Common variable immunodeficiency (CVID) is a heterogeneous disorder that is associated with low serum-immunoglobulin concentrations, defective specific-antibody production and an increased susceptibility to bacterial infections of the respiratory and gastrointestinal tracts.

The term "common variable immunodeficiency" is used to designate a group of as yet undifferentiated syndromes. All are characterized by defective antibody formation. The diagnosis is based on the exclusion of other known causes of humoral immune defects.

Synopsis

 several patterns of inheritance (autosomal recessive, autosomal dominant, and X-linked)
 possible sporadic cases
 Among populations of European origin, common variable immunodeficiency is the most frequent of the primary specific immunodeficiency diseases.
 It affects men and women equally.
 The usual age at presentation is the second or third decade of life.

 recurrent pyogenic sinopulmonary infections
 serious chronic obstructive lung disease
 bronchiectasis
 possible unusual organisms (Pneumocystis carinii, mycobacteria, or various fungi)
 recurrent attacks of herpes simplex virus (HSV)
 herpes zoster (20%)
 unusual enteroviral infections

• chronic enteroviral meningoencephalitis
• syndrome resembling dermatomyositis

 digestive anomalies

• CVID-associated gastritis
• gastric mucosal dysplasia
• gastric adenocarcinoma
• digestive infections
  • chronic Giardia lamblia infection

 Lymphomas

 gastrointestinal tumors

• gastric carcinoma Risk x50-fold)

 diffuse lymphadenopathy
 splenomegaly
 striking reactive follicular hyperplasia
 gastrointestinal tract

• nodular lymphoid hyperplasia
• malabsorption with weight loss, diarrhea, hypoalbuminemia. vitamin deficiencies.
• inflammatory bowel diseases (IBDs)

 autoimmune disorders

• pernicious anemia
• hemolytic anemia
• thrombocytopenia
• neutropenia

 noncaseating tuberculoid granulomas occur in the skin, the gut, and other viscera

 defective antibody formation

• decreased serum IgG concentrations
• decreased serum IgA
• decreased serum IgM

 no convincing evidence of any intrinsic B-cell defects.

• The number of B cells may be reduced but with they can produce and secrete immunoglobulins appropriate stimulation.
• B cells are immature. The findings in common variable immunodeficiency are consistent with insufficient in vivo stimulus for B-cell activation rather than an intrinsic failure of B cells to differentiate.

 Relatives of patients with common variable immunodeficiency

• unusually high incidence of IgA deficiency
• increased incidence of autoimmune disorders
• increased incidence of autoantibodies (including antilymphocyte antibodies)
• increased incidence of malignant conditions

 Families whose members include persons with common variable immunodeficiency and IgA deficiency often have certain fixed haplotypes in the MHC.

 One or more genes in the MHC may be involved in the pathogenesis of common variable immunodeficiency and IgA deficiency.

 Since immature B cells in common variable immunodeficiency appear to be functionally intact, the defect might logically reside in the T-cell component of the interaction between B cells and T cells requisite for B-cell maturation. However, it is often difficult to interpret studies of T cells in common variable immunodeficiency, because of the activation of T cells that is probably a result of recurrent or chronic infections65 or infusions of intravenous immune globulin.66

 In most patients with common variable immunodeficiency, stimulation of T-cell receptors67 produces diminished responses and there is decreased gene transcription of cytokines such as interleukin-2, interleukin-4, interleukin-5, and interferon-.68,69 Decreased production of interleukin-2 after direct stimulation of T-cell receptors70 is correlated with diminished expression of CD40 ligand71 and may reflect an abnormality in CD4+ T cells in common variable immunodeficiency.72,73 This abnormality of T-cell triggering can be bypassed by direct activation of signal transduction.74,75

 Thus, many patients with common variable immunodeficiency appear to have defective interactions between T cells and B cells. Defective T-cell signal transduction could contribute to the diminished humoral immunity found in these disorders in the presence of immature but otherwise potentially normal B cells.

 In the absence of appropriate T-cell signaling, B cells would fail not only to produce antibody, but also to proliferate and differentiate, which would result in both the decreased numbers and the arrested maturation of B cells seen frequently in common variable immunodeficiency.

