Common Variable Immune Deficiency Syndromes

Diagnosis

Indications for Testing

Chronic or recurrent infections occurring at two or more sites or severe in nature

Criteria for Diagnosis

• Several systems of diagnostic criteria are in use for common variable immune deficiency syndromes
  • The basis has remained relatively unchanged – delayed onset hypogammaglobulinemia with recurrent infections and poor antibody response to vaccines, unexplained by other diagnoses
• Pan-American Group for Immunodeficiency and European Society for Immunodeficiencies (ESID) criteria for diagnosis of common variable immune deficiency (Conley, 1999)
  • Probable diagnosis of common variable immune deficiency
    • Marked decrease (≥2 standard deviations [SDs] below mean for age, in male or female) in serum IgG AND IgA PLUS all of the following criteria
      • Onset of immunodeficiency >2 years
      • Absent antibodies and/or poor response to vaccines
      • Exclusion of other defined causes of hypogammaglobulinemia
  • Possible diagnosis of common variable immune deficiency
    • Marked decrease (≥2 SDs below mean for age, in male or female) in ONE of the major antibodies (IgA, IgG, and IgM) PLUS all of the following criteria
      • Onset of immunodeficiency >2 years
      • Absent antibodies and/or poor response to vaccines
      • Exclusion of other defined causes of hypogammaglobulinemia
• Clinical criteria for probable diagnosis of common variable immune deficiency (ESID, 2015)
  • At least one of the following
    • Increased susceptibility to infection
    • Autoimmune manifestations
    • Granulomatous disease
    • Unexplained polyclonal lymphoproliferation
    • Affected family member with antibody deficiency
  • AND marked decrease of IgG and marked decrease of IgA with or without low IgM levels (measure at least twice; <2 SDs from normal levels for age)
  • AND at least one of the following
    • Poor antibody response to vaccines and/or absent isohemagglutinins
    • Low switched memory B cells (<70% of age-related normal value)
  • AND secondary causes of hypogammaglobulinemia excluded
  • AND diagnosis established after the fourth year of life (symptoms may be present before)
  • AND no evidence of profound T-cell deficiency, defined as two of the following
    • CD4 numbers/μL
      • 2-6 years: <300
      • 6-12 years: <250
      • >12 years: <200
    • Naive CD4 percent
      • 2-6 years: <25%
      • 6-16 years: <20%
      • >16 years: <10%
    • T-cell proliferation absent

Laboratory Testing

• Common variable immune deficiency is largely a diagnosis of exclusion
  • Defined causes of hypogammaglobulinemia should be excluded
• Initial testing
  • CBC with differential
    • Common variable immune deficiency is often associated with granulocytopenia, lymphocytopenia, small platelets, and thrombocytopenia
    • May indicate need to test for other immunodeficiency syndromes
  • Immunoglobulin (IgG, IgA, IgM) concentrations
    • IgG <4.5-5.0 g/L suggestive of the disease
    • Must be accompanied by low IgA (<2 SDs below normal level), with or without low IgM
    • Elevated IgM suggests other syndromes
    • Reference ranges must be age-matched
  • B cell subset analysis
    • Low cell numbers of switched memory B cells are used as alternate criteria to low antibody responses to vaccines (ESID, 2015)
    • Cell numbers may be helpful in ruling out other diseases associated with recurrent infections
  • Vaccination response
    • Evaluate pre- and postvaccination IgG titers
    • Pneumococcal, diphtheria, tetanus, Haemophilus influenzae are commonly used
    • Limitations to each test type are known (eg, poorly immunogenetic, residual antibody after childhood immunization)
    • Evaluation of both protein (eg, tetanus) and polysaccharide (eg, pneumococcal polysaccharide) vaccines is recommended
  • T-cell and B-cell immunodeficiency profile testing (lymphocyte testing)
    • T-cell testing at minimum should include CD3, CD4, CD8, CD19, CD45RA, CD45RO, NK cell, and CD4:CD8 ratio
    • Severe deficiencies in T cells or B cells should initiate other disease evaluation
• Associated testing – may help identify alternate diagnosis
  • Monoclonal protein detection, characterization, and quantitation (serum protein and immunofixation electrophoresis)
    • Rule out monoclonal gammopathy
    • Recommended in all patients >15 years with symptoms of hypogammaglobulinemia
  • Chemistries
  • Qualitative IgG, IgA, and IgM
  • Ferritin: elevated concentrations may suggest hereditary hemochromatosis
  • Fibrinogen​

Genetic Testing

• Recommended for familial cases, complicated cases (eg, infectious phenotype combined with autoimmunity, granulomas, malignancy, or other signs of immune dysregulation)
  • Some monogenic forms may be amenable to additional therapeutic approaches (eg, lipopolysaccharide-responsive, beige-like anchor protein [LRBA] deficiency)
  • Currently, monogenic causes can be identified in approximately 10% of patients
• Useful for establishing a diagnosis and supporting the need for intravenous immune globulin therapy
• Primary antibody deficiency gene panel testing
  • Includes tests for conditions similar to common variable immune deficiency, as well as other antibody deficiency syndromes
  • See Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication for genes associated with common variable immune deficiency

Screening

There is no standard consensus statement to define the indication for screening for common variable immune deficiency or other PIDs; however, clinicians should maintain a high level of suspicion for these disorders in individuals with increased susceptibility to infection.

Monitoring

• Monitoring for autoimmune disorders and malignancy is recommended every 6-12 months in diagnosed individuals 
• Monitoring of patients on IgG therapy
  • Monitor IgG yearly
    • Collect trough level immediately before scheduled infusion
    • Monthly monitoring may be indicated at the initiation of therapy to identify an optimal dose
  • Yearly screening for hepatitis C in patients on IgG therapy is standard of care in European Union; testing for hepatitis A and B may be indicated periodically
  • Serum creatinine and liver tests are recommended every 6-12 months