95%
(Edouard et al. J Clin Microbiol. 2015;53:824-9; Houpikian & Raoult. Clin Diagn Lab Immunol. 2003;10:95-102)
Non adsorbed Non adsorbed Adsorbed Bq Adsorbed B Adsorbed Bh Adsorbed B
1 2 1 2
1. B. quintana 1. B. quintana 2. B. henselae 2. B. henselae
1 2
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Serology
Brucella sp.: IFA: Ig > 1:160
Legionella pneumophila: IFA: Ig > 1:256
Mycoplasma pneumoniae: enzyme immunoassay
Aspergillus sp.: ELISA
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Antigen detection for Candida endocarditis
18 patients with proven Candida endocarditis tested for serum mannan (Platelia Candida Ag Plus [Bio-Rad, France], anti-mannan antibodies (Platelia Candida Ab Plus (Bio-Rad] and (1,3)-β-d-glucans (Fungitell assay [Associates of Cape Cod, MA])
Sensitivity 100%
(Lefort A. et al. Clin Microbiol Infect. 2012;18:E99-E109) ESCMID Online Lectu
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Should we perform all serology assays in BCNE?
Microorganism Present study
(n = 676)
France 2005
(n = 348)
Medicine
2005;
84:162-73
France
(n = 88)
Clin Infect Dis
1995;
20:501-6
Great Britain
(n = 63)
Heart 2003;
89:258-62
Algeria
(n = 62)
Emerg Infect
Dis 2005;
11:216-24
C. burnetii 33.9 48 7.9 12.7 3.2
Bartonella sp. 12.7 28.4 0 9.5 22.6
Streptococcus sp. 4.6 0 1.1 6.3 3.2
Staphylococcus sp. 1.9 0 3.4 11.1 6.4
T. whipplei 1.8 0.3 0 0 0
Corynebacterium sp. 0.6 0 1.1 0 1.6
Enterobacteriaceae 0.6 0 0 0 0
HACEK bacteria 0.4 0 0 0 3.2
Brucella melitensis 0 0 0 0 1.6
Chlamydia sp. 0 0 2.2 0 0
Other bacteria 3.1 1.1 1.1 1.6 1.6
Fungi 1.2 0 0 6.3 1.6
No aetiology 36.5 22.1 82.9 50.8 54.8
Marseille study
(n = 819)
Clin Infect Dis
2010;
51:131-40
The serology panel should be adapted to local epidemiology (Bartonella endocarditis <1% in Scandinavia to > 10% in North Africa)
(Naber and Erbell. Int J Antimicrob Agents. 2007:30S:S32-6; Brouqui et al. FEMS Immunol Med Microbiol. 2006:47:1-13) ESCMID Online Lecture Library
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PCR from blood
Broad range assays for bacteria (16S rRNA) or fungi
(18S rRNA) => detection and identification
Low sensitivity and specificity may be increased with pre-PCR decontamination by enzymatic digestion (Rothman et al. J Infect Dis. 2002;186:1677-81)
Multiplexed RT-PCR: LightCycler® SeptiFast (Roche): detects 19 bacterial and 6 fungal species
Less sensitive than blood culture (11/50 vs 19/50) (Casalta et al. Eur J Clin Infect Dis. 2009:28:569-573)
But may be useful in patients who have taken early antibiotics
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Cardiac valve testing
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Should cardiac valves be cultured? (Munoz et al. J. Clin. Microbiol. 2008:46:2897-901; Voldstedlund et al. APMIS. 2008;116:190-8)
Valve culture: sensitivity 13 - 32%, specificity 72 – 98% (Munoz et al. J. Clin. Microbiol. 2008:46:2897-901; Marin et al. Medicine. 2007;86:195-202; Boussier et al. Diagn Microbiol Infect Dis. 2013;75:240-4)
CIEDs: sonication improves culture sensitivity (Rohacek et al. Pace. 2015;38:247-53)
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PCR from valvular biopsies
Highest diagnostic yield, fast
Widely used
Broad range assays (16S rRNA, 18S rRNA) +/- confirmed by
specific assays
