Immune Deficiency
Immunoglobulin levels vs. age
Types of immunity
Innate (natural) immunity responds to infection regardless of previous
exposure to the agent
Ex: PNL, phagocytic cells, complement system
Acquired (adaptive) immunity develops as a result of exposure to previous
immunogens
Ex: T lymphocytes, B lymphocytes, NK cells
Immunologic defects
(1) T cell
(2) B cell
(3) Macrophage
(4) Complement
• Primary immunodeficiency
Inherited genetic defects in the immune cell development or
function or inherited deficiency in a particular immune molecule
• Secondary immunodeficiency
Loss of previously functional immunity due to infection, toxicity,
radiation, splenectomy and malnutrition
When to suspect immunodeficiency ?
Family history of immunodeficiency
Failure to thrive
Need for IV antibiotics and or hospitalization to clear infection
4 or more ear infections with in one year
2 or more episodes of sepsis or meningitis in a life time
2 or more months of antibiotic treatment with little effect
Recurrent or resistant candidiasis
Serious infections occuring at unusual sites (brain, liver abscess)
Infection with opportunistic organisms
Complications from live vaccines (rota virus, varicella)
Non healing wounds
Granulomas
Lymphoma in infancy
Features suggestive of PID in neonates
Hypocalcemia
Congenital heart defects (conotruncal anomalies)
Absence of thymic shadow in CXR
Delayed umbilical cord detachment (>30 days)
History
Birth history – maternal illness, drug intake, length of gestation, birth weight
neonatal problems, umbilical cord detachment
Feeding history
Growth and development
Immunization history – especially live vaccines (OPV, rota virus vaccines),
vaccine failure
Previous illnesses, school abscences
Family history
Consanguinity (autosomal recessive immunodeficiencies)
Infection history
1. Age of onsetBirth to 6 months – congenital neutropenias, leukocyte adhesion defects, severe combined immunodeficiency (SCID), and complete DiGeorge syndrome.6 months to 2 years – normal child, child with allergy. Persistent diarrhea, chronic cough, or failure to thrive suggests cystic fibrosis, or PID2 to 6 years – children developing infection in this age group may also fit into any of the 4 categories. Secondary immunodeficiencies resulting from malignancy, nephrotic syndrome, or gastrointestinal problems start at this age6 to 18 years – it is unusual for recurrent infections to first present beyond the age of six
2. Sites of infection:Upper respiratory tract
Most common site, usually viralChronic purulent nasal discharge and cough chronic siunsitisChronic or seasonal clear nasal discharge, congestion, itchy
eyes, nocturnal cough allergic diseaseRecurrent oral thrush, stomatitis, gingivitis, t-cell and
phagocytic cell disorderLower respiratory tract
Recurrent pneumonia is rare in normal children or children with allergic diseaseSuggest chronic cardiopulmonary disease or immunodeficiencyRecurrent pneumonia limited to a particular anatomic region local anatomical abnormality
Blood and brain
Bacterial meningitis and sepsis suggest antibody deficiency or complement
defect
Chronic enteroviral encephalomyelitis occurs in patients with profound
antibody deficiency and commonly follows OPV
Other
Recurrent and or chronic GIT infections occur in patients with IgA
deficiency
Recurrent UTI is uncommon in immunodeficiency and suggests structural
abnormality
Abscesses of the skin, intestine, or LN suggest phagocytic or antibody
deficiency
3. Isolated organisms
Recurrent sinopulmunary infections with encapsulated organisms
B cell abnormalities
Pneumocystis carnii is the hallmark of SCID and other T cell defects
Enteroviral meningoencephalitis x-linked agammaglobulinemia
Recurrent staph infections hyperimmunoglubulin E syndrome
Severe candidiasis abnormal t cell immunity
Organisms that suggests an immunodeficiency
Organism disease
Pneumocystis jiroveci HIV,SCID,HyperIgM,XLA
Serratia marcescens Chronic granulomatous disease
Aspergillus, nocardia Chronic granulomatous disease
Psedomonas sepsis XLA,ARA
Mycobacteria/salmonella IFN-gamma,IL12 pathway
Physical Examination
General appearance, dysmorphic features
Failure to thrive (growth charts)
Discharging ears, perforated tympanic membrane suggest
immunodeficiency
Pallor without anemia, allergic shiners, conjunctivitis, transverse nasal
crease, clear nasal discharge, suggest allergy
Mouth ulcers, gingivitis, oral thrush, poor dentition, suggest
immunodeficiency
Atopic dermatitis (eczema) suggest allergic disease.
• Immunodeficiencis associated with eczema: wiskott-aldrich, hyper IgE,
SCID,
• Diminished or absent tonsils and cervical lymph nodes in the presence
of recurrent respiratory infections suggest antibody deficiency
• Absence of lymphoid tissue suggest SCID or x – linked
agammaglobulinemia
• Adenopathy and HSM can be seen in IgA deficiency, common variable
immunodeficiency, and HIV infection.
