PRIMARY IMMUNODEFICIENCY

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PRIMARY IMMUNODEFICIENCY

• DR MOHAN
• MODERATOR DR PUSHPALATA

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• 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.

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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

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TYPES OF IMMUNODEFICIENCY

• PRIMARY
• SECONDARY

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• 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
  well-functioning immune system, young children
  can have up to six upper respiratory tract
  infections per year for the first 3 to 5 years of
  life .

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• 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

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• Several factors contribute to the risk for
  infections during childhood -
• Increased infectious agent exposure, school-aged
  siblings, peer group
• passive smoking
• Atopy , hyper reactive air way disease
• Anatomic factors, structural or ciliary defects
• Foreign body
• Cystic fibrosis
• Gastroesophageal reflux

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• 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.

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CHARASTERISTICS OF INFECTION

• CHARESTERISTICS OF INFECTION
• Increasing susceptibility to infections
• Increasing severity of infection
• Increasing duration of infections
• Unusual infection
• Infection with opportunistic agents
• Continuous illness
• Dependence to antibiotics

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10 WARNING SIGNS OF PRIMARY IMMUNODEFICIENCY
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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 deep-seated infections.
Two or more pneumonias within 1 year.
A family history of Primary Immunodeficiency.
Failure of an infant to gain weight or grow
normally.
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PRIMARY IMMUNODEFICIENCY

• 1) B-cell defects
• 2) T-cell defects
• 3) complement system defects
• 4) phagocytic system defects .

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Antibody deficiencies include
X-linked agammaglobulinemia (XLA) Common
variable immunodeficiency (CVID) Selective IgA
deficiency (SIgAd) Hyper IgM syndrome (HIgM)
Transient hypogammaglobulinemia of Infancy (THI)
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Cellular deficiencies include
Combined immunodeficiency (CID) Severe combined
immunodeficiency (SCID) Ataxia-Telangiectasia
syndrome (AT) Wiskott-Aldrich syndrome (WAS)
DiGeorge syndrome
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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
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• 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.

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B-Cell Defect
Age at the onset Onset after maternal antibodies diminish, usually after 5-7 mo of age, later childhood to adulthood
Specific pathogens involved Bacteria streptococci, staphylococci, Haemophilus, Campylobacter Viruses 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
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T-Cell Defect
Age at the onset Early onset, usually 2-6 mo of age
Specific pathogens involved Bacteria mycobacteria Viruses CMV, EBV, varicella, enterovirus Fungi and parasites Candida opportunistic infection, PCP
Affected organs Failure to thrive, protracted diarrhea, extensive mucocutaneous candidiasis
Special features Graft-versus-host disease caused by maternal AB or nonirradiated blood transfusion Postvaccination, disseminated BCG or paralytic polio hypocalcemic tetany in infancy
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APROACH TO A CHILD WITH PRIMARY IMMUNODEFICIENCY
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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

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MICROORGANISM SUSCEPTIBILITY

• AGAMMAGLOBULINEMIA -
• encapsulated bacteria - Streptococcus pneumoniae
  or Haemophilus influenzae. Complicating
  septicemia .
• viral meningoencephalitis caused by enteroviruses
  ( coxsakievirus or echovirus)

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• Giardia lamblia - CVID and IgA deficiency.
• Small-bowel bacterial overgrowth with Yersinia
  and Campylobacter CVID
• bacterial infections and opportunistic
  infections. Mycobacterium avium-intracellulare
  and Pneumocystis carinii severe T-cell defects

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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 X-linked immunodeficiency .
• family history is the presence of relatives with
  autoimmune disorders, which commonly occurs in
  families with patients who have CVID and IgA
  deficiency

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• A negative family history does not rule out this
  inheritance pattern , a significant rate of new
  mutations for X-linked disorders exists.

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T-cell defects X-linked SCID (common gamma-chain deficiency)X-linked hyper-IgM syndromeWiskott-Aldrich syndromeX-linked lymphoproliferative syndrome
B-cell defects Bruton's X-linked agammaglobulinemia
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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.

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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

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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

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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

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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.

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SKIN

• Skin Findings Associated Immune
  Defect
• Eczema and petechiae Wiskott-Aldrich syndrome
• Telangiectasia Ataxia-telangiectasi
  a
• syndrome
• Dermatomyositis-like rash B-cell dysfunction
• Generalized molluscum contagiosumT-cell
  deficiency
• Extensive warts T-cell deficiency
• Candidiasis T-cell deficiency

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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.

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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.

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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.

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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,

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LYMPHIOD SYSTEM..

