Transcript Primary Immunodeficiency Disorders (PID)

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 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,
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 measurement
Isohemagglutinins
Antibody titers to Tetanus, Diphteria,
H.influenza, and S.Pneumonia
Initial Lab testing, cont..

Screening tests for phagocytic cell
defects:
Absolute neutrophil count
Respiratory 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 69 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-Bcell 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 antibiotics
Regular 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 rare
true anaphylaxis due to anti IgA antibody (IgE)