Sensitivity 41 – 96 %, lower for paraffin-embedded biopsies
Specificity 91 - 100% (Millar et al. Scand J Infect Dis. 2001;33:673-80; Bosshard et al. Clin Infect Dis. 2003;37:167-72; Breitkopf et al. Circulation. 2003;111:1415-21; Greub et al. Am J Med. 2005;118-230-8; Fournier et al. Clin Infect Dis. 2010;51:131-40; Harris et al. Eur J Clin Microbiol Infect Dis. 2014;33:2061-6; Marin et al. Medicine. 2007;86:195-202)
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Multiplexed PCR from valvular biopsies
LightCycler® SeptiFast (Roche): Se 95%, Sp 100% (Fernandez et al. Rev Esp Cardiol. 2010;63:1205-8; Leli et al. Diagn Microbiol Infect Dis. 2014;79:98-101)
SepsiTest ® (Molzym): 10 BCNE, 6 diagnoses but 3 false + (Haag et al. Diagn Microbiol Infect Dis. 2013;76:413-8)
Plex-ID ® (Abbott): PCR-electrospray ionization-MS => 66 positive in 83 paraffin-embedded valves
(Brinkman et al. J Clin Microbiol. 2013;51:2040-6)
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DNA may persist in valvular tissues
After completion of antibiotic therapy
5 months to 7 years (streptococci, Bartonella sp.)
No histological lesion but past history of IE positive for the same bacterium
(Branger and Raoult. J Clin Microbiol. 2003;41:4435-7; Lang et al. Clin Microbiol Infect. 2004;10:579-81; Rovery et al. J Clin Microbiol. 2005;43:163-7)
Pitfalls of PCR
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Pitfalls of PCR
Many home-made assays => lack of standardization
False positive may occur specifically using broad range
assays
Negative controls are critical
Significance of identified agents should be evaluated in
the light of epidemio-clinical data
Identication of an unusual microorganisms = > confirm
by using a second gene target
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Application of NGS metagenomics to 4 patients with NVE
~300,000 reads per sample (>99% human sequences)
In two, metagenomics confirmed blood cultures (E. faecalis and S. mutans)
In two (BCNE with sterile valve culture), identification of S. sanguinis and A. defectiva (Imai et al. Int J Cardiol. 2014;172:e288-9, Fukui et al. J. Infect. Chemother. 2015;21:882-4)
Are the extra-cost (PCR x 20) and time needed worth it?
Metagenomics for the diagnosis of IE?
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Histopathological examination
Major Duke criterion (Durack et al. Am J Med. 1994;96:200-22; Li et al. Clin Infect Dis. 2000;30:633-8)
Gold standard for diagnosis of IE (Castonguay et al. Cardiovasc Pathol. 2013;22:19-27; Habib et al. Eur Heart J. 2005;30:2369-413; Lepidi et
al. Infect Dis Clin North Am. 2002;16:339-61; Morris et al. Clin Infect Dis. 2003;36:697-704)
Sensitivity for native valves 73%, for prostheses 42%
Specificity 100% (Greub et al. Am J Med. 2005;118:230-8)
Crucial for BCNE
But sampling-dependent
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Fluorescence in situ hybridization
Combines histopathology and molecular methods
Screening with a probe panel (pan bacteria, streptococci, enterococci, Granulicatella, B. quintana, T. whipplei)
Detection of a pathogen in 5/13 BCNE (38.5%)
Streptococci, B. quintana, T. whipplei
Valuable but requires specific probes and trained personnel
(Mallmann et al. Clin Microbiol Infect 2010;16:767-73) ESCMID Online Lectu
