1. Primary Immunodeficiency Disorders (PID) Soheila Alyasin M.D. AssOCIAT Professor of Pediatrics Division of Immunology and Allergy

2. Definition The immunodeficiency disorders are a diverse group of illnesses that, as a result of one or more abnormalities of the immune system, increase susceptibility to infection. The PID are not associated with other illnesses that impair the immune system. Many are genetic disorders with a characteristic inheritance pattern.

3. Incidence Estimated occurrence of PID is 1 per 10000 live birth, excluding the asymptomatic Ig A def First IRPID report: CVID was the most common PID in Iran Since 1952 more than 150 different PID disorders had been defined

4. Problems in Early Diagnosis of PID Early diagnosis needs high index of suspicion No screening is available in the perinatal period or later in childhood Wide spread use of antibiotics for respiratory infections mask the course of disease

5. Indications for evaluation of a child for PID one or more systemic or serious bacterial infections (sepsis, meningitis) TWO or more serious respiratory or documented bacterial soft tissue infections (cellulitis, ABCESS, pneumonia, draining otitis media, or lymphadenitis ), within one year Infections occurring at unusual sites (liver or brain abscess)

6. Indications for evaluation of a child for PID, Cont.. Infections with unusual pathogens (Aspergillus, Serratia marcescens, Nocardia or Burkholderia cepacia,pneumocystis jiroveci) Severe unusual infections with common childhood pathogens

7. Initial evaluation of immune system History Ab,C & neutrophil:encapculated bacteria Nl G/D unless bronchiectasis T :oppurtunistic infections,FTT Physical exam Family history

8. Relative distribution of the primary immunodeficiency Antibody deficiencies 65% Combined cellular and antibody deficiencies 15% Phagocytic deficiencies 10% Cellular deficiencies 5% Complement deficiencies 5%

9. Initial Immunology Testing of Patients With Recurrent Infections CBC+manual differential count ESR ANC, ALC, Howell-Jolly bodies, platelet count Screening test for B cell defects : IgA, IgG, IgM measurement Isohemagglutinins Antibody titers to Tetanus, Diphteria, H.influenza, and S.Pneumonia

10. Initial Immunology Testing of Patients With Recurrent Infections CBC+manual differential count ESR ANC,(Nl: LAD & neutropenia unlikely) ALC,(Nl: unlikely T cell defect) Howell-Jolly bodies,( exclude asplenia) platelet count(Nl exclude WAS)

11. Initial Immunology Testing of Patients With Recurrent Infections Screening test for B cell defects : IgA, IgG, IgM measurement Isohemagglutinins Antibody titers to Tetanus, Diphteria, H.influenza, and S.Pneumonia

12. Initial Lab testing, cont.. Screening tests for phagocytic cell defects: Absolute neutrophil count Respiratory burst assay (NBT, RDT)

13. Initial Lab testing, cont.. Screening tests for T cell defects: Absolute lymphocyte count (Nl: unlikelyTcell defect) Candida albicans intradermal test

14. Initial Lab testing, cont,.. Screening test for complement deficiency: CH50

15. Primary Defects of Antibody Production Recurrent infections with encapsulated bacteria Repeated respiratory infections since 6- 9 months of life The most common PID Selective IgA deficiency:1/333 persons to 1/16000, XLA 1/50000

16. X-Linked Agammaglobulinemia (XLA or Bruton Agamma) Profound defect in B lymphocyte development Severe hypogammaglobulinemia Absence of circulating B cells Small to absent tonsils No palpable lymph node Xq22 encode the B-cell protein Tyrosine Kinase (Btk) which is responsible for pre-B- cell expansion and maturation

17. Genetic Diagnosis of XLA Low or undetectable Btk mRNA and kinase activity in all patients ( >250 mutations) Carrier: Non random X-chromosome inactivation in B-cells or by direct mutation analysis

