What are the diagnostic criteria and treatment options for Common Variable Immunodeficiency (CVID)?

Common Variable Immunodeficiency (CVID) Diagnosis and Treatment

Diagnostic Criteria

CVID should be diagnosed in patients older than 4 years with low IgG and IgA levels, impaired antibody responses to both protein and polysaccharide antigens, and exclusion of other causes of primary or secondary immunodeficiency. 1

Required Laboratory Findings

• 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 have less than 3% B cells among peripheral blood lymphocytes) 1

Essential Exclusions Before Diagnosis

You must exclude other primary causes of agammaglobulinemia before confirming CVID 1:

• X-linked agammaglobulinemia (XLA) 2
• X-linked lymphoproliferative disease (XLP1 and XLP2) 2
• Immunoglobulin class-switch defects 2
• Good syndrome 2
• Myelodysplasia with hypogammaglobulinemia 2

Genetic Testing Considerations

While genetic mutations are identified in approximately 25% of CVID cases in non-consanguineous populations, a genetic diagnosis is not required for CVID diagnosis 3. However, when a causative mutation is identified, patients are reclassified as having a CVID-like disorder rather than CVID 3.

Common genetic mutations include 2:

• TNFRSF13B (TACI) mutations (approximately 10% of patients) 2
• LRBA deficiency 2
• PIK3CD gain-of-function mutations 2
• PIK3R1 mutations 2
• NFKB1 deficiency 2
• Mutations in CD19, CD20, CD21, CD81, BAFFR 2

B-Cell Subset Analysis

The EUROclass classification system based on B-cell subsets can help predict clinical phenotypes 1:

• Decreased 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 associates with lymphadenopathy 1

Common Diagnostic Pitfall

Diagnostic delay averages 10.5 years in adult-onset CVID 4. The mean age at diagnosis is 43 years, indicating that clinicians often fail to consider CVID in adults with recurrent infections 4.

Treatment Options

Immunoglobulin Replacement Therapy (Primary Treatment)

Regular intravenous or subcutaneous immunoglobulin replacement therapy is the cornerstone of CVID treatment and significantly reduces the frequency and severity of infections 1.

Standard dosing protocol 1:

• Dose: 0.5 g/kg every 3-4 weeks
• Target IgG trough levels: 8-11 g/L

Both IVIG and subcutaneous immunoglobulin (scIG) are effective treatment modalities 5. Regular infusions every 3 weeks substantially reduce pneumonic episodes 4.

Antimicrobial Management

CVID should be managed aggressively with antimicrobials in addition to IgG replacement 2.

Even with adequate IgG replacement that prevents invasive bacterial infections like pneumonia, many patients continue to have recurrent sinusitis, otitis media, and bronchitis 2. These patients often benefit from antibiotic prophylaxis added to their maintenance regimen for months, years, or permanently 2.

Common pathogens include 1:

• Encapsulated bacteria (nontypeable H. influenzae, S. pneumoniae)
• Atypical bacteria (Mycoplasma, Ureaplasma species)
• Viral pathogens (particularly rhinovirus)

Pulmonary Monitoring and Management

Careful attention to pulmonary status is critical, as noninfectious chronic pulmonary disease occurs in nearly 30% of patients and is associated with reduced survival 2.

Key pulmonary complications requiring surveillance 2:

• Bronchiectasis (10-20% of patients) - more likely with frequent bronchitis and pneumonia
• Granulomatous and lymphocytic interstitial lung disease (GLILD) (approximately 10% of patients) - frequently accompanied by splenomegaly and diffuse adenopathy, associated with increased mortality
• Infectious lung disease (majority of patients)

Gastrointestinal Monitoring

Gastrointestinal status should be monitored regularly, as approximately 20-25% of patients develop GI complications 2.

Common GI manifestations include 2:

• Chronic gastritis with or without pernicious anemia
• Lymphoid nodular hyperplasia
• Villous atrophy
• Inflammatory bowel disease
• Giardiasis, C. jejuni, and salmonellosis infections
• Chronic viral enteritis (CMV, norovirus, parechovirus)

Approximately 40% of patients have abnormal liver function tests, with alkaline phosphatase elevation being most frequent 2. Nodular regenerative hyperplasia leading to nonicteric portal hypertension is the most common chronic liver disease in CVID 2.

Autoimmune Disease Surveillance

Vigilance for autoimmune diseases should be maintained during follow-up, as the overall prevalence is approximately 20% 2. The spectrum of autoimmune diseases is broad, with autoimmune cytopenias being particularly common 2.

Monitoring Requirements

Regular monitoring of IgG trough levels is essential to ensure adequate replacement therapy 1. Additionally, regular monitoring of blood counts and serum chemistry can detect potential adverse effects of immunoglobulin replacement therapy 1.

Critical Caveat

T-cell abnormalities are frequently found in CVID patients despite classification as predominantly humoral immunodeficiency 1, 6. When significant impairment of humoral immunity is observed, T-cell abnormalities should be evaluated, as they could indicate a component of combined immunodeficiency 1.