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Primary Immunodeficiency Disorders (PID)

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Primary Immunodeficiency Disorders (PID) Soheila Alyasin M.D. AssOCIAT Professor of Pediatrics Division of Immunology and Allergy – PowerPoint PPT presentation

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Title: Primary Immunodeficiency Disorders (PID)


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 neutrophilencapculated 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
  • CBCmanual 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
  • CBCmanual 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 deficiency1/333 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 ( gt250 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,malefemale,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 lt10 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)

35
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