CVID - Common Variable Immunodeficiency

Definition and diagnostic criteria

Definition: Heterogeneous group of disorders characterized by low serum immunoglobulins (typically low IgG with low IgA and/or IgM) and impaired antibody responses to vaccines after excluding secondary causes of hypogammaglobulinemia.

Diagnostic notes: Diagnosis requires demonstration of hypogammaglobulinemia with poor specific antibody production, clinical history of recurrent infections or immune dysregulation, and exclusion of defined genetic or secondary causes.

Epidemiology and age at presentation

Prevalence: Estimated around 1:25,000 to 1:50,000.

Age distribution: Many patients present in the second to fourth decades, but presentations occur across the lifespan including infancy and childhood; diagnosis may be delayed after symptom onset.

Typical clinical presentation

• Infections: Recurrent upper and lower respiratory tract infections are common and may progress to bronchiectasis if untreated or recurrent.
• Autoimmunity: Autoimmune cytopenias such as autoimmune hemolytic anemia and immune thrombocytopenia are frequent manifestations of immune dysregulation.

Gastrointestinal manifestations

GI disease occurs in a substantial minority of patients and may be infectious or immune mediated.

• Infections: Chronic or recurrent diarrhea caused by pathogens including Giardia, norovirus, Salmonella, Campylobacter, Yersinia, and cytomegalovirus; consider targeted stool and tissue testing.
• Gastric disease: Atrophic gastritis and pernicious anemia; gastric biopsies may show increased apoptosis and reduced plasma cells.
• Celiac-like enteropathy: Villous atrophy and malabsorption resembling celiac disease but often with absent or markedly reduced plasma cells; patients frequently have limited or no response to a gluten‑free diet and may require immunomodulatory therapy.
• Other: IBD-like colitis, nodular lymphoid hyperplasia, increased risk of GI malignancy (including gastric cancer and lymphoma), sclerosing cholangitis, and autoimmune hepatitis in some patients.

Diagnostic considerations for gastroenterologists

Suspect CVID when

Patients have chronic/recurrent GI infections, unexplained malabsorption with hypogammaglobulinemia, biopsy showing absent plasma cells, or IBD‑like disease refractory to standard therapy.

Key tests

Serum IgG, IgA, IgM; specific antibody responses to vaccines; stool studies for pathogens; CMV testing when ulcerative disease is present; endoscopic biopsies with immunostaining for plasma cells.

Histopathology pitfalls

Biopsies may mimic celiac disease, IBD, or graft‑versus‑host disease; absence of plasma cells and prominent lymphoid aggregates or apoptosis are diagnostic clues suggesting CVID enteropathy.

Management

• Immunoglobulin replacement therapy: Mainstay for reducing infections and morbidity; dose and route individualized in consultation with immunology.
• Infection management: Treat enteric and systemic infections promptly with pathogen‑directed therapy and consider prolonged or suppressive regimens for chronic viral or protozoal infections.
• Immune dysregulation: Autoimmune cytopenias or severe inflammatory GI disease may require corticosteroids or steroid‑sparing immunosuppressants or biologics guided by multidisciplinary discussion with immunology.
• Surveillance: Monitor for bronchiectasis, chronic liver disease, and malignancy; ensure appropriate vaccination where feasible and assess vaccine responses.

Prognosis and follow-up

Long‑term outcomes depend on infection control, management of immune dysregulation, and early recognition of complications such as bronchiectasis or malignancy. Regular follow‑up with immunology and gastroenterology is recommended for those with GI involvement.

Clinical pearls