Transcript Septic Shock

PRIMARY IMMUNODEFICIENCY
DR MOHAN
• MODERATOR – DR PUSHPALATA
• The immune system, which protects the
body from disease, works through a
complicated web of cells and chemicals. A
defect in any one of these parts can damage
the body's ability to fight off disease. Such a
defect is called an immunodeficiency
disease.
IMMUNE SYSTEM
Innate immunity –
phagocytic cells, natural killer (NK) cells,
complement system, and other plasma
factors
Adaptive immunity –
T and B lymphocytes and their secreted
products
TYPES OF
IMMUNODEFICIENCY
• PRIMARY
• SECONDARY
• The immune system is not fully mature at birth
and may not be well developed in some aspects
until a child reaches school age. Even with a wellfunctioning immune system, young children can
have up to six upper respiratory tract infections per
year for the first 3 to 5 years of life .
• Typically, children with an intact immune
system and no other predisposing factors
handle these infections well, with rapid
resolution of bacterial infections using
appropriate antibiotics
• Several factors contribute to the risk for
infections during childhood – Increased infectious agent exposure, schoolaged siblings, peer group
– passive smoking
– Atopy , hyper reactive air –way disease
– Anatomic factors, structural or ciliary defects
– Foreign body
– Cystic fibrosis
– Gastroesophageal reflux
• Primary immunodeficiencies are generally the
result of genetic defects in the immune system cells.
These disorders are rare, with the exception of IgA
deficiency, which occurs with a frequency of
approximately 1 : 500-700 among the white
population. The estimated range of prevalence for
other primary immunodeficiencies is 1 : 10,000 to
1 : 200,000 depending on the specific diagnosis.
• CHARESTERISTICS
OF INFECTION
CHARASTERISTICS
OF
INFECTION
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Increasing susceptibility to infections
Increasing severity of infection
Increasing duration of infections
Unusual infection
Infection with opportunistic agents
Continuous illness
Dependence to antibiotics
10 WARNING SIGNS OF
PRIMARY
IMMUNODEFICIENCY
Eight or more new ear
infections within 1 year.
Recurrent, deep skin or
organ abscesses.
Two or more serious sinus
infections within 1 year.
Persistent thrush in mouth or
elsewhere on skin, after age 1.
Two or more months on
antibiotics with little effect.
Need for intravenous
antibiotics to clear infections.
Two or more pneumonias
within 1 year.
Two or more
deep-seated infections.
Failure of an infant to gain
weight or grow normally.
A family history of
Primary Immunodeficiency.
PRIMARY IMMUNODEFICIENCY
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1) B-cell defects
2) T-cell defects
3) complement system defects
4) phagocytic system defects .
Antibody deficiencies include:
X-linked agammaglobulinemia (XLA)
Common variable immunodeficiency (CVID)
Selective IgA deficiency (SIgAd)
Hyper IgM syndrome (HIgM)
Transient hypogammaglobulinemia of Infancy (THI)
Cellular deficiencies include:
Combined immunodeficiency (CID)
Severe combined immunodeficiency (SCID)
Ataxia-Telangiectasia syndrome (AT)
Wiskott-Aldrich syndrome (WAS)
DiGeorge syndrome
Phagocytic disorders include:
Chronic granulomatous disease (CGD)
Leukocyte adhesion defect (LAD)
Chediak-Higashi syndrome (CHS)
Swhachman syndrome (Swh.S)
Hyper IgE syndrome (Job syndrome)
Complement deficiencies
• B- cell defects are the commonest immune
abnormalities, accounting for more than 50%
primary immunodeficiency. Combined B and T
cell defects constitute 20% to 30% cases,
followed by phagocytic defects, at 18%, and
complement deficiencies, at 2%.
B-Cell Defect
Age at the Onset after maternal antibodies diminish,
onset
usually after 5-7 mo of age, later childhood
to adulthood
Specific Bacteria: streptococci, staphylococci,
pathogens Haemophilus, Campylobacter Viruses:
involved enterovirus Fungi and parasites: giardia,
cryptosporidia
Affected
organs
Recurrent sinopulmonary infections, chronic
gastrointestinal symptoms, malabsorption,
arthritis, enteroviral meningoencephalitis
Special
features
Autoimmunity, lymphoreticular malignancy:
lymphoma, thymoma; postvaccination
paralytic polio
T-Cell Defect
Age at the
onset
Specific
pathogens
involved
Affected
organs
Special
features
Early onset, usually 2-6 mo of age
Bacteria: mycobacteria Viruses: CMV, EBV,
varicella, enterovirus
Fungi and parasites: Candida; opportunistic
infection, PCP
Failure to thrive, protracted diarrhea, extensive
mucocutaneous candidiasis
Graft-versus-host disease caused by maternal AB
or nonirradiated blood transfusion;
Postvaccination, disseminated BCG or paralytic
polio; hypocalcemic tetany in infancy
APROACH TO A CHILD WITH
PRIMARY
IMMUNODEFICIENCY
AGE AT ONSET
• 2 – 5 months of age – T cell defect
(severe combined immunodeficiency )
• 5 – 7 months of age – B cell defect
( X linked agammaglobinimia )
Later childhood & adult hood – common
variable immunodeficiency
• Younger age at onset – severe the deficiency
MICROORGANISM
SUSCEPTIBILITY
• AGAMMAGLOBULINEMIA • encapsulated bacteria - Streptococcus
pneumoniae or Haemophilus influenzae.
Complicating septicemia .
• viral meningoencephalitis caused by
enteroviruses ( coxsakievirus or echovirus)
• Giardia lamblia - CVID and IgA
deficiency.
• Small-bowel bacterial overgrowth with
Yersinia and Campylobacter – CVID
• bacterial infections and opportunistic
infections. Mycobacterium aviumintracellulare and Pneumocystis carinii
severe T-cell defects
FAMILY HISTORY
• A family history of maternal male relatives affected
with unusually frequent infections or who died in
early infancy should alert the possibility of an Xlinked immunodeficiency .
• family history is the presence of relatives with
autoimmune disorders, which commonly occurs in
families with patients who have CVID and IgA
deficiency
• A negative family history does not rule out
this inheritance pattern , a significant rate of
new mutations for X-linked disorders exists.
T-cell
defects
B-cell
defects
X-linked SCID (common
gamma-chain deficiency)
X-linked hyper-IgM syndrome
Wiskott-Aldrich syndrome
X-linked lymphoproliferative
syndrome
Bruton's X-linked
agammaglobulinemia
MEDICAL HISTORY
• VACCINE • Adverse reaction to live viral vaccines , Paralytic
polio has occurred in patients with B-cell
deficiency and in patients with combined T-cell
and B-cell immunodeficiency.
MEDICAL HISTORY…..
• BLOOD TRANSFUSION –
• Only irradiated blood products should be given
to patients with severe T-cell defects because
blood transfusions contain lymphocytes that can
cause graft-versus-host disease.
• Patients with complete IgA deficiency can
produce IgE antibodies to IgA, so they are at risk
for an anaphylactic reaction to plasma or blood
transfusions
PHISICAL EXAMINATION
• a normal physical examination does not rule
out an underlying immunodeficiency .
• In children with X-linked
lymphoproliferative disease, symptoms or
signs of disease typically do not develop
before Epstein-Barr virus infection develops
PHISICAL EXAMINATION…
• Patients with antibody-deficiency syndromes
can demonstrate normal growth and
development despite frequent and severe RTIs.
Antibody-deficiency syndromes can be
characterized by asymptomatic periods
PHISICAL EXAMINATION…
• Some children with underlying
immunodeficiency appear chronically ill
and underweight. If initial onset of the
disease occurs early in life, growth and
development may be delayed, leading to
failure to thrive.
SKIN……
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Skin Findings
Associated Immune Defect
Eczema and petechiae Wiskott-Aldrich syndrome
Telangiectasia
Ataxia-telangiectasia
syndrome
Dermatomyositis-like rash B-cell dysfunction
Generalized molluscum contagiosumT-cell
deficiency
• Extensive warts
T-cell deficiency
• Candidiasis
T-cell deficiency
DYSMORPHIC FEATURES
• In patients with DiGeorge anomaly,
abnormalities in the embryologic
development of the third and fourth
pharyngeal pouches produce dysmorphic
features, including hypoplastic mandible,
small mouth, hypertelorism and
antimongoloid slant, and low-set and
posteriorly rotated ears.
DYSMORPHIC FEATURES…
• DiGeorge anomaly also is associated with
hypoparathyroidism; an aplastic or
hypoplastic thymus; and conotruncal
abnormalities of the heart, such as tetralogy
of Fallot, ventricular septal defect/atrial
septal defect (VSD/ASD), and pulmonic
artery atresia or stenosis.
