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

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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.

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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

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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

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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)

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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

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Initial evaluation of immune system

• History
• Ab,C neutrophilencapculated bacteria
• Nl G/D unless bronchiectasis
• T oppurtunistic infections ,FTT
• Physical exam
• Family history

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Relative distribution of the primary
immunodeficiency

• Antibody deficiencies 65
• Combined cellular and antibody deficiencies 15
• Phagocytic deficiencies 10
• Cellular deficiencies 5
• Complement deficiencies 5

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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

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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)

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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

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Initial Lab testing, cont..

• Screening tests for phagocytic cell defects
• Absolute neutrophil count
• Respiratory burst assay (NBT, RDT)

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Initial Lab testing, cont..

• Screening tests for T cell defects
• Absolute lymphocyte count
• (Nl unlikelyTcell defect)
• Candida albicans intradermal test

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Initial Lab testing, cont,..

• Screening test for complement deficiency
• CH50

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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

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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

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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

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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)

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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

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Phenotyping Diagnosis of XLA, Cont..

• Flow cytometry The absence of circulating B
  cells (vs. CVID)
• Normal Tcell count and function
• TREATMENT IVIG ,Abx

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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

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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)

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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

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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)

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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

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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

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Selective IgA Def, Clinical manifestation, cont..

• Auto antibody autoimmune dis
• Malignancy
• Anti IgA antibodies (44)
• IVIG infusion is not indicated

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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

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THI

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

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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

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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

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Clinical Manifestation of XLP

• Previously healthy male
• Three major clinical phenotypes
• Fulminant infectious mononucleosis (50)
• Lymphomas, B cell lineage (25)
• Acquired hypogamm (25)

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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

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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)

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