Common Variable Immunodeficiency

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DESCRIPTION

  • Common variable immunodeficiency (CVID) is the most common clinically important primary immunodeficiency syndrome, characterized by:
    • Low IgG plus low IgA and/or IgM
    • Recurrent infections, especially sinopulmonary
    • A wide spectrum of immunologic abnormalities, including autoimmune disease, inflammatory conditions, and the development of lymphomas
  • CVID is a diagnosis of exclusion.
    • Requires low IgG and variable reduction in IgA and/or IgM, impaired specific antibody responses, and characteristic clinical manifestations (infection or autoimmunity)
    • Low IgG alone (hypogammaglobulinemia) is not sufficient for diagnosis.

EPIDEMIOLOGY

  • Prevalence has been estimated at between 1:100,000 and 1:10,000 of the population, varying across populations.
  • May present at any age:
    • Bimodal peak in the 1st and 3rd decades of life
    • Diagnosis is usually made several years after the onset of recurrent infections (pneumonia, sinusitis, otitis).
    • Definite diagnosis should wait until age 4 years, given difficulties assessing vaccine response and competing diagnoses before this age (e.g., transient hypogammaglobulinemia of infancy)
  • A subgroup of children has been described in which the onset of disease is most often <5 years of age.
    • Characterized by a relapsing and remitting course in which autoimmune disease predominates
  • About 20–25% of patients with CVID have one or more autoimmune conditions at time of diagnosis.
  • Affects males and females equally overall, although in children, there is a male predominance

ETIOLOGY

  • The primary immunologic defect(s) leading to this syndrome is unknown.
  • Multiple defects have been associated with CVID, including the following:
    • Lack of somatic mutation within variable region genes
    • Lack of memory B cells
    • Impaired maturation, IL-12 secretion, and upregulation of costimulatory molecules by antigen-presenting cells may impair T cells, which are important for providing help to B cells for antibody production.
    • Toll-like receptor 9 (TLR9) response and expression by B cells may also be impaired. TLR signaling pathways are being investigated for their potential role in pathogenesis of CVID
  • In general, <2% of patients will have a monogenic cause identified through genetic testing.

RISK FACTORS

Genetics

  • Evidence for genetic inheritance is based off familial cohorts and described, but monogenic causes are rare.
  • Rare recessive mutations have been described in
    • T-cell inducible costimulatory (ICOS) in one kindred, <1% of patients
    • CD19 in a few unrelated families
    • B-cell activating factor (BAFF)
    • CD20 and CD81
    • Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI, TNFRSF13B) in 8% of patients, associated with autoimmunity and lymphoid hyperplasia; heterozygous mutation more common than homozygous; significance not clear due to similar mutation found in healthy family members
  • IgA deficiency is more likely in offspring of parents with CVID
  • Incidence of IgA deficiency, autoimmune disease, and malignancies is increased in family members of patients with CVID

PATHOPHYSIOLOGY

  • Main characteristic is hypogammaglobulinemia due to impaired B- or T-cell function.
  • Impaired immunoglobulin and specific antibody production despite normal B cell numbers
  • Often increased proportion of immature B cells
  • Deficiency of class-switched memory B cells is associated with more complex disease (autoimmunity, granulomatous disease, hypersplenism, and lymphoid hyperplasia).

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