ENT EXAMINATION
• Extensive mucous membrane candidiasis
suggests a T-cell defect. Examination of the
pharynx and nasal cavities for signs of sinusitis,
like, postnasal drainage, or purulent nasal
discharge. Tympanic membranes can appear
scarred and disfigured as a sign of previous
recurrent and chronic infection of the middle ear.
LYMPHIOD SYSTEM
• Absence of tonsils and lymph nodes
suggests a severe immunodeficiency, as
seen in patients with XLA or SCID.
• Cervical adenopathy and enlarged liver or
spleen can be seen in patients with a B-cell
deficiency, such as CVID or IgA deficiency,
LYMPHIOD SYSTEM..
• Lymphoreticular malignancies occur more
commonly in certain primary
immunodeficiencies, including WiskottAldrich syndrome, ataxia-telangiectasia,
and CVID
SYSTEMIC EXAMINATION
• RESPIRATORY SYSTEM –
• Rales on auscultation of the chest may
suggest bronchiectasis occurring as a
complication of recurrent lung infections.
Digital clubbing points to significant lung
disease.
SYSTEMIC EXAMINATION…
• CARDIOVASCULAR SYSTEM –
• Pulmonary hypertension can occur in
patients with chronic lung disease
NEUROLOGICAL
EXAMINATION
• progressive ataxia in a young child could be
the first sign of ataxia-telangiectasia even
before immunodeficiency becomes
clinically apparent.
NEUROLOGICAL
EXAMINATION…..
• Signs of posterior and lateral column
involvement of the spinal cord with loss of
vibratory sense in the lower extremities,
positive Babinski's response, or poor finger
coordination can be signs of pernicious
anemia complicating the course of CVID or
IgA deficiency.
LAB DIAGNOSIS
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CBC, ESR
B cell defects
Screening tests
1. IgA, IgG, IgM measurement
2. Isohemagglutinins
3.Antibody titres to tetanus, diphtheria, S.
pneumoniae, H. influenzae
ADVANCED TESTS
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B cell enumeration(CD19 or CD20)
IgG subclass estimation
IgD and IgE measuremen
In vitro stimulation of B cells to produce
immunoglobulins
• Coculture of T and B cells to assess help
and suppression
LAB TESTS IN
IMMUNODEFICIENCY
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T-CelI Deficiency- screening tests
Delayed skin tests: e.g.,Trichophyton. Candida
Lymphocyte count and
morphology Chest x-ray for thymic size
Advanced tests
• T-cell enumeration and phenotyping by flow
cytometry
• In vitro proliferative responses to mitogens, specific
antigens, or allogeneic cells (mixed lymphocyte
culture)
• Intracellular cytokine production by flow cytometry
• T-cell cytotoxicity assays
LAB TESTS IN
IMMUNODEFICIENCY…..
• Anemia of chronic disease can develop in
patients with chronic infections, whereas
pure erythrocyte aplasia can be seen in
patients with thymoma and CVID.
LAB TESTS IN
IMMUNODEFICIENCY….
• Persistent lymphopenia can be a sign of
cellular immunodeficiency. Lymphopenia
is defined as less than 3000 cells/mm3 in
infants, whereas in older children or adults,
a total lymphocyte count of less than 1500
cells/mm3 is abnormal.
LAB TESTS IN
IMMUNODEFICIENCY…
• Thrombocytopenia and small platelet size
are characteristic of patients with WiskottAldrich syndrome.
• Autoantibodies causing autoimmune
hemolytic anemia, thrombocytopenia, or
neutropenia can occur in some of the B-cell
immunodeficiencies
LAB TESTS IN
IMMUNODEFICIENCY….
• Quantitation of serum immunoglobulins
(IgG, IgM, IgA) is the first step in
evaluating humoral or B-cell immunity
• low IgA level - IgA deficiency or other
immunoglobulin deficiency diseases.
• High IgM level - hyper-IgM syndrome
LAB TESTS IN
IMMUNODEFICIENCY….
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The IgE level commonly is elevated in
atopy
Wiskott-Aldrich syndrome.
Specific antibody titers against
glycoprotein antigens, such as tetanus and
diphtheria, or polysaccharide antigens, such
as pneumococcal polysaccharide, can be
assessed
ROLE OF PEDIATRICIAN
• Prompt recognition of infection and
aggressive treatment are essential to avoid
life-threatening complications and improve
prognosis and quality of life. Initiation of
early empiric coverage for suspected
pathogens till appropriate cultures obtained.