• Lymphoreticular malignancies occur more commonly
  in certain primary immunodeficiencies, including
  Wiskott-Aldrich syndrome, ataxia-telangiectasia,
  and CVID

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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.

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SYSTEMIC EXAMINATION

• CARDIOVASCULAR SYSTEM
• Pulmonary hypertension can occur in patients with
  chronic lung disease

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NEUROLOGICAL EXAMINATION

• progressive ataxia in a young child could be the
  first sign of ataxia-telangiectasia even before
  immunodeficiency becomes clinically apparent.

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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.

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LAB DIAGNOSIS

• CBC, ESR
• B cell defects
• Screening tests
• 1. IgA, IgG, IgM measurement
• 2. Isohemagglutinins
• 3.Antibody titres to tetanus, diphtheria, S.
  pneumoniae, H. influenzae

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ADVANCED TESTS

• 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

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LAB TESTS IN IMMUNODEFICIENCY

• T-CelI Deficiency- screening tests
• Delayed skin tests e.g.,Trichophyton. Candida
• Lymphocyte count and
• morphology Chest x-ray for thymic size

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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

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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.

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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.

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LAB TESTS IN IMMUNODEFICIENCY

• Thrombocytopenia and small platelet size are
  characteristic of patients with Wiskott-Aldrich
  syndrome.
• Autoantibodies causing autoimmune hemolytic
  anemia, thrombocytopenia, or neutropenia can
  occur in some of the B-cell immunodeficiencies

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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

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LAB TESTS IN IMMUNODEFICIENCY.

• 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

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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.

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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 .

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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.

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IMMUNISATION.

• Measles-mumps-rubella, varicella, and BCG
  vaccines can be given to family members

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BLOOD TRANSFUSION.

• Only irradiated, leukocyte-poor, and virus-free
  (i.e., cytomegalovirus) products should be used
  in patients with T-cell defects to avoid
  graft-versus-host disease and cytomegalovirus
  infection.

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• SPECIFIC TREATMENT OPTIONS
• Currently available treatment techniques include
  bone marrow transplantation, immunoglobulin
  replacement, and enzyme-replacement. Gene therapy
  for some diseases has been initiated in clinical
  trials.

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• 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.

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B - CELL DEFECTS
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AGAMMAGLOBULINEMIA
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• agammaglobulinemia is the severe of the
  antibody-deficiency syndromes
• Significant decreases in all major classes of
  immunoglobulins.
• An absence of circulating B cells .

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• Small tonsils and no palpable lymphnodes.
• T cells are present normally, with preservation
  of delayed hypersensitivity and other
  cell-mediated immune functions.
• neutropenia

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PATHOGENESIS

• EARLY B- CELL MATURATION FAILS IN
  AGAMMAGLOBULINEMIA

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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 B-cell linker protein

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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.

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• Fatal meningoencephalitis with enteroviruses can
  occur due to lack of Ig A

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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

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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

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COMMON VARIABLE IMMUNODEFICIENCY
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• CVID is also called
• hypogammaglobulinemia
• adult-onset agammaglobulinemia
• late-onset hypogammaglobulinemia
• acquired agammaglobulinemia

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• 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 .

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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.

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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.

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• 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

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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

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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.

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• 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.

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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

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SELECTIVE IgA DEFICIENCY
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• 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

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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 .

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PATHOGENESIS

• Terminal differention of B cells fails to
  result in IgA deficiency.

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TYPES

• ISOLATED IgA DEFICIENCY
• ASSOCIATED WITH
• IgE DEFICIENCY
• IgG2 OR IgG4 DEFICIENCY

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• 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 IgA-deficiency are
  likely to have other problems, including
  allergies, asthma, and autoimmune diseases.

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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.

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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.

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• 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

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HYPERIgM SYNDROME
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• Hyper-IgM is a rare immunodeficiency disease in
  which the immune system fails to produce IgA and
  IgG antibodies

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• 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.

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• 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

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• 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

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• The hyper-IgM syndrome also should be suspected
  in the presence of cryptosporidium-related
  diarrhea, sclerosing cholangitis, or
  parvovirus-induced aplastic anemia.

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• Another aspect of Hyper-IgM Syndrome is
  autoimmune disease. Autoimmune attacks on red
  blood cells lead to anemia, while autoimmune
  destruction of infection-fighting neutrophils
  further increases the risk of infection

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• IgM concentrations, suggesting that IgM increases
  only when the immune response is stimulated and
  the immunoglobulin shift cannot occur.

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• 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.

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Lab tests

• Normal numbers of T and B cells.
• High levels of IgM
• Very low IgG and IgA.
• Neutropenia.

