What is the diagnostic approach for Common Variable Immunodeficiency (CVID)?

Diagnostic Approach for Common Variable Immunodeficiency (CVID)

The diagnosis of CVID requires low serum IgG levels, low IgA and/or IgM levels, impaired specific antibody production to vaccines or infections, exclusion of other causes of hypogammaglobulinemia, and age >4 years, with normal or reduced B cell numbers in peripheral blood. 1

Initial Laboratory Evaluation

1. Immunoglobulin Quantification:

   • Measure serum IgG, IgA, and IgM levels
   • CVID diagnosis requires:
     • Low IgG (typically <450-500 mg/dL)
     • Low IgA and/or IgM (below 5th percentile for age) 2

2. Specific Antibody Response Testing:

   • Essential for diagnosis 2
   • Test antibody responses to:
     • Protein antigens (e.g., tetanus, diphtheria toxoids)
     • Polysaccharide antigens (e.g., pneumococcal vaccines)
   • Impaired responses to both types of antigens support CVID diagnosis

3. B-cell Enumeration:

   • Flow cytometry to quantify peripheral blood B cells (CD19+)
   • B-cell numbers may be normal or reduced (about 13% of patients have <3% B cells) 2
   • Normal B-cell numbers with hypogammaglobulinemia supports CVID over agammaglobulinemia

Advanced Diagnostic Workup

1. B-cell Subset Analysis:

   • Flow cytometry to evaluate B-cell subsets:
     • Switched memory B cells (IgD-CD27+)
     • Marginal zone B cells (IgD+CD27+)
     • Transitional B cells (IgMhighCD38high)
     • CD21low B cells 2
   • Classification schemes (Freiburg, Paris, EUROclass) correlate with clinical phenotypes:
     • Decreased switched memory B cells correlate with granulomatous disease
     • Expanded CD21low B cells correlate with splenomegaly
     • Expanded transitional B cells associate with lymphadenopathy 2

2. T-cell Assessment:

   • Although CVID is primarily a humoral immunodeficiency, T-cell abnormalities are common 2
   • Evaluate:
     • T-cell counts (CD4+, CD8+)
     • T-cell function (proliferative responses)
     • Regulatory T cells (Tregs)

3. Genetic Testing:

   • Whole exome sequencing (WES) to identify potential genetic defects 3
   • Common genetic mutations in CVID include:
     • LRBA
     • NFKB1
     • Other genes associated with CVID phenotype 3

Exclusion of Other Causes

1. Rule out secondary hypogammaglobulinemia:

   • Medications (e.g., certain anticonvulsants, immunosuppressants)
   • Protein loss (gastrointestinal, renal, lymphatic)
   • Malignancies (especially B-cell lymphomas)
   • Bone marrow failure 2

2. Rule out other primary immunodeficiencies:

   • X-linked agammaglobulinemia (BTK deficiency)
   • X-linked lymphoproliferative disease
   • Hyper-IgM syndromes 2

Clinical Correlation

1. Clinical History:

   • Recurrent sinopulmonary infections (bronchitis, pneumonia)
   • Gastrointestinal infections (Giardiasis, Campylobacter, Salmonella)
   • Viral enteritis (CMV, norovirus, parechovirus) 1
   • Onset of symptoms (CVID diagnosis not appropriate before age 4) 2

2. Assessment for Complications:

   • Pulmonary: bronchiectasis (10-20%), granulomatous and lymphocytic interstitial lung disease (10%)
   • Gastrointestinal: chronic gastritis, inflammatory bowel disease (20-25%)
   • Autoimmune disorders: cytopenias (11-12%), arthritis, psoriasis
   • Liver abnormalities (40%)
   • Lymphoproliferative disorders: lymphadenopathy, splenomegaly 1

Diagnostic Pitfalls and Considerations

1. Diagnostic Delay:

   • CVID diagnosis is often delayed worldwide 4
   • Early symptoms may be nonspecific (common respiratory infections)
   • Autoimmune or lymphoproliferative manifestations may divert attention from underlying immunodeficiency 4

2. Age Considerations:

   • CVID diagnosis should not be made before age 4 years 2
   • Transient hypogammaglobulinemia of infancy should be considered in younger children

3. Family History:

   • Assess for family history of immunodeficiencies
   • Family members may share the same B-cell abnormalities 5

4. Monitoring After Diagnosis:

   • Regular assessment of IgG trough levels
   • Pulmonary function testing
   • Radiologic studies based on clinical manifestations
   • Surveillance for malignancy (especially lymphoma and gastric carcinoma) 4, 6

Early diagnosis and prompt initiation of immunoglobulin replacement therapy are crucial to prevent permanent organ damage such as bronchiectasis and improve long-term outcomes in patients with CVID 1.