ROLE OF PEDIATRICIAN….
• Prophylactic antibiotics are recommended for
children with significant T-cell defects because of
the risk for Pneumocystis carinii pneumonia with
Co-trimaxazole .
• Children with B-cell defects who continue to
experience recurrent infections despite adequate
intravenous immunoglobulin therapy , should be
considered for antimicrobial therapy to avoid
complications, such as bronchiectasis .
IMMUNISATION….
• Live-attenuated vaccines, such as oral polio,
varicella, and BCG should not be given to children
with suspected or diagnosed antibody or T-cell
defects, because vaccine-induced infection is a risk
in these patients. Inactivated polio vaccine should be
given to household members to prevent transmission
of the virus that can occur by shedding of the
attenuated virus in the stool.
IMMUNISATION….
• Measles-mumps-rubella, varicella, and
BCG vaccines can be given to family
members
BLOOD TRANSFUSION….
• Only irradiated, leukocyte-poor, and virusfree (i.e., cytomegalovirus) products should
be used in patients with T-cell defects to
avoid graft-versus-host disease and
cytomegalovirus infection.
• SPECIFIC TREATMENT OPTIONS
• Currently available treatment techniques
include bone marrow transplantation,
immunoglobulin replacement, and enzymereplacement. Gene therapy for some
diseases has been initiated in clinical trials.
• Genetic counseling is important not only for
a child's parents but also for siblings .
• Prenatal diagnosis can be established by
performing analyses on fetal blood samples,
amniotic fluid cells, or chorionic villus
biopsy specimens.
B - CELL DEFECTS
AGAMMAGLOBULINEMIA
• agammaglobulinemia is the severe of the
antibody-deficiency syndromes
• Significant decreases in all major classes of
immunoglobulins.
• An absence of circulating B cells .
• Small tonsils and no palpable
lymphnodes.
• T cells are present normally, with
preservation of delayed hypersensitivity
and other cell-mediated immune
functions.
• neutropenia
PATHOGENESIS
• EARLY B- CELL MATURATION FAILS
IN AGAMMAGLOBULINEMIA
ETIOLOGY….
• X-linked recessive - commonest form
• XLA is caused by mutations in the Btk
gene, located on chromosome Xq 21.3-22
• autosomal recessive - caused by
abnormalities in the mu-chain gene that
codes for the heavy chain of IgM or the Bcell linker protein
CLINICAL FEATURES
• Extracellular pyogenic bacterial infections,
particularly otitis, sinusitis, and pneumonia,
may begin as early as age 4 to 6 months,
when the maternal IgG level decreases.
Approximately 20% of patients present with
overwhelming sepsis.
• Fatal meningoencephalitis with
enteroviruses can occur due to lack of Ig A
DIAGNOSIS
• The diagnosis is supported by the presence of
affected maternal male cousins, uncles, or
nephews.
• The serum IgG level is usually less than 200
mg/dL .
• IgM and IgA levels typically are less than 20
mg/DL
DIAGNOSIS
• Test for natural antibodies to A & B RBC
antigens will be abnormal .
• Tests for antibodies to routine vaccines will
be abnormal .
• Flow cytometry showing less than 2%
CD19+ B cells in circulation .
• Normal number of Pre B - cells in bone
marrow
COMMON VARIABLE
IMMUNODEFICIENCY
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CVID is also called
hypogammaglobulinemia
adult-onset agammaglobulinemia
late-onset hypogammaglobulinemia
acquired agammaglobulinemia
• CVID is a late-onset, highly variable
hypogammaglobulinemic primary immune
deficiency that can occur after age 18
months, with two peaks at approximately
ages 1 to 5 years and 16 to 20 years.
• It affects approximately 1 in 10,000 to
100,000 general population
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It is characterised by –
Variable deficiency of immunoglobulins .
Normal number of B – cells .
Normal sized or enlarged tonsils ,lymph
nodes & spleenomegaly.
• Autoimmune diseases .
• Malignancies .
ETIOLOGY
• The exact cause is unknown.
• Most cases of CVID occur sporadically;
however, familial inheritance
( Chromosome 6 )may be found in as many
as 25% of cases. In 10% of patients, CVID
or a related immunodeficiency disease
(e.g., IgA deficiency) is found in more than
one family member
• CVID is commonly associated with HLA –
B8 & HLA – DR3.