Types of infections

 encapsulated bacteria
 mycoplasma
 Toxoplasma gondii (#15320909#)
 disseminated histoplasmosis (#14533988#)
 CMV (cytomegalovirus)

Synopsis

 short stature
 recurrent bacterial infections (encapsulated bacteria, mycoplasma)

• acute sinusitis
• acute otitis media
• conjunctivitis
• recurring infectious pneumonia with frequent bronchiectasis
• meningitis

 digestive anomalies

• Helicobacter gastritis (#10369708#)
• Helicobacter-associated gastric adenocarcinoma (#10369708#)
• Helicobacter-associated gastric dysplasia (#10369708#)
• chronic active gastritis (#10369708#)
• multifocal atrophic gastritis (#10369708#)
• intestinal nodular lymphoid hyperplasia (NLH)
• malabsorption
• giardiasis
• sprue
• digestive infections
  • CMV enteritis (#14746434#)

 chronic persisting hepatitis (#6604451#)

 lymphoproliferative lesions (#1334378#)

• chronic granulomatous inflammation
• reactive lymphoid hyperplasia
• atypical lymphoid hyperplasia
• B-cell lymphomas
  • BALT lymphoma (pulmonary marginal zone B-cell lymphoma) (#11223743#)

 autoimmune diseases

• atrophic gastritis
• arthritis
• hemolytic anemia

 granulomatous-lymphocytic interstitial lung disease (GLILD) (31% of associated lymphoproliferative disease)(#15316526#)

• granulomatous lung disease
• pulmonary lymphoid hyperplasia
  • lymphocytic interstitial pneumonia
  • follicular bronchiolitis (BALT hyperplasia)

 organizing penumonia (#10940808#)

• BOOP (bronchiolitis obliterans organizing pneumonia)

 usual interstitial pneumonitis (UIP)

 granulomatous lesions (#15320909#)

• non-caseating granulomas
• chronic granulomatous inflammation (#10881789#, #9341059#)

 digestive anomalies (#8827031#)

• malabsorption with mild to severe villous atrophy
• Giardia infection (intestinal giardiasis)
• small bowel lymphoma associated with nodular lymphoid hyperplasia
• intestinal foamy histiocytes in the lamina propria, resembling Whipple disease or chronic granulomatous disease, with numerous apoptotic bodies in crypts
• colitis with features similar to ulcerative colitis
• poorly formed granulomas
• nodular lymphoid hyperplasia

 autoimmune disorders

• autoimmune cytopenias

 pityriasis lichenoides
 splenomegaly

Biology

 low plasma cells number in bone marrow
 normal numbers of T cells
 variable degree of T cell dysfunction
 normal numbers of surface immunoglobulin positive B cells
 markedly reduced IgA levels
 markedly reduced IgG levels
 reduced IgM levels
 anti-IgA antibodies commonly present

Transmission

 genetic CVID

• autosomal recessive inheritance
• autosomal dominant inheritance
• ICOS deficiency (MIM.607594) by mutations in ICOS gene(MIM.604558)
• sporadic cases

 drug-induced CVID

• sulfasalazine
• hydantoin
• carbamazepine
• levamisole

Etiology

 germline mutations of TNFRSF13B in common variable immunodeficiency (CVID) (MIM.240500)

References

 Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schaffer AA, Hammarstrom L, Grimbacher B. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005 Aug;37(8):820-8. PMID: #16007087#

 Bayry J, Hermine O, Webster DA, Levy Y, Kaveri SV. Common variable immunodeficiency: the immune system in chaos. Trends Mol Med. 2005 Aug;11(8):370-6. PMID: #15996517#

 Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004 Aug;114(2):415-21. PMID: #15316526#

 Washington K, Stenzel TT, Buckley RH, Gottfried MR. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol. 1996 Oct;20(10):1240-52. PMID: #8827031#

 Sander CA, Medeiros LJ, Weiss LM, Yano T, Sneller MC, Jaffe ES. Lymphoproliferative lesions in patients with common variable immunodeficiency syndrome. Am J Surg Pathol. 1992 Dec;16(12):1170-82. PMID: #1334378#