Key Points
Disease summary:
Common variable immune deficiency (CVID) is a heterogeneous immunodeficiency disease characterized by low serum levels of the immunoglobulin isotypes IgG and IgA, impaired ability to produce specific antibodies after immunization and recurrent infections of the sinopulmonary or gastrointestinal tract.
First described in 1953 and later coined in 1973, CVID may present in childhood, adolescence, or adulthood and is the most common primary immunodeficiency syndrome that comes to medical attention.
In addition to being more susceptible to infections, CVID also can manifest aspects of immune dysregulation with noninfectious complications including autoimmunity (most typically autoimmune cytopenias), noninfectious gastrointestinal disease, granulomatous inflammation, lymphoid disease, and an increased risk of malignancy.
Although most cases of CVID are sporadic mutations, seven disease-causing or contributing genes have been identified that give rise to a CVID phenotype in the past 10 years.
Prevalence:
The prevalence of CVID has been estimated at between 1:10000 and 1:100000 depending on geographic location.
Differential diagnosis:
Because CVID is a diagnosis of exclusion, other causes of hypogammaglobulinemia must be ruled out. These include
X-linked agammaglobulinemia; X-linked lymphoproliferative disease; hyper-IgM syndromes; IgG subclass deficiency; selective antibody deficiency; secondary hypogammaglobulinemia; decreased production due to malignancy, drugs such as gold salts, penicillamine, antimalarial drugs, corticosteroids, phenytoin, carbamazapine, viral infections, and systemic illnesses causing bone marrow suppression are associated with the decreased production of immunoglobulins; increased loss due to protein-losing enteropathies, such as intestinal lymphangiectasia, nephrotic syndrome, burns, and other traumas leading to loss of fluids.
Diagnostic Criteria and Clinical Characteristics
CVID is defined as a diagnosis of exclusion.
The current PAGID diagnostic criteria state that CVID is probable in a male or female patient who has a marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, and fulfills all of the following criteria:
Onset of immunodeficiency at greater than 2 years of age.
Absent isohemagglutinins and/or poor response to vaccines.
Defined causes of hypogammaglobulinemia have been excluded.
Most patients with CVID are recognized to have a clinically significant immunodeficiency in the second, third, or fourth decades of life, after they have had several infections. Viral, fungal, and parasitic infections as well as bacterial infections may be causative.
The serum concentration of IgM is normal in about half of the patients. Abnormalities in T-cell numbers or function are common. The majority of patients have normal numbers of B cells; however, some have low or absent B cells with a unique subset being deficient in class switched memory B cells.
Acute and chronic infections account for a large part of morbidity in patients with CVID. Recurrent respiratory tract infections are the most common feature, affecting up to 98% of patients, with the most common organisms isolated being Streptococcus pneumoniae and Haemophilus influenzae.
Recurrent respiratory tract infections can result in development of bronchiectasis, which is present in 4% to 76% of patients depending on the cohort.
Approximately 20% to 60% of patients with CVID develop gastrointestinal disease. Diarrhea is the most frequently seen gastrointestinal manifestation in CVID with commonly identified pathogens including Giardia, Campylobacter, and Salmonella species. Infection with Helicobacter pylori infection is not uncommon and is associated with gastritis and an increased risk of development of malignancy.
Noninfectious pathologies have also been observed including pernicious anemia, inflammatory bowel disease, lymphocytic colitis, collagenous enterocolitis, and flattened villi. Abnormalities in liver function tests, autoimmune hepatitis, and primary biliary cirrhosis have been described in CVID.
Autoimmune disease is seen in 25% to 48% of CVID patients depending on the country. The most common diseases are autoimmune thrombocytopenia and autoimmune hemolytic anemia although multiple other immune diseases including vitiligo, psoriasis, pernicious anemia, rheumatoid arthritis, systemic lupus, Sjogren syndrome, primary biliary cirrhosis, hepatitis, and thyroiditis have all been described.
Granulomatous inflammation affects between 8% and 22% of patients with CVID and commonly affects the lungs, lymph nodes, and spleen but can be found in many other organs including liver, parotid glands, meninges, and bone marrow.
The overall incidence of malignancy is increased in CVID with gastric carcinoma and non-Hodgkin lymphomas being the greatest risks with increased risks of 7 to 16 and 12 to 18 times higher, respectively. Multiple other malignancies have been observed to incur a greater risk with CVID including colorectal, breast, ovarian cancer, prostate, and multiple myeloma.
Screening and Counseling
No single screening tool has been identified nor is required for the diagnosis of CVID. Genome-wide association study (GWAS) has identified many associations with CVID. When a primary humoral deficiency is suspected, serum levels of IgM, IgA, IgE, IgG, and IgG subclasses should be evaluated. Laboratory tests for antitetanus, H flu, and hepatitis B can be assessed for response to protein antigens if the patient has received these vaccines at least 1 month prior. Immune response to polysaccharide antigens can be assessed after receiving pneumovax by checking pneumococcal serotype antibodies at least 1 month prior to the vaccine.
Genetic testing for some of the more recognized mutations in CVID such as TACI, ICOS, CD19, BAFF-R, MSH5
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