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Common variable immunodeficiency
Common variable immunodeficiency (CVID) comprises a heterogeneous group of diseases characterized by a significant hypogammaglobulinemia of unknown cause, failure to produce specific antibodies after immunizations and susceptibility to bacterial infections, predominantly caused by encapsulated bacteria.
ORPHA:1572Classification level: Disorder
- Idiopathic immunoglobulin deficiency
- Primary antibody deficiency
- Primary hypogammaglobulinemia
- Prevalence: 1-9 / 100 000
- Inheritance: Autosomal dominant or Autosomal recessive or Not applicable
- Age of onset: All ages
- ICD-10: D83.0 D83.1 D83.2 D83.8 D83.9
- OMIM: 146830 240500 607594 613493 613494 613495 613496 614699 615577 616576
- UMLS: C0009447
- MeSH: D017074
- GARD: 6140
- MedDRA: 10021449
Prevalence is estimated at 1/25,000 among Caucasians and CVID affects men and women equally.
While some patients are diagnosed with CVID in early childhood, the major peak of onset lies between the second and third decade of life, frequently with several years delay between onset and diagnosis. Over 98% of patients present with recurrent bronchitis, sinusitis, otitis and pneumonia, and chronic pulmonary damage is the major complication. About 25% of patients develop autoimmune phenomena; immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are the most common (see these terms). Lymphoproliferative disorders such as generalized lymphadenopathy and/or splenomegaly are present in up to 40% of patients, and there is an increased risk of developing gastrointestinal and lymphoid malignancies, especially non-Hodgkin's lymphoma (see this term). Up to 57% of patients develop bronchiectasis. Patients with TACI-deficiency are more likely to be affected by lymphoproliferation and autoimmunity. There is considerable variation in the clinical presentation in patients with a similar genotype.
CVID can be due to an intrinsic B cell defect (for example CD19-deficiency caused by mutations in CD19; 16p11.2), an intrinsic T cell defect (for example ICOS-deficiency caused by mutations in ICOS; 2q33), mutations in TNF receptors (such as TACI-deficiency or BAFFR-deficiency caused by mutations in TNFRSF13B and TNFRSF13C respectively; 17p11.2 and 22q13.1-q13.31) or without a known genetic defect. Other monogenic defects reported include MSH5, CD81 and CD20 deficiencies.
Diagnosis should be suspected in patients with recurrent sinopulmonary infections exceeding an age-specific frequency, and is based on exclusion of other causes of hypogammaglobulinemia. Analyses of lymphocyte function, including analysis of specific antibody responses after vaccination, and immunophenotyping of T and B cells strengthen the diagnosis and indicate subgroups of CVID. Ultrasound and CT of the abdomen may be necessary to assess additional complications including enlarged abdominal lymph nodes, spleen and liver pathology or granulomas.
Differential diagnosis include other causes of hypogammaglobulinemia including loss of gammaglobulins via the intestine or urine, hematological malignancies, viral infections or drug-induced loss of B-cell function.
Most cases are sporadic but about 20% are thought to be familial with either autosomal dominant (80%) or autosomal recessive (20%) inheritance. TACI-deficiency is estimated to occur in approximately 10% of cases; the other defects are very rare.
Management and treatment
There is no curative therapy. Treatment is based on immunoglobulin replacement therapy, using pooled human immunoglobulin, usually administered intravenously or subcutaneously. To reduce long-term pulmonary sequelae, targeted antibiotic treatment is necessary. Patients with bronchiectasis may benefit from lung physiotherapy. The frequently occurring cytopenias require monitoring, and specific treatment such as splenectomy may be indicated. Concurrent autoimmune disorders or malignant disease require specific treatment.
Patients with bacterial infections only have a better prognosis than patients with additional complications and can have nearly normal life expectancy, especially if diagnosis and treatment occurs soon after the onset of symptoms.
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