Common Variable Immune Deficiency - CVID

Diagnosis

Indications for Testing

• Chronic or recurrent infections

Criteria for Diagnosis

• Significantly decreased levels of immunoglobulin G, A, or M with poor or absent antibody production (lack of two vaccination responses)
• 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 – includes quantitative IgG, IgA, and IgM, along with serum protein electrophoresis and immunofixation electrophoresis
  • Rule out monoclonal gammopathy
  • Recommended in all patients >15 years with symptoms of hypogammaglobulinemia
• T-cell and B-cell immunodeficiency profile testing
  • T-cell testing at minimum should include CD4, CD45RA, CD45RO, CD8, CD4:8 ratio, CD3, CD19, and NK cell
  • Severe deficiencies in T cells or B cells should initiate differential workup based on deficiency
• Pneumococcal or diphtheria vaccination – pre- and postvaccination IgG titers
  • Defective antibody production after vaccination supports diagnosis of CVID
  • Not necessary if severe immunoglobulin deficiency already detected on quantitative immunoglobulin testing
• TACI sequencing – low yield (10% clinical sensitivity), but it can provide positive evidence for CVID that is diagnosed mainly as an exclusion

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

Clinical Background

Common variable immune deficiency (CVID), the most common immunodeficiency disease, is characterized by recurrent 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
• 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

• Impaired B cell differentiation leads to increased susceptibility to infections and diminished response to protein and polysaccharide vaccines
  • T-cell function abnormalities appear in ~50% of patients

Clinical Presentation

• Frequent delay in diagnosis – median 2-5 years
• 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
  • Tenfold 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

Treatment

• Intravenous immunoglobulin

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Diagnostic Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm