Common variable immune deficiency, or CVID, is the most common clinically significant primary immunodeficiency disease (PID). Clinically, it is characterized by recurrent or chronic infections, especially of the sinopulmonary system, and carries an increased risk of autoimmune manifestations and malignancy. It is due to defective antibody production and hypogammaglobulinemia with a late onset as a result of delayed antibody failure. There is a multitude of PIDs, and a diagnosis of common variable immune deficiency requires that the patient’s infection history, physical examination findings, family history, and laboratory data be taken into account. Early identification and initiation of treatment with intravenous and subcutaneous immunoglobulin can prevent major organ dysfunction.
Advances in genetic testing have made it possible to identify many monogenic forms of similar conditions. Despite these advances, the genetic basis of common variable immune deficiency has not been completely identified, making it a diagnosis of exclusion and suggesting that it may be a polygenic condition in many patients.
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
- 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
- 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
- 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
- Probable diagnosis of common variable immune deficiency
- 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
- CD4 numbers/μL
- At least one of the following
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
- CBC with differential
- 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
- Monoclonal protein detection, characterization, and quantitation (serum protein and immunofixation electrophoresis)
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
- Monitor IgG yearly
ARUP Laboratory Tests
Initial test in workup of immunoglobulin disorders
Order in conjunction with serum protein electrophoresis and immunofixation to rule out plasma cell dyscrasia in adults and older children (>15 years) with suspected hypogammaglobulinemia
Quantitative Immunoturbidimetry
Assess B-cell subsets in immunodeficiencies
Supports diagnosis of common variable immune deficiency and helps predict clinical phenotype
Assess B-cell reconstitution after bone marrow or hematopoietic stem cell transplantation
Not recommended for rituximab monitoring; refer to B-cell CD20 expression
Measures B cells (CD19+), total memory B cells (CD19+ CD27+), class-switched memory B cells (CD19+ CD27+ IgD-IgM-), nonswitched/marginal zone memory B cells (CD19+ CD27+ IgD+IgM+), and naive B cells (CD19+ CD27-IgD+)
Flow Cytometry
Detect presence of isohemagglutinins
Hemagglutination
Useful for assessing primary T-cell immunodeficiency disorders
Test enumerates percent and absolute cell count of lymphocyte subsets in whole blood for CD4 (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD4:CD8 ratio, CD3 (total T cells), CD19 (B cells), NK cells
Quantitative Flow Cytometry
Acceptable lymphocyte subset panel for investigation of primary immunodeficiency disorders
Test includes percentage and absolute counts for CD2, CD3 (total T cells), HLA-DR, CD4 (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD19 (B cells), NK cells, and CD4:CD8 ratio
Quantitative Flow Cytometry
Evaluate NK- and NKT-cell subsets
Panel includes
- Pct CD3-CD16-/+CD56br/dim (total NK cells)
- Abs CD3-CD16-/+CD56br/dim (total NK cells)
- Pct CD3-CD16+CD56dim (cytotoxic NK cells)
- Abs CD3-CD16+CD56dim (cytotoxic NK cells)
- Pct CD3-CD16-CD56br (cyto secreting NK)
- Abs CD3-CD16-CD56br (cyto secreting NK)
- Pct CD3-CD57+ (CD57 NK cells)
- Abs CD3-CD57+ (CD57 NK cells)
- Pct CD3+CD56+ (CD56 NKT cells)
- Abs CD3+CD56+ (CD56 NKT cells)
- Pct CD3+CD57+ (CD57 NKT cells)
- Abs CD3+CD57+ (CD57 NKT cells)
- Pct CD45+CD3+ (T cells)
- Abs CD45+CD3+ (T cells)
- Pct CD45+CD3- (Non T cells)
- Abs CD45+CD3- (Non T cells)
- Natural killer T-cell panel interpretation
Semi-Quantitative Flow Cytometry
Evaluate NK cells in patients with suspected immune deficiency
Quantitative Flow Cytometry
Preferred genetic test for individual with clinical phenotype of primary antibody deficiency (eg, agammaglobulinemia, hyper-IgM syndrome, or common variable immune deficiency)
Refer to Test Fact Sheet for complete list of genes tested
Refer to Test Fact Sheet for complete list of limitations
Massively Parallel Sequencing/Sequencing
Evaluate patients with suspected immunodeficiency diseases, including severe combined immunodeficiency
Cell Culture
Evaluate ability of patient to produce antibody to pure polysaccharide vaccines (Pneumovax) or protein conjugated vaccines (Prevnar)
Quantitative Multiplex Bead Assay
Quantitative Multiplex Bead Assay
Quantitative Multiplex Bead Assay
Evaluate the ability of a patient to produce antibody to pure protein vaccines after vaccination to rule out antibody deficiency
Quantitative Multiplex Bead Assay
Use to assess immunocompetence following Neisseria meningitidis vaccination
To assess suspected immunodeficiency, use pre- and postvaccination serology
Quantitative Multiplex Bead Assay
Use to detect and quantify serum monoclonal protein
Aid in diagnosis and management of multiple myeloma and related disorders
Components include serum protein electrophoresis and immunofixation electrophoresis
Qualitative Immunofixation Electrophoresis/Quantitative Capillary Electrophoresis/Colorimetry
Detect presence of isohemaglutinins
Hemagglutination
Hemagglutination
Primarily for evaluating recall antigen responses in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies
Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy
Do not order for patients younger than 3 months unless clinical history of candidiasis is present
Cell Culture
Primarily for evaluating lymphocyte function in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies
Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy
Cell Culture
Determine if fibrinogen deficiency is a potential cause of bleeding
Electromagnetic Mechanical Clot Detection
Aid in diagnosis of iron deficiency anemia and iron overload
Monitor treatment of hemochromatosis
Quantitative Chemiluminescent Immunoassay
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