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HYPOGAMMAGLOBULINEMIA OF INFANCY
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• 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

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• Most patients have normal IgM and IgA
  concentrations and a normal circulating B-cell
  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.

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XLA Hyper IgM CVID HGI
AGE gt 6 m gt 6 m 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
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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.

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• 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.

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• Continuous prophylactic antibiotics often are
  beneficial, particularly in recurrent infection
  in agammaglobulinemia despite IG therapy.

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• 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 .

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• High doses of IVIG (400 to 800 mg/kg/mo) can be
  given and are beneficial to some
  antibody-deficient 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, gt 500 mg/dL)
• Plasma has been used as an alternative to IG, but
  because of the risk of disease transmission, it
  is rarely indicated

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T CELL DEFECTS
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• 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 T-cell help

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SELECTIVE T-CELL DEFECTS
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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

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• The specific cardiac anomalies most frequently
  associated with DGS are interrupted aortic arch,
  tetralogy of Fallot, and truncus arteriosus

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• 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.

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• The dysmorphic features include,
• Hypertelorism, antimongloid slant of eyes
• Low set notched ears, short philtrum of the upper
  lip
• Mandibular hypoplasia

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• The immune defects in DGS include
• decreased (lt1500 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.

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Treatment

• Bone marrow transplantation.

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SEVERE COMBINED IMMUNODEFICIENCY SYNDROMES
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• Severe combined immunodeficiency syndrome (SCID)
  is a heritable disorder in children characterized
  by profoundly defective or absent T-cell and
  B-cell function

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• 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

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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, IL-21) which mediates
  intracellular signalling.
• Characterised by T-, B, NK-.

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• 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-.

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• 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-.

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• 3.IL -7 R alpha deficiency.
• Accounts for 10 cases, due to mutation at 5p13.
• Characterised by T-, B, NK.

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• 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.

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• 5. CD45 DEFICIENCY.
• Recently identified entity, accounting for very
  few cases.
• Gene not yet mapped.
• Required for T and B cell antigen receptor
  transduction.

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• 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.

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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.

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• In general, the following infections may develop
  in affected infants
• BacteriaGram-negative sepsisDisseminated BCG
  after immunization
• Fungi and protozoaCandidiasisAspergillusPneumoc
  ystis carinii pneumonia
• VirusesCytomegalovirusParainfluenza
  virusesAdenovirusRespiratory syncytial
  virusDisseminated varicellaVaccine-acquired
  paralytic poliomyelitisMolluscum contagiosum

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• 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.

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• 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.

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• A diagnosis of SCID is suggested when an affected
  infant has
• lymphopenia (lt1500 cells/mm3 normal range,
  4000-13,500 cells/mm3 ),
• less than 20 CD3 T lymphocytes,
• and severe hypogammaglobulinemia (IgG, lt150
  mg/dL).

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TREATMENT

• Bone marrow transplantation

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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 toErythrodermaLymphadenopathyHep
  atosplenomegalyFailure to thrive secondary to
  diarrheaFever

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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.

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• Laboratory findingsHypoalbuminemiaEosinophilia
  (gt1000 cells/mm3 )Variable lymphocyte
  countsDecreased CD3 T-cell countlow or
  Absent B cellsNormal NK-cell countMarkedly
  defective T-cell and B-cell functionHypogammaglo
  bulinemiaSeverely decreased IgG, IgM, and IgA
  levels

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Wiskott-Aldrich Syndrome

• Wiskott-Aldrich syndrome (WAS) is an X-linked
  inherited immunodeficiency characterized by
  eczema, congenital thrombocytopenia with small
  platelets, and recurrent infections

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ETIOLOGY

• Due to mutation at Xp11 coding for WASP which is
  required for microvesicles formation in blood
  cells.

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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

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• 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.

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LAB DIAGNOSIS

• Lymphopenia (lt1000 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,

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TREATMENT

• Bone marrow transplantation.

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Ataxia Telangiectasia

• Ataxia-telangiectasia (AT) is a complex AR
  disorder characterized by cerebellar ataxia,
  oculocutaneous telangiectasia, radiosensitivity,
  predisposition to malignancy and combined
  immunodeficiency

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ETIOLOGY

• Due to mutation at 11q22.
• There is incraesed sensitivity to ionising
  radiation and defective DNA repair.

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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

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• 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 .

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• growth retardation, hypogonadism and pubertal
  delay, and insulin-resistant nonketotic diabetes
  mellitus

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• 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
  

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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 AT-associated
  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

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REFERRENCES

• Nelsons textbook of pediatrics
• PCNA
• Ganongs textbook of physiology
• Harrisons textbook of internal medicine

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THANK YOU