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primary immunodeficiencies

  • these are genetic conditions and there are over 100 known conditions
  • most present in childhood with abnormally frequent (recurrent) or unusual infections
  • transmission is often X-linked and thus males are affected more than females
  • overall incidence of symptomatic cases is 1/280

humoral (B-cell) immunodeficiencies

  • account for 50-60%
  • characterized by:
    • low levels of serum immunoglobulins
    • recurrent bacterial infections

common variable immunodeficiency (CVID)

  • prevalence: 1 case per 50,000 population
  • low levels of IgG, IgA and perhaps IgM
  • lack of B lymphocytes or plasma cells that are capable of producing antibodies
  • variable inheritance, 5 distinct phenotypes
  • recurrent bacterial infections eg. recurrent sinusitis, bronchiectasis, chronic giardiasis, etc
  • usually diagnosed in young adults aged 20-40yrs, although peak of onset is in those aged 1-5 years and in those 16-20 years
  • 20% develop autoimmune complications such as:
  • malignancies - esp. B-cell lymphoma and stomach cancer
  • splenomegaly

Hyper-IgM syndromes

  • with AID or UNG deficiencies
    • autosomal recessive
    • similar to X-linked hyper-IgM syndrome but with lymphoid hyperplasia
  • with CD40 deficiency
    • autosomal recessive
    • similar to X-linked hyper-IgM syndrome
    • lymphoid hypoplasia
  • with CD40 ligand deficiency
    • X-linked
    • similar to X-linked agammaglobulinemia (eg, recurrent pyogenic bacterial sinopulmonary infections) but greater frequency of Pneumocystis jirovecii pneumonia, cryptosporidiosis, severe neutropenia, and lymphoid hypoplasia

Selective antibody deficiency with normal immunoglobulins

  • recurrent sinopulmonary infections
  • sometimes atopic manifestations

Selective IgA deficiency

  • occurs in 1 in 400 to 1 in 18,500 depending upon ethnic population
  • it is a heterogeneous disorder and may be partial or total deficiency
  • it has a similar pathogenesis as CVID
  • variable genetics, but may also be acquired from infections or drugs although in these cases tends to be reversible
  • usually asymptomatic
  • may cause recurrent sinopulmonary infections, diarrhea, genito-urinary infections, allergies, autoimmune disorders (eg, celiac disease, inflammatory bowel disease, SLE, chronic active hepatitis)
  • as 10-44% have anti-IgA antibodies, rarely, severe allergic reactions to blood transfusions may occur as these contain IgA
  • occurs in ~2% of patients with celiac disease while celiac disease occurs in 10-30% of these patients
  • the condition may result in failed diagnosis of celiac disease as the high levels of certain IgA antibodies usually seen in celiac disease do not occur
  • not associated with increased risk of cancer
  • may progress to CVID

Transient hypogammaglobulinemia of infancy

  • usually asymptomatic
  • sometimes recurrent sinopulmonary or GI infections, candidiasis, meningitis

X-linked agammaglobulinemia (XLA) or Bruton agammaglobulinaemia

  • 1 case per 250,000 population, only males are affected
  • most men live into their 40's
  • recurrent sinopulmonary and skin infections during infancy
  • transient neutropenia
  • lymphoid hypoplasia
  • persistent CNS infections resulting from live-attenuated oral polio vaccine, echoviruses, or coxsackieviruses
  • increased risk of infectious arthritis, bronchiectasis, and certain cancers

cellular (T-cell) immunodeficiencies

  • 5-10% of immunodeficiencies
  • predispose to infections by viruses, fungi, opportunistic and other pathogens
  • characterized by:
    • an incomplete reduction in T-cell number or activity
    • autoimmunity
    • inflammatory diseases
    • increased frequency or severity of infections
    • lymphoproliferation and lymphoma
    • elevated immunoglobulin E (IgE) production
DiGeorge syndrome (DGS)
  • autosomal
  • unusual facies with low-set ears, a congenital heart disorder (eg, aortic arch abnormalities), thymic hypoplasia or aplasia, hypoparathyroidism with hypocalcemic tetany, recurrent infections, developmental delay
chromosomal breakage syndromes (CBSs)
Wiskott-Aldrich Syndrome (WAS)
  • X-linked
  • typically, pyogenic and opportunistic infections, eczema, thrombocytopenia
  • possibly GI bleeding (eg, bloody diarrhea), recurrent respiratory infections, cancer (in 10% of patients > 10 yr), varicella-zoster virus infection, herpesvirus infection
chronic mucocutaneous candidiasis
  • persistent or recurrent candidal infections, onychomycosis
  • autosomal recessive autoimmune polyendocrinopathy–candidosis-ectodermal dystrophy (with hypoparathyroidism and adrenal insufficiency)
X-linked lymphoproliferative syndrome
  • asymptomatic until onset of EBV infection, then fulminant or fatal infectious mononucleosis with liver failure, B-cell lymphomas, splenomegaly, aplastic anemia
ζ-Associated protein 70 (ZAP-70) deficiency
  • no CD8 cells
Omenn Syndrome

