How should I evaluate and treat an adult or adolescent with recurrent bacterial sinusitis, bronchitis, pneumonia, chronic diarrhea, unexplained weight loss, and autoimmune cytopenias for common variable immunodeficiency?

Evaluation and Treatment of Common Variable Immunodeficiency (CVID)

Initial Diagnostic Approach

Suspect CVID in any adult or adolescent over 4 years old presenting with recurrent bacterial sinopulmonary infections (sinusitis, bronchitis, pneumonia), chronic diarrhea, unexplained weight loss, and autoimmune cytopenias who has low IgG and IgA levels with impaired antibody responses. 1

Immediate Laboratory Evaluation

• Measure serum immunoglobulins (IgG, IgA, IgM) to establish hypogammaglobulinemia. CVID requires IgG <450-500 mg/dL plus IgA or IgM below the 5th percentile. 1

• Obtain B-cell enumeration by flow cytometry (CD19+ B cells) to differentiate CVID from agammaglobulinemia. CVID patients have normal or only moderately reduced B-cell numbers, whereas agammaglobulinemia shows <2% B cells. 1, 2

• Assess functional antibody responses by measuring pre-existing vaccine-specific antibodies (tetanus, diphtheria, pneumococcal). If low, immunize with 23-valent pneumococcal polysaccharide vaccine and recheck 4-8 weeks later. Failure to mount protective antibody levels confirms functional antibody deficiency. 1, 2

• Measure serum total protein and albumin to exclude secondary hypogammaglobulinemia from protein loss (nephrotic syndrome, protein-losing enteropathy). CVID shows normal albumin because only immunoglobulin synthesis is impaired. 2

• Obtain complete blood count with differential and lymphocyte subset analysis (CD3, CD4, CD8, CD19) since T-cell abnormalities frequently occur in CVID. 1, 2

Exclude Secondary Causes

Before diagnosing CVID, systematically rule out other causes of hypogammaglobulinemia: 1

• Medications: phenytoin, carbamazepine, valproic acid, sulfasalazine, gold, penicillamine, hydroxychloroquine, NSAIDs 2
• B-cell lymphoproliferative disorders: obtain serum protein electrophoresis to detect monoclonal proteins 1
• HIV infection 1
• Bone marrow failure 1
• Genetic causes: BTK mutations (X-linked agammaglobulinemia), LRBA deficiency, PIK3CD/PIK3R1 mutations 1

The diagnostic delay for CVID averages 8-15 years, which correlates with worse outcomes including chronic pulmonary complications. 3, 4 Recurrent upper respiratory infections or pneumonia should trigger immediate immunoglobulin measurement. 4

Immediate Management

Initiate immunoglobulin replacement therapy and aggressive antimicrobial treatment immediately upon diagnosis without waiting for complete genetic workup. 1, 5

Immunoglobulin Replacement Therapy

• Intravenous immunoglobulin (IVIG): 0.4-0.6 g/kg every 3-4 weeks, targeting trough IgG levels >500-600 mg/dL (some experts recommend >800-1000 mg/dL for patients with chronic lung disease) 1, 2

• Subcutaneous immunoglobulin (SCIG): provides more stable IgG levels with fewer systemic reactions 2

• Monitor IgG trough levels monthly initially, then every 6-12 months once stable 6, 2

• Adjust dosing based on clinical response (infection frequency) rather than solely on IgG levels, as persistent infections correlate with severe memory B-cell defects, not just trough levels 4

Antimicrobial Management

• Treat acute infections aggressively with appropriate antibiotics targeting Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma, and Ureaplasma species—the most common respiratory pathogens in CVID 1

• Consider antibiotic prophylaxis for patients with frequent breakthrough infections (recurrent sinusitis, otitis media, bronchitis) despite adequate IgG replacement. This may be needed for months, years, or permanently. 1

• For chronic diarrhea, evaluate and treat Giardia lamblia, Campylobacter jejuni, Salmonella, and chronic viral enteritis (CMV, norovirus, parechovirus). Giardiasis and Campylobacter infections are significantly more frequent in patients with undetectable IgA. 1, 4

Monitoring for Complications

CVID has two distinct phenotypes: infection-predominant versus inflammatory/autoimmune-predominant. The latter carries worse prognosis. 7

Pulmonary Complications (Monitor Every 6-12 Months)

• Bronchiectasis develops in 10-20% of patients and is associated with frequent bronchitis/pneumonia. Obtain baseline chest CT and repeat if symptoms worsen. 1, 7

• Granulomatous and lymphocytic interstitial lung disease (GLILD) occurs in ~10% of patients, frequently with splenomegaly and diffuse adenopathy. GLILD is associated with increased mortality. 1

• Pulmonary function tests should be performed regularly to detect progressive lung disease early 1

Gastrointestinal Complications (20-25% of Patients)

• Chronic gastritis with or without pernicious anemia 1
• Lymphoid nodular hyperplasia, villous atrophy, inflammatory bowel disease 1
• Liver disease: 40% have abnormal liver function tests; nodular regenerative hyperplasia leading to portal hypertension is most common 1

Autoimmune Complications (20% Overall Prevalence)

• Autoimmune cytopenias (immune thrombocytopenic purpura, autoimmune hemolytic anemia) occur in 11-12% of patients and are the most common autoimmune manifestations 1, 7

• Treat autoimmune complications as in immunocompetent patients, using corticosteroids, immunosuppressants, or rituximab as indicated 1

Malignancy Surveillance

• Lymphoproliferative disease and lymphoma risk is significantly increased. Maintain vigilance with physical examination for lymphadenopathy and splenomegaly. 1, 7

• Gastric cancer risk is elevated; consider periodic endoscopic surveillance in patients with chronic gastritis 7

Critical Pitfalls to Avoid

• Do not delay immunoglobulin replacement while awaiting genetic testing or complete immunologic workup. The immediate infection risk outweighs diagnostic delays. 2

• Do not diagnose CVID in children under 4 years old, as transient hypogammaglobulinemia of infancy can present similarly but resolves spontaneously 1

• Do not rely solely on IgG levels to assess treatment adequacy. Infection frequency is the primary therapeutic endpoint. 4

• Recognize that patients lacking IgA may develop anti-IgA antibodies, increasing anaphylaxis risk with blood products. Use IgA-depleted products if transfusion is needed. 2

• Do not confuse CVID with isolated IgG deficiency. CVID patients have lower IgG levels, greater vaccine unresponsiveness, lower memory B cells, lower CD4 counts, and significantly higher rates of bronchiectasis and non-infectious complications. 8

• Do not overlook gastroesophageal reflux disease (GERD) as a contributor to chronic sinusitis refractory to conventional therapy. Consider evaluation and treatment with proton-pump inhibitors. 1

Advanced Therapeutic Considerations

• Hematopoietic stem cell transplantation should be considered for patients with malignancy or severe organ damage (end-stage lung disease, liver failure) refractory to conventional therapy 1

• Lung transplantation has been performed in select patients with life-threatening chronic lung disease, though experience is limited 1