PATHOGENESIS
• T- cell signaling to B- cells is defective in
CVID
• B – cells do not function properly and fail to
receive proper signals from T – cells .
• T- cell defects have not been well defined.
• Frequent bacterial infections of the ears,
sinuses, bronchi, and lungs
• painful swollen joints in the knee, ankle,
elbow, or wrist
• problems involving the digestive tract
• an enlarged spleen and swollen glands or
lymph nodes
CLINICAL FEATURES
An increased susceptibility to Respiratory tract
infections and gastrointestinal infection is the
commonest clinical presentation of CVID.
RTI may be caused by H. influenzae and S.
pneumoniae, whereas G. lamblia and
Campylobacter jejuni are responsible for
most gastrointestinal infection
CLINICAL FEATURES…
• Autoimmune disorders, such as idiopathic
thrombocytopenia (ITP), autoimmune
hemolytic anemia, pernicious anemia,
rheumatoid arthritis, systemic lupus
erythematosus, autoimmune thyroiditis,
vitiligo, and primary biliary cirrhosis also
may develop in patients with CVID.
Sarcoid-like granulomata of the lungs, liver,
spleen, and conjunctivae also may affect
patients with CVID.
• Malignancies are increased in patients with
CVID. A 100-fold increased risk for
malignant lymphoma and a 50-fold
increased risk for gastric cancer with CVID.
LAB TESTS
• Serum concentrations of IgM ,IgG , IgA are
reduced .
• A normal number of B cells .
• A variable degree of T-cell dysfunction .
• Isohemagglutinins are absent.
• Responses to protein and polysaccharide
vaccines are poor
SELECTIVE IgA DEFICIENCY
• It is the most prevalent primary
immunodeficiency disease, occurring in
approximately 1/500 to 1/1000 general
population.
• Serum IgA levels less than 7 mg/dl with
normal levels of other immunoglobulin
classes
• Normal serum antibody responses.
• normal cell mediated immunity
ETIOLOGY
• The exact cause is unknown
• Since the associated factors like
malignancy, family history, autoimmunity
are common to both CVID & IgA
deficiency , same genetic cause may be
present .
PATHOGENESIS
• Terminal differention of B – cells fails to
result in IgA deficiency.
TYPES
• ISOLATED IgA DEFICIENCY
• ASSOCIATED WITH
IgE DEFICIENCY
IgG2 OR IgG4 DEFICIENCY
• Many people with IgA-deficiency are
healthy, with no more than the usual number
of infections. Those who do have symptoms
typically have recurring ear, sinus, or lung
infections that may not respond to regular
treatment with antibiotics. People with IgAdeficiency are likely to have other
problems, including allergies, asthma, and
autoimmune diseases.
CLINICAL FEATURES
• Susceptibility to recurrent RTI ,GIT
infections.
• RTI may be caused by H. influenzae and S.
pneumoniae, whereas G. lamblia and
Campylobacter jejuni are responsible for
most gastrointestinal infection.
• Associated autoimmune disorders may be
present.
DIAGNOSIS
• serum IgA level of less than 7 mg/Dl
• normal serum IgG and IgM levels and a
normal IgG antibody response to
vaccination.
• Normal number of B – cells.
• Diagnosed reliably only after age 4 years.
• Differentiate between
(1) patients in whom no IgA is detected
(2) patients who have low but detectable
IgA concentrations
HYPERIgM SYNDROME
• Hyper-IgM is a rare immunodeficiency
disease in which the immune system fails to
produce IgA and IgG antibodies
• The faulty T cells do not give B cells a
signal they need to switch from making IgM
to making IgA and IgG. Most cases of
hyper-IgM syndrome are linked to the X
chromosome.
• Most male patients with the hyper-IgM syndrome
have a mutation in the CD40L gene on the X
chromosome. The interaction between CD40 on
the B cell and the CD40L on the activated T cell is
essential for the switch from IgM to IgG
production, which explains why a deficiency in
CD40L leads to hyper-IgM production with
deficient IgG. These patients have normal or
elevated numbers of B cells, normal numbers of T
cells and normal T-cell proliferation
• In addition to the recurrent RTIs, patients with
CD40L deficiency also have an increased
susceptibility to infections with some intracellular
pathogens, such as P. carinii pneumonia, CNS
histoplasmosis, and toxoplasmosis.The increased
susceptibility to intracellular pathogens is caused
by the role of the CD40L in host defenses against
some intracellular pathogens
• The hyper-IgM syndrome also should be
suspected in the presence of
cryptosporidium-related diarrhea, sclerosing
cholangitis, or parvovirus-induced aplastic
anemia.