18. Clinical Manifestations of XLA Maternally transmitted IgG antibodies protect the patient for the first 6-9 mo Frequent respiratory infections with extra cellular pyogenic organisms: Strep pneumonia, H.influenza,Mycoplasma, Not frequent viral and opportunistic infections (except for p.c.,enterovirus,echovirus, hepatitis viruses)

19. Phenotypic Diagnosis of XLA Lymphoid hypoplasia Decreased IgG, IgA, IgM and IgE far below 95% confidence limit, usually less than 100 mg/dl of total immunoglobulin Abnormal titer of isohemagglutinins and post vaccination antibody titer

20. Phenotyping Diagnosis of XLA, Cont.. Flow cytometry: The absence of circulating B cells (vs. CVID) Normal Tcell count and function TREATMENT : IVIG,Abx

21. Common Variable Immunodeficiency (CVID) Hypogammaglobulinemia with phenotypically normal B cells The same kind of infections and organisms as XLA Later onset of infections, and less severe infections,male=female,no echo virus

22. Genetic of CVID No identified molecular diagnosis A shared hereditary influence with selective IgA deficiency ( MHC class III over the chromosome 6) Drugs( phenytoin, D pencillamine, gold,sulfasalazin)

23. Phenotypic characteristics of CVID Normal B cell number but no response to pokeweed mitogen in vitro T cell number is normal but T cell function is depressed in some patients

24. Clinical manifestation of CVID Low serum immunoglobulin Auto antibody GI and autoimmune manifestations,CVD(tymoma,A. areata,hemolytic anemia) Nodular follicular lymphoid hyperplasia Normal or enlarged size of LN Splenomegaly (25%) Malignancy in older age(lymphoma 400 fold)

25. Selective IgA deficiency Isolated absence of serum and secretory IgA Serum IgA <10 mg/dl The most common well defined PID 0.33% in healthy blood donors Basic genetic defect is still unknown B cells are normal Autosomal dominant inheritance with variable expressivity Commonly occurs in pedigree with CVID

26. Selective IgA Def, Clinical Manifestations Mostly asymptomatic Infections occur predominantly in the respiratory, gastrointestinal, and urogenital tracts Polio vaccination induce the local IgM and IgG production IgG2 subclass def is reported

27. Selective IgA Def, Clinical manifestation, cont.. Auto antibody & autoimmune dis Malignancy Anti IgA antibodies (44%) IVIG infusion is not indicated

28. Transient Hypogamm of Infancy (THI) The nadir amount of IgG is reached at 3-4 months of life Extension of the physiologic hypogamm beyond 6 months of age so called: THI Normal T and B cell number and normal T cell function Normal titer of isohemagglutinins and post vaccination antibody response

29. THI Increased frequency of otitis media and sinusitis, not life threatening infection IVIG therapy is not indicated

30. Hyper IgM syndrome Heterogeneous genetic basis Low serum IgG and IgA Normal or elevated IgM Mutations in two genes on the X chromosome: CD154 (CD40 ligand) and NEMO and two genes on the autosomal chromosomes; AID and CD40 Bacterial infections, Opportunistic infections, and Malignancy

31. X Linked lymphoproliferative disease (XLP) Duncan disease Defective gene: Xq25 led to absence of a regulatory molecule (SH2D1A) Uncontrolled cytotoxic T-cell immune response to EBV Antibody def is frequently present

32. Clinical Manifestation of XLP Previously healthy male Three major clinical phenotypes: Fulminant infectious mononucleosis (50%) Lymphomas, B cell lineage (25%) Acquired hypogamm (25%)

33. Treatment of B cell ID The only effective treatment: Judicious use of antibiotics Regular replacement therapy with IVIG Except for CD40 ligand defect and XLP: B.M. transplantation

34. IVIG Therapy IVIG has a broad spectrum of antibodies from pool of plasma of more than 60000 donors Safe and effective but expensive needed to give monthly(3-4 wks): 400-600mg/kg iv infusion Systemic reactions can occur but rare true anaphylaxis due to anti IgA antibody (IgE)