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Immunohistochemistry
Specific mono- or polyclonal antibodies
Immunoperoxidase stain (Brouqui et al. Am J Med. 1994;97:451-8)
Capture-ELISA (Thiele et al. Eur J Epidemiol. 1992;8:568-74)
Immunofluorescence (Muhlemann et al. J Clin Microbiol. 1995;33:428-31; McCaul and Williams. Ann NY Acad Sci. 1990;590:136-47)
Q fever Bartonella sp. T. whipplei
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Auto-immunohistochemistry
Patients’ own antibodies
Useful when no agent is identified by other methods
Sensitivity 80% in streptococcal IE, 100% in T. whipplei endocarditis
(Lepidi et al. J Infect Dis. 2006;193:1711-7)
T. whipplei endocarditis Streptococcal endocarditis
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Recent developments in BCNE imaging
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18FDG-PET/CT in BCNE
56-year-old man Fatigue and weight loss (–6
kgs) over 6 months Aortic bioprosthesis (7 years) TEE => thickened and partial
aortic stenosis but no vegetation
PET/CT => aortic periprosthetic FDG uptake
Serology (IFA and WB) and PCR from EDTA blood positive for B. henselae
Recovery using doxycycline – gentamicin
(Gouriet F et al. Emerg Infect Dis. 2014;20:1396-1397)
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18FDG-PET/CT in BCNE
77-year-old woman Right hemiplegia and aphasia Recent spleen and right kidney
ischemic episodes Aortic bioprosthesis (4 years) TEE => diffuse aortic thickening
+ bioprosthesis stenosis and insuficiency
PET/CT => FDG uptake around the metal ring of the aortic graft
Valve replacement => detection of T. whipplei by PCR and IHC
Treatment with doxycycline and OH-chloroquine
(Jos SL et al. BMC Res Notes. 2015;8:56)
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4-Dimensional-Flow MRI in BCNE
42-year-old man Headaches and word-finding
difficulties (left temporal lobe ischemic infarction)
Pandiastolic murmur TTE => aortic insufficiency TEE => bicuspid aortic valve +
suspicion of leaflet perforation MRI => regurgitation through
leaflet perforation + dilated ascending aorta
Positive Q fever serology Doxycycline + OH-chloroquine Aortic root and valve replacement (Thadani SR et al. Texas Heart Inst J. 2014;41:351-2)
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Our diagnostic strategy in 2017
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Questionnaire
Bag 1: H0 1 pair of aero-anaerobic blood cultures 1 whole blood tube => serology Bartonella sp., Q fever, C. psittacii, L. pneumophila, Brucella sp., Aspergillus sp.
=> RF, antinuclear Abs, antiphospholipid
Abs, anti-pork IgE
1 whole blood tube => ACE, Ca15-3, Ca12-5, -FP
1 heparinized blood tube => cell culture 1 EDTA blood tube => PCR
Bags 2 (H2) and 3 (H4)
1 aerobic blood culture
Use of a diagnostic kit
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Our diagnostic strategy 2017
Negative blood cultures
Rheumatoid factor Antiphospholipid
antibodies
Antinuclear antibodies
Dedicated RT-PCR for Bartonella spp. and
Tropheryma whipplei from EDTA blood
Q fever and Bartonella serologies
Dedicated RT-PCR for Streptococcus oralis and gallolyticus groups,
Enterococcus sp., Staphylococcus aureus, Mycoplasma hominis
Other serologies (Brucella melitensis,
Legionella pneumoniae, Mycoplasma pneumoniae,
western blot for Bartonella spp.)