• Another aspect of Hyper-IgM Syndrome is
autoimmune disease. Autoimmune attacks
on red blood cells lead to anemia, while
autoimmune destruction of infectionfighting neutrophils further increases the
risk of infection
• IgM concentrations, suggesting that IgM
increases only when the immune response is
stimulated and the immunoglobulin shift
cannot occur.
• Infants usually develop recurring upper and
lower respiratory infections within the first
year of life. Other signs of the disease
include enlarged tonsils, liver, and spleen,
chronic diarrhea, and an increased risk of
unusual or opportunistic infections.
Lab tests
Normal numbers of T and B cells.
High levels of IgM
Very low IgG and IgA.
Neutropenia.
HYPOGAMMAGLOBULINEMIA
OF INFANCY
• Transient hypogammaglobulinemia of
infancy is an ill-defined entity in which a
child's postnatal decrease in serum IgG
level is accentuated
• A delay in the onset of endogenous
immunoglobulin synthesis occurs, possibly
because of deficiency in T helper cells
• Most patients have normal IgM and IgA
concentrations and a normal circulating Bcell level. The initial serum IgG levels are
typically higher than those of patients with
agammaglobulinemia.
• IgG concentrations usually normalize by
the time these patients reach age 2 or 3
years.
XLA
Hyper IgM CVID
HGI
AGE
>6m
>6m
anytime
1-2yrs
IgG
A/ low
Low
Low
Low
IgM
A/ low
High
Low
Normal
IgA
A/ low
Low
Low
Normal
B cell
A/ low
normal
Present
Present
defect
B tk
CD40
legand
unknown
unknown
Treatment of B cell defects
• General management of patients with
immunodeficiency requires an extraordinary
amount of care to maintain optimal health
and nutrition, manage infections, prevent
emotional problems related to their illness,
and cope with costs.
• Antibiotics are lifesaving for treating infections;
selection and dosage are identical to those used
normally
• fever or other manifestations of infection are
assumed to be secondary to bacterial infection,
and antibiotic treatment is begun immediately.
Throat, blood, or other cultures are obtained
before most therapy; these are especially useful
subsequently when the infection does not respond
to the initial antibiotic and when the infectious
organism is unusual.
• Continuous prophylactic antibiotics often
are beneficial, particularly in recurrent
infection in agammaglobulinemia despite
IG therapy.
• Immune globulin (IG) is effective
replacement therapy in most forms of
antibody deficiency. It is a 16.5% solution
of IgG with trace quantities of IgM and IgA
for IM or subcutaneous injection, or a 3 to
12% solution for IV infusion (IVIG).
• The loading dose is 200 mg/kg given in 2 or
3 doses over 2 to 5 days followed at
monthly intervals by 100 mg/kg .
• High doses of IVIG (400 to 800 mg/kg/mo) can be
given and are beneficial to some antibodydeficient patients not responding well to
conventional doses, particularly those with chronic
lung disease. The aim with high-dose IVIG is to
keep IgG trough levels in the normal range (ie, >
500 mg/dL)
• Plasma has been used as an alternative to IG, but
because of the risk of disease transmission, it is
rarely indicated
T CELL DEFECTS
• Primary T-cell immunodeficiencies are rare
inherited disorders that affect T-cell development
and function.
• These disorders usually present in infancy or early
childhood; however, the age of symptom onset
may vary depending on the underlying gene
defect.
• Although T-cell immune responses may be
selectively affected, abnormal B-cell function
often is associated, in part because of concomitant
intrinsic B-cell defects but also because
production of most antibodies is dependent on Tcell help
SELECTIVE T-CELL DEFECTS
DiGeorge Syndrome
•
•
•
•
•
DGS classically includes
conotruncal cardiac malformations
persistent hypocalcemia and
cellular immunodeficiency
secondary to a defect in the development of
third and fourth pharyngeal pouches that
affects the parathyroid glands and thymus
• The specific cardiac anomalies most
frequently associated with DGS are
interrupted aortic arch, tetralogy of Fallot,
and truncus arteriosus
• DiGeorge (DGS), velocardiofacial, and
conotruncal anomaly face syndromes, have
been demonstrated to share a microdeletion
of one copy of chromosome 22q.