combined B-cell and T-cell immunodeficiencies

  • account for 20%
Severe Combined Immunodeficiency (SCID)
  • AR (50%) or X-linked (50%)
  • 1 case per 50,000-75,000 births
    • 15% are due to adenosine deaminase (ADA) deficiency which is AR and occurs in 1:100,000 births, and these may present later in life
  • most present before 3 months age with mean age at diagnosis of 6-7 months
  • without intervention, SCID usually results in severe infection and death in children by age 2 years
  • oral candidiasis, P. jirovecii pneumonia, diarrhea before 6 mo, failure to thrive, graft vs host disease, absent thymic shadow, lymphopenia, bone abnormalities (in ADA deficiency), exfoliative dermatitis as part of Omenn syndrome
CD70 deficiency
  • AR
  • reduced activity of pathogen-fighting T cells, poor activation of antibody-producing B cells and low production of antibodies
  • poor immune control over EBV
  • homozygous patients are predisposed to Hodgkin's lymphoma if also infected by EBV 1)
  • CD70 deficiency may also impair macrophage function and increase atheroclerosis 2)
ataxia telangiectasia
  • AR
  • ataxia, telangiectasias, recurrent sinopulmonary infections, endocrine abnormalities (eg, gonadal dysgenesis, testicular atrophy, diabetes mellitus), increased risk of cancer
Cartilage-Hair Hypoplasia
  • AR
  • short-limbed dwarfism, common and opportunistic infections
Combined immunodeficiency with inadequate but not absent T-cell function and normal or elevated Igs
  • AR or X-linked
  • common and opportunistic infections, lymphopenia, lymphadenopathy, hepatosplenomegaly, skin lesions resembling those of Langerhans cell histiocytosis in some patients
Hyper-IgE syndrome
  • AD or AR
  • sinopulmonary infections; staphylococcal abscesses of skin, lungs, joints, and viscera; pulmonary pneumatoceles; pruritic dermatitis; coarse facial features; delayed shedding of baby teeth; osteopenia; recurrent fractures; tissue and blood eosinophilia
MHC antigen deficiencies
  • AR
  • common and opportunistic infections

phagocytic cell immunodeficiencies

  • account for 10-20%
  • predispose to cutaneous staphylococcal and gram-negative infections in particular
chronic granulomatous disease
  • X-linked or AR
  • granulomatous lesions in the lungs, liver, lymph nodes, and GI and GU tract (causing obstruction); lymphadenitis; hepatosplenomegaly; skin, lymph node, lung, liver, and perianal abscesses; osteomyelitis; pneumonia; staphylococcal, gram-negative, and aspergillus infections
leukocyte adhesion deficiency
  • types 1 and 2
  • AR
  • soft-tissue infections, periodontitis, poor wound healing, delayed umbilical cord detachment, leukocytosis, no formation of pus
  • developmental delay (type 2)
cyclic neutropenia
  • AD
  • pyogenic bacterial infections during recurrent episodes of neutropenia (eg, every 14 to 35 days)
Chédiak-Higashi syndrome
  • AR
  • oculocutaneous albinism, recurrent infections, fever, jaundice, hepatosplenomegaly, lymphadenopathy, neurologic changes, pancytopenia, bleeding diathesis
Mendelian susceptibility to mycobacterial disease (MSMD)

complement immunodeficiencies

  • account for up to 2% of primary cases
  • are generally autosomal recessive except for:
    • deficiencies of C1 inhibitor (autosomal dominant)
    • deficiencies of properdin (X-linked)
  • may cause:
    • recurrent bacterial infections due to defective opsonization
    • autoimmune disorders (eg, SLE, glomerulonephritis) due to defective clearance of antigen-antibody complexes

secondary immunodeficiencies

immunodeficiency.txt · Last modified: 2017/04/04 10:27 (external edit)