Primary Immunodeficiency Disorders (PID)

Soheila Alyasin M.D. AssOCIAT Professor of Pediatrics Division of Immunology and Allergy

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.

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

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

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)

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

Initial evaluation of immune system

History Ab,C & neutrophil:encapculated

bacteria Nl G/D unless bronchiectasis T :oppurtunistic infections ,FTT Physical exam Family history

Relative distribution of the primary immunodeficiency Antibody deficiencies 65% Combined cellular and antibody

deficiencies 15% Phagocytic deficiencies 10% Cellular deficiencies 5% Complement deficiencies 5%

Initial Immunology Testing of Patients With Recurrent

InfectionsCBC+manual differential count ESR

ANC, ALC, Howell-Jolly bodies, platelet countScreening test for B cell defects :IgA, IgG, IgM measurementIsohemagglutininsAntibody titers to Tetanus, Diphteria, H.influenza, and

S.Pneumonia

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)

Initial Immunology Testing of Patients With Recurrent

Infections

Screening test for B cell defects :IgA, IgG, IgM measurementIsohemagglutininsAntibody titers to Tetanus, Diphteria,

H.influenza, and S.Pneumonia

Initial Lab testing, cont..

Screening tests for phagocytic cell defects:

Absolute neutrophil countRespiratory burst assay (NBT, RDT)

Initial Lab testing, cont..

Screening tests for T cell defects:

Absolute lymphocyte count (Nl: unlikelyTcell defect) Candida albicans intradermal test

Initial Lab testing, cont,..

Screening test for complement deficiency:

CH50

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

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

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

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)

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

Phenotyping Diagnosis of XLA, Cont..

Flow cytometry: The absence of circulating B cells (vs. CVID)

Normal Tcell count and function

TREATMENT : IVIG ,Abx

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

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)

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

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)

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

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

Selective IgA Def, Clinical manifestation, cont..

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

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

THI

Increased frequency of otitis media and sinusitis, not life threatening infection

IVIG therapy is not indicated

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

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

Clinical Manifestation of XLP

Previously healthy male Three major clinical phenotypes:Fulminant infectious mononucleosis

(50%)Lymphomas, B cell lineage (25%)Acquired hypogamm (25%)

Treatment of B cell ID

The only effective treatment:Judicious use of antibioticsRegular replacement therapy with

IVIG Except for CD40 ligand defect and

XLP:B.M. transplantation

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 raretrue anaphylaxis due to anti IgA antibody

(IgE)