Diagnostic Criteria and Treatment for Common Variable Immunodeficiency (CVID)
The diagnosis of CVID should be considered in male or female subjects older than 4 years who have low IgG and IgA levels and impaired antibody response but do not have genetic lesions or other causes of primary or secondary antibody deficiency. 1
Diagnostic Criteria for CVID
Laboratory Findings Required for Diagnosis
- Serum IgG level less than 450-500 mg/dL 1
- Serum IgA or IgM level less than the fifth percentile 1
- Decreased ability to make specific antibodies to both protein and polysaccharide antigens 1
- Normal or reduced B-cell numbers in peripheral blood (approximately 13% of patients will have less than 3% B cells among peripheral blood lymphocytes) 1
Essential Diagnostic Steps
- Exclude other primary causes of agammaglobulinemia (e.g., X-linked agammaglobulinemia, X-linked lymphoproliferative disease) 1
- Exclude secondary causes of hypogammaglobulinemia (medications, protein loss through gastrointestinal tract/lymphatics/kidney, B-cell lymphomas, bone marrow failure) 1, 2
- Document impaired production of specific antibodies in response to protein or polysaccharide antigens, which is essential for diagnosis 1
- Assess B-cell subsets in peripheral blood, which can correlate with clinical phenotypes and may be useful for classification 1
Age Consideration
- CVID diagnosis is not considered appropriate before age 4 years, as hypogammaglobulinemia in young children may resolve as they age 1, 3
Classification Systems
- The EUROclass classification incorporates features of the Freiburg and Paris classifications, based on:
- Decreased numbers of marginal zone and class-switched B cells correlate with granulomatous disease and splenomegaly 1
- Expansion of CD21low B cells correlates with splenomegaly 1
- Expansion of transitional B cells (IgMhigh CD38high) is associated with lymphadenopathy 1
Clinical Manifestations
Infectious Complications
- Recurrent and chronic bacterial respiratory tract infections (most frequent) 1, 4
- Common pathogens include:
- Recurrent and/or persistent viral respiratory tract infections, particularly rhinovirus 1
Non-infectious Complications
- T-cell abnormalities are frequently found in CVID patients despite being classified as predominantly humoral immunodeficiency 1
- Autoimmune disorders, particularly hemolytic anemia and thrombocytopenia 3, 5
- Lymphoproliferative disorders 5
- Gastrointestinal manifestations and enteropathy 5
- Granulomatous disease 1, 5
- Increased risk of malignancy 3, 5
Treatment Options
Immunoglobulin Replacement Therapy
- Regular intravenous or subcutaneous immunoglobulin replacement therapy is the cornerstone of CVID treatment 6, 4
- Standard dosing: approximately 0.5g/kg administered every 3-4 weeks 6, 4
- Target IgG trough levels: 8-11 g/L 6
- Benefits:
Monitoring
- Regular monitoring of IgG trough levels is essential to ensure adequate replacement therapy 6
- Regular monitoring of blood counts and serum chemistry to detect potential adverse effects 6
- Ongoing assessment for non-infectious complications 5
Common Pitfalls and Caveats
- Diagnosis is often delayed in adults (average delay of 10.5 years in one study) 4, 2
- Multiple diagnostic criteria exist without a universally adopted consensus, leading to diagnostic challenges 7, 2
- Patients may present with autoimmune or lymphoproliferative manifestations rather than infections 5
- Despite immunoglobulin replacement therapy, patients remain at risk for non-infectious complications 5
- Genetic testing should be considered as approximately 10% of cases have identifiable mutations (e.g., in TACI, ICOS, CD19, BAFF-R) 3
- T-cell abnormalities should be evaluated when significant impairment of humoral immunity is observed, as they could be a component of combined immunodeficiency 1