• CATCH 22 syndrome(cardiac, abnormal
facies, thymic hypoplasia, cleft palate,
hypocalcemia) includes broad spectrum of
conditions with 22q11 deletions.
• The dysmorphic features include,
• Hypertelorism, antimongloid slant of eyes
• Low set notched ears, short philtrum of the
upper lip
• Mandibular hypoplasia
• The immune defects in DGS include
• decreased (<1500 cells/mm3 ) CD3+ T
lymphocytes, a CD4+ T-cell count of less
than 1000 cells/mm3 , and impaired cellular
immunity
• 50% or less of normal T-cell numbers.
• 20% have in vitro T-cell proliferative
responses of less than 50% of normal.
Treatment
• Bone marrow transplantation.
SEVERE COMBINED
IMMUNODEFICIENCY
SYNDROMES
• Severe combined immunodeficiency
syndrome (SCID) is a heritable disorder in
children characterized by profoundly
defective or absent T-cell and B-cell
function
• fatal within the first year of life unless
curative hematopoietic stem cell
transplantation or, in the case of adenosine
deaminase (ADA) deficiency, enzyme
replacement is accomplished
ETIOLOGY
• X- LINKED RECESSIVE.
• It accounts for 45% of the cases.
• Occurs due to mutation at Xq 13 which
codes for gamma chain of the cytokine
receptors,( IL-2, IL-4, IL-7, IL-9, IL15, IL21) which mediates intracellular signalling.
• Characterised by T-, B+, NK-.
•
•
•
•
AUTOSOMAL RECESSIVE FORM
There are 6 subtypes.
1. Adenosine deaminase deficiency –
Accounts for 15% of cases due to mutation
at 20q 13.
• Accumulation of adenosine, 2’ deoxy
adenosine, 2’ 0 methyladenosine leads to T
cell apoptosis.
• Characterised by T-, B-, NK-.
• 2. Jak 3- accounts for 6% of cases
• Occurs due to mutation at 19p13.
• Jak 3 is required for the transduction of
gamma chain cytokine receptors.
• Characterised by T-, B+, NK-.
• 3.IL -7 R alpha deficiency.
• Accounts for 10% cases, due to mutation at
5p13.
• Characterised by T-, B+, NK+.
• 4.RAG1 or RAG2 (RECOMBINASE
ACTIVATING GENES) DEFICIENCY.
• Accounts for 10% caeses.
• Due to mutation at 11p13.
• The genes are essential for generation of T
cell and B cell antigen receptors.
• Characterised by T-, B-, NK+.
• 5. CD45 DEFICIENCY.
• Recently identified entity, accounting for
very few cases.
• Gene not yet mapped.
• Required for T and B cell antigen receptor
transduction.
• 6. ARTIMIS DEFICIENCY.
• Occurs due to mutation at 10p13.
• Defect in repair of DNA following cuts
produced by products of RAG1 or RAG2.
• Characterised by T-, B-, NK+.
CLINICAL FEATURES
• Despite underlying genetic heterogeneity,
patients with SCID present similarly within
the first 6 months of life with recurrent
diarrhoea, pneumonia, otitis media, sepsis,
cutaneous infections.
• In general, the following infections may develop in affected
infants:
• Bacteria
Gram-negative sepsis
Disseminated BCG after immunization
• Fungi and protozoa
Candidiasis
Aspergillus
Pneumocystis carinii pneumonia
• Viruses
Cytomegalovirus
Parainfluenza viruses
Adenovirus
Respiratory syncytial virus
Disseminated varicella
Vaccine-acquired paralytic poliomyelitis
Molluscum contagiosum
• Failure to thrive secondary to diarrhea and
malabsorption also may be present. The
appearance of an early-onset erythematous
maculopapular rash unresponsive to
medical management may suggest chronic
graft-versus-host disease (GVHD) from
engrafted maternal T cells.
• Most SCID patients have thymic hypoplasia
and absent or small, poorly developed
lymph nodes and tonsils;
hepatosplenomegaly may be detected in
affected infants with maternal GVHD.
A diagnosis of SCID is suggested when an
affected infant has
• lymphopenia (<1500 cells/mm3 ; normal
range, 4000-13,500 cells/mm3 ),
• less than 20% CD3+ T lymphocytes,
• and severe hypogammaglobulinemia (IgG,
<150 mg/dL).