Characteristic features of primary immunodeficiencyCharacteristic Predominant T-
cell defectPredominant B-cell defect
Granulocyte defect
Complement defect
Age Early onset,2-6mo
After maternal antibodies diminish,>5m
Early onset Any age
Sp pathogen involved
Bact:mycobactViruses:CMV,EBV,adenoFungi:candida
Bacteria: strep.staphylo,hemophilusVirus:entero
Bact:staph,pseudo,klebsiella
Neisseria,E-coli
Affected organ FTT,protracted diarrhea,
Recurrent sinupulmonary infections,GI infections,malabsorption
Skin abscess,suppurative adenitis
Meningitis, Recurrent sinupulmonary infections
Special features GVH diseases,post vaccination,disseminated BCG
Autoimmunity,lymphoma,post vaccination paralytic polio
Prolonged attachment of umblical cord,poor wound healing
Rheumatoid disotder:SLE,Vasculitis,glomerulonephritis
Clinical patterns of immunodeficiencyWiskott – aldrich syndrome : petechiae, easy bleeding, eczema, chronic draining ears
Ataxia – telangiectasia: ataxia, telangiectasia, developmental delay
Warts hypogammaglobulinemia infections myelokathexis (WHIM) syndrome : extensive warts or molluscum contagiosum
Hyper IgE syndrome: coarse features, chronic infected eczema, deep seated abscesses
DiGeorge syndrome: short stature, CHD, developmental delay, low set ears, downturning eyes, micrognathia
Chediak Higashi disease: oculocutaneous albinism
Laboratory Evaluation
Initial tests (screening evaluation) – should be done for all children with
recurrent infections
Abnormalities of these initial tests may suggest allergy, immunodeficiency or
a chronic illness, and will need further investigations
If screening tests are normal, the patient’s family can be reassured that a
serious disorder has been excluded.
General screening tests
Complete Blood CountWith special attention paid to the total absolute lymphocyte count:
lymphopenia <1500cells/uL in patients over 5 years or <2500 cells/uL inyounger children
Eisinophilia suggests allergyThrombocytosis suggests chronic inflammation
Electrolytes, glucose, KFT, albuminUrine analysisESR, CRP, appropriate cultures should be done for evaluation of infectionChest X-ray
should be done if the child has chronic cough or other features suggesting lung problems it should also be done in newborns presenting with recurrent infections for assessment of thymic size
Other initial investigations:
Immunoglobulin levels:
Antibody defeciency is suggested by:
◦ IgG <200 mg/dL
◦ Total Ig (M + G + A) <400 mg/dL
◦ Complete absence of IgM or IgA
An elevated IgE (>100mg/dL) suggests allergy, eczema, or chronic skin
infections or may be found in hyper IgE syndrome, phagocytic disorders
Intermediate tests for immunodeficiency
These tests are indicated when the screening tests are abnormal or the
clinical picture is highly suggestive for an immunodeficiency.
Antibody titres The function of the antibody system is best assessed by
checking antibody titres to previously administered vaccines (tetanus,
diphtheria, and hemophilus influenza type b.
Complement activity should be assessed in patients with recurrent sepsis
of neisserial infection. A normal level of CH50 excludes nearly all
hereditary complement deficiencies. Levels of individual complement
componenets are measured of the CH50 is significantly reduced or zero.
Diagnostic tests
Should be done when previous tests are abnormal or if there is a convincing
history of immunodeficiency.
Lymphocyte subset analysis: done by flow cytometry including CD3 (total T
cells), CD4 (T helper), CD8 (cytotoxic), CD19 or CD20 (B cells) and CD16/56
(natural killer cells) is done when B or T cell defect is suspected.
• CD4 is the most valuable reflection of the cellular immune system
• CD19 (B cell) count <100 cells/uL suggests hereditary agammaglobulinemia
• A low CD16/56 count suggests a NK cell deficiency
Vaccine challenge
Vaccine responsiveness is used to further assess the antibody system.
A killed vaccine that has not been administered previously is given and titres
are measured before and 6 weeks after vaccination.
Other tests
HIV Testing should be done in any patient suspected of a T cell deficiency
Lymphoproliferative Assays these are in vitro assays used to further assess
the cellular immune system
Management of the child with recurrent infection
1. Infections should be promptly recognized and treated with emperic
antibiotic therapy until appropriate culture results are available
2. Prophylactic antibiotics may be administered
3. Live – virus vaccines and live BCG vaccines must not be administered to
the child
4. Only irradiated, leukocyte - poor, virus free should be used if blood
transfusion is necessary
5. IVIG should not be administered until there has been a thorough
evaluation of the childs immune system. (expensive, side effects)
Initial immunologic testing of the child with recurrent infections
Complete blood count, differential, ESR• Lymphocyte, neutrophils, platelets,• Howell jolly bodies, ESRScreening tests for B-cell cefects• IgA, if abnormal IgG, IgM measurement• Isohemagglutinins• Antibody titres to tetanus, diphtheria, H.influenzaeScreening test for Tcell defect• Absolute lymphocyte count• Candida albicans intradermal testScreening test for phagocytic cell defect• Absolute neutrophil count• Respiratory burst assayScreening test for complement deficiency• CH50