Valvular biopsies (when available)
Anti-pork antibodies in patients with
porcine bioprosthesis
16S rRNA PCR for bacteria, ITS PCR for
fungi
Histological examination
Auto-immunohistochemistry
Dedicated PCR for Streptococcus oralis and gallolyticus groups,
Enterococcus spp., Staphylococcus aureus, Mycoplasma hominis, Bartonella spp., Tropheryma
whipplei
If culture is negative
If negative
If negative
If negative
If negative
ACE, CA19-9, CA15-3, CA12-5,
Α-FP
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Marseille experience 2001-2010
1,334 cases of BCNE
Fournier PE et al., Clin Infect Dis. 2010; 51:131-40
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Diagnosis of endocarditis excluded In 68 patients, including:
- 1myxoma of the left atrium - 1 angiosarcoma
1,334 cases of BCNE
Marseille experience 2001-2010
Fournier PE et al., Clin Infect Dis. 2010; 51:131-40
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1,268 patients with endocarditis
Diagnosis of endocarditis excluded In 68 patients, including:
- 1myxoma of the left atrium - 1 angiosarcoma
1,334 cases of BCNE
795 patients
-
- Fastidious bacteria : 25 (19 T. whipplei) - Fungi: 15 - Usual bacteria : 186
-
- - -
-
- - -
With an identified aetiological agent - Zoonotic agents: 569 (420 Q fever,
149 Bartonella sp.)
- -
Marseille experience 2001-2010
Fournier PE et al., Clin Infect Dis. 2010; 51:131-40
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327 patients with possible endocarditis
126 patients with definite endocarditis
453 patients without identified aetiology
Diagnosis of endocarditis excluded In 68 patients, including:
- 1myxoma of the left atrium - 1 angiosarcoma
1,334 cases of BCNE
1,268 patients with endocarditis
795 patients
-
- Fastidious bacteria : 25 (19 T. whipplei) - Fungi: 15 - Usual bacteria : 186
-
- - -
-
- - -
With an identified aetiological agent - Zoonotic agents: 569 (420 Q fever,
149 Bartonella sp.)
- -
Marseille experience 2001-2010
Fournier PE et al., Clin Infect Dis. 2010; 51:131-40
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20 patients with
- 7 marantic - 9 - 2 - 1 Behcet disease
- - - 2 - 1
- - 9 - 2 - 1
noninfective endocarditis) - - systemic lupus erymathosus - 2 rheumatoid athritis - 1
Diagnosis of endocarditis excluded In 68 patients, including:
- 1myxoma of the left atrium - 1 angiosarcoma
1,334 cases of BCNE
1,268 patients with endocarditis
795 patients
-
- Fastidious bacteria : 25 (19 T. whipplei) - Fungi: 15 - Usual bacteria : 186
-
- - -
-
- - -
With an identified aetiological agent - Zoonotic agents: 569 (420 Q fever,
149 Bartonella sp.)
- -
453 patients without identified aetiology
327 patients with possible endocarditis
126 patients with definite endocarditis
- 1 allergy to pork - 1 - 1 - 1
Marseille experience 2001-2010
Fournier PE et al., Clin Infect Dis. 2010; 51:131-40
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Serology => 74.8% of diagnostics
PCR => 22.9% additional diagnoses
Blood: only 13.6% positive
Valves: 69.1% positive
Culture => no additional diagnosis
Auto-immunohistochemistry and differential amplification should be reserved to negative and recurrent cases
Diagnostic yield of the various methods used
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Lessons from the Marseille study
No Chlamydia endocarditis (serological cross-reactions with Bartonella sp.)
No viral endocarditis (BUT: Coxsackie B2 endocarditis on an atrio-ventricular patch)
Major role of fastidious microorganisms (C. burnetii, Bartonella sp., T. whipplei)
Non-infectious aetiologies
Diagnostic strategies should be adapted to local epidemiology, notably for zoonoses (IFA)
Blumental et al. Clin Infect Dis. 2011; 52:710-6
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Improving the diagnosis of BCNE Use of standardized sampling
Broad range +/- pathogen-specific PCR from valves +/- blood
Should valve culture still be used?
Importance of histopathological analysis
PET-CT and MRI may help confirm the diagnosis
Keep an open mind for new and noninfective etiologies!
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U R
Thank you ESCMID Online Lectu
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