Common Variable Immune Deficiency

Indications for Testing

Chronic or recurrent infections
Diagnosis by exclusion

Criteria for Diagnosis

Significantly decreased levels of immunoglobulin G, A and/or M with poor or absent antibody production (lack of two vaccination responses) and exclusion of other causes of hypogammaglobulinemia

Laboratory Testing

Quantitative immunoglobulin levels by nephelometry
- IgG, IgA – low, usually ≥2 standard deviations below age-related norms
- IgM – sometimes low
Monoclonal protein detection, characterization, and quantitation recommended in all patients >15 years with symptoms of hypogammaglobulinemia, which include quantitative IgG, IgA, and IgM along with serum protein electrophoresis and immunofixation electrophoresis
- Rule out monoclonal gammopathy
Profiles for circulating number of B-cells/T-cells
- Normal, increased or decreased
- Severe deficiencies in T- or B-cells should initiate differential workup based on deficiency
Pneumococcal or diphtheria vaccination – pre- and post-vaccination IgG titers
- Defective antibody production after vaccination
- Not necessary if severe immunoglobulin deficiency already detected on quantitative immunoglobulin testing

Differential Diagnosis

Bruton agammaglobulinemia
Complement deficiency
Immunoglobulin disorders
T-cell deficiency disorder
Monoclonal gammopathies, including myelomas and monoclonal gammopathy of undetermined significance
Neutrophil disorders
Leukocyte adhesion deficiency
Immunodeficiency, innate system
Chronic granulomatous disease
Severe combined immunodeficiency
Transient hypogammaglobulinemia of infancy

Common variable immune deficiency (CVID) is the most common immunodeficiency disease and is characterized by recurrent and/or chronic infections resulting from defective antibody production and hypogammaglobulinemia.

Epidemiology

Incidence – estimates vary from 1/50,000 to 1/100,000
Age – bimodal peaks
- <10 years
- 10-29 years
  - Can occur in elderly patients ≥90 years
Sex – M:F, equal

Risk Factors

Genetic defect – molecular defects have been identified in only 20% of cases
- Genes include ICOS, CD19, TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B), TNFRSF13C (BAFF-R)

Pathophysiology

Patients have normal or decreased B-cell production but have a major defect in antibody production
T-cells also show some deficiency in 50% of patients

Clinical Presentation

Frequent delay (median 2-5 years) in diagnosis
Recurrent infection is hallmark
- Pyogenic bacteria (encapsulated organisms are frequent pathogens)
- Sinusitis
- Respiratory tract infections
  - Pneumonia
  - Chronic bronchitis
- Bronchiectasis
Malabsorption, diarrhea
Increased incidence of malignancy
- Predominantly lymphoreticular (especially B-cell lymphomas)
- Ten- to twentyfold increased incidence
Increased incidence of autoimmune disease (20% of patients)
- Cytopenias (most common disorder), including autoimmune thrombocytopenia and autoimmune hemolytic anemia
- Sarcoidosis-like disease
- Inflammatory bowel disease
- Rheumatoid arthritis
- Pernicious anemia
Benign lymphoid proliferation
- 10-25% develop lymphadenopathy, splenomegaly
- Must be differentiated from lymphoproliferative disorders