1. Immune Deficiency

2. Immunoglobulin levels vs. age

3. 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

4. Immunologic defects (1) T cell (2) B cell (3) Macrophage
(4) Complement

5. 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

6. 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)

7. 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)

8. 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)

9. Infection history Age of onset
Birth 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 PID
2 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 age
6 to 18 years – it is unusual for recurrent infections to first present beyond the age of six

10. 2. Sites of infection: Upper respiratory tract Most common site, usually viral Chronic purulent nasal discharge and cough  chronic siunsitis Chronic or seasonal clear nasal discharge, congestion, itchy eyes, nocturnal cough  allergic disease Recurrent oral thrush, stomatitis, gingivitis,  t-cell and phagocytic cell disorder Lower respiratory tract Recurrent pneumonia is rare in normal children or children with allergic disease Suggest chronic cardiopulmonary disease or immunodeficiency Recurrent pneumonia limited to a particular anatomic region  local anatomical abnormality

11. 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

12. 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

13. Organisms that suggests an immunodeficiency
disease
Pneumocystis jiroveci
HIV,SCID,HyperIgM,XLA
Serratia marcescens
Chronic granulomatous disease
Aspergillus, nocardia
Psedomonas sepsis
XLA,ARA
Mycobacteria/salmonella
IFN-gamma,IL12 pathway

14. 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.

15. 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.

16. Characteristic features of primary immunodeficiency
Predominant T-cell defect
Predominant 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:mycobact
Viruses:CMV,EBV,adeno
Fungi:candida
Bacteria: strep.staphylo,hemophilus
Virus: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

17. Clinical patterns of immunodeficiency
Wiskott – 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

18. 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.

19. General screening tests
Complete Blood Count With special attention paid to the total absolute lymphocyte count: lymphopenia <1500cells/uL in patients over 5 years or <2500 cells/uL in younger children Eisinophilia suggests allergy Thrombocytosis suggests chronic inflammation Electrolytes, glucose, KFT, albumin Urine analysis ESR, CRP, appropriate cultures should be done for evaluation of infection Chest 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

20. 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

21. 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.

22. 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

23. 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

24. Management of the child with recurrent infection
Infections should be promptly recognized and treated with emperic antibiotic therapy until appropriate culture results are available
Prophylactic antibiotics may be administered
Live – virus vaccines and live BCG vaccines must not be administered to the child
Only irradiated, leukocyte - poor, virus free should be used if blood transfusion is necessary
IVIG should not be administered until there has been a thorough evaluation of the childs immune system. (expensive, side effects)

25. Initial immunologic testing of the child with recurrent infections
Complete blood count, differential, ESR
Lymphocyte, neutrophils, platelets,
Howell jolly bodies, ESR
Screening tests for B-cell cefects
IgA, if abnormal IgG, IgM measurement
Isohemagglutinins
Antibody titres to tetanus, diphtheria, H.influenzae
Screening test for Tcell defect
Absolute lymphocyte count
Candida albicans intradermal test
Screening test for phagocytic cell defect
Absolute neutrophil count
Respiratory burst assay
Screening test for complement deficiency
CH50