TREATMENT
• Bone marrow transplantation
OMENN SYNDROME
• OS is a rare AR disorder described in 1965 by
Omenn as SCID characterized by profound
susceptibility to infection with T cell infiltration
into skin, intestine, liver and spleen leading to
Erythroderma
Lymphadenopathy
Hepatosplenomegaly
Failure to thrive secondary to diarrhea
Fever
PATHOGENESIS
• mutations in RAG1 or RAG2 that result in
partial recombinase activity and the
development of rare activated, but anergic,
oligoclonal T cells were identified in
patients with OS.
Laboratory findings
Hypoalbuminemia
Eosinophilia (>1000 cells/mm3 )
Variable lymphocyte counts
Decreased CD3+ T-cell count
low or Absent B cells
Normal NK-cell count
Markedly defective T-cell and B-cell function
Hypogammaglobulinemia
Severely decreased IgG, IgM, and IgA levels
Wiskott-Aldrich Syndrome
• Wiskott-Aldrich syndrome (WAS) is an Xlinked inherited immunodeficiency
characterized by eczema, congenital
thrombocytopenia with small platelets, and
recurrent infections
ETIOLOGY
• Due to mutation at Xp11 coding for WASP
which is required for microvesicles
formation in blood cells.
CLINICAL FEATURES
• Present in the newborn period or early infancy
with petechiae,bloody diarrhea, intracranial
hemorrhage, and excessive bleeding from an
umbilical stump or after circumcision
• Eczema develops in more than 80% of patients
and often is seen before 6 months of age
• Recurrent sinopulmonary infections with
encapsulated organisms develop within the first 2
years of life
• Opportunistic infections, such as
Pneumocystis carinii pneumonia and
recurrent herpesvirus infections
• The prevalence of leukemia, lymphomas of
the abdomen and CNS, and Epstein-Barr
virus (EBV)-associated tumors is markedly
increased
• Autoimmune disease, including hemolytic
anemia, arthritis, vasculitis, inflammatory
bowel disease, and glomerulonephritis, is
seen in approximately 40% of patients with
WAS.
LAB DIAGNOSIS
• Lymphopenia (<1000 cells/mm3 ) with
declining numbers of CD3+ and CD8+ T
cells
• B-cell and NK-cell numbers remain normal.
• Normal serum IgG but decreased IgM, in
association with defective production of
pneumococcal antibodies and absent
isohemagglutinins,
TREATMENT
• Bone marrow transplantation.
Ataxia Telangiectasia
• Ataxia-telangiectasia (AT) is a complex AR
disorder characterized by cerebellar ataxia,
oculocutaneous telangiectasia,
radiosensitivity, predisposition to
malignancy and combined
immunodeficiency
ETIOLOGY
• Due to mutation at 11q22.
• There is incraesed sensitivity to ionising
radiation and defective DNA repair.
CLINICAL FEATURES
• The presenting symptom in AT is ataxic gait
seen in more than 85% of patients 4 years of
age
• The ataxia progressively involves the trunk,
extremities, and palatal muscles, resulting in
dysarthric speech, drooling, ocular apraxia,
and inability to ambulate independently by
10 years of age
• Telangiectasia of the sclerae and skin
subsequently develops between the ages of
4 and 8 years
• recurrent upper and lower respiratory tract
infections and chronic lung disease.
• increased predisposition to T-cell and B-cell
malignancies, particularly leukemia and
Hodgkin and non-Hodgkin lymphomas .
• growth retardation, hypogonadism and
pubertal delay, and insulin-resistant
nonketotic diabetes mellitus
• progressive lymphopenia involving both T
and B cells, including selective loss of
CD4+ T cells, with inversion of the normal
CD4-CD8 ratio.
• IgA and IgE deficiency in most AT patients
and decreased isohemagglutinins and serum
IgG2 levels
TREATMENT
• Cellular radiosensitivity does not make
transplantation a viable option for the treatment of
AT. Moreover, standard chemotherapy protocols
cannot be used in the management of ATassociated malignancies.
• Some AT patients have survived for several years
with lymphoid tumors, but the long-term outcome
is dismal. Most patients with AT do not survive
beyond the third decade of life
REFERRENCES
•
•
•
•
Nelson’s textbook of pediatrics
PCNA
Ganong’s textbook of physiology
Harrison’s textbook of internal medicine