Common Variable Immune Deficiency Syndromes - CVID

Common variable immune deficiency (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 CVID diagnosis requires that the patient’s infection history, physical examination findings, family history, and laboratory data be taken into account to differentiate CVID from other immune disorders. 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 CVID-like conditions. Despite these advances, the genetic basis of CVID 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 CVID syndromes
    • The basis has remained relatively unchanged – delayed onset hypogammaglobulinemia with recurrent infections and poor antibody response to vaccines, unexplained by other diagnosis
  • Pan-American Group for Immunodeficiency and European Society for Immunodeficiencies (ESID) criteria for diagnosis of CVID (Conley, 1999)
    • Probable diagnosis of common variable immune deficiency (CVID)
      • 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 CVID
      • 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 CVID (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 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

  • CVID is largely a diagnosis of exclusion
    • Defined causes of hypogammaglobulinemia should be excluded
  • Initial testing
    • CBC with differential
      • CVID is often associated with granulocytopenia, lymphocytopenia, small platelets, thrombocytopenia
      • May indicate need to test for other immunodeficiency syndromes
    • Immunoglobulin (IgG, IgA, IgM) concentrations
      • IgG <4.5-5.0 g/L suggestive of CVID
      • 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 used as alternate criterion to low antibody response 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 hemochromocytosis
    • 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 cause can be identified in approximately 10% of patients
  • Useful for establishing diagnosis and supporting need for intravenous immune globulin therapy
  • Primary antibody deficiency gene panel testing
    • Includes tests for CVID-like conditions, as well as other antibody deficiency syndromes

Differential Diagnosis

  • Agammaglobulinemia or hypogammaglobulinemia
    • X-linked agammaglobulinemia
    • Autosomal recessive agammaglobulinemias
      • µ heavy-chain deficiency
      • Ig-alpha deficiency
      • Ig-beta deficiency
  • Other primary immunodeficiency disorders (International Union of Immunological Societies [IUIS], 2014)
    • B-cell and T-cell deficiency
    • Other defined immunodeficiency syndromes
    • Defects of innate immunity
    • Autoinflammatory disorders
    • Complement deficiencies
    • Diseases of immune dysregulation
    • Congenital defects of phagocyte numbers, function, or both
    • Immunodeficiency associated with autoantibodies
  • Secondary immunodeficiency syndromes
    • Human immunodeficiency syndrome
    • Chemotherapy/immunotherapy
    • Burns
    • Malnutrition
  • Malignancy

Screening

There is no standard consensus statement to define the indication for screening for CVID 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 individuals with a diagnosis of CVID
  • Monitoring of patients on IgG therapy
    • Monitor IgG yearly
      • Collect trough level immediately before scheduled infusion
      • Monthly monitoring may be indicated at initiation of therapy to identify 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

Background

Classification

While several phenotypes have been identified and discussed, a clinically relevant phenotype classification does not appear to have been established.

Epidemiology

  • Prevalence
    • 1:30,000-1:200,000 (Chapel, 2009; Park, 2008)
  • Age – bimodal peaks
    • Childhood – 6-10 years (Urschel, 2009)
    • 10-29 years
  • Sex – M:F, equal

Genetics

Genes Associated with Monogenic Forms of Common Variable Immune Deficiency (CVID)
Gene Inheritance Onset CVID Designation and/or Separate Entity
Genes Encoding Receptors and Ligands

ICOSa

AR

Infancy to adulthood

CVID1, ICOS deficiency

TNFRSF13Ba

AR

Early childhood to adulthood

CVID2, disease predisposing

TNFRSF13Ca

AR

Infancy to late adulthood

CVID4, disease predisposing

TNFSF12

AD

Infancy

CVID

CD19a

AR

Infancy to early childhood

CVID3

CD81a

AR

Infancy

CVID6

CR2a

AR

Early childhood to childhood

CVID7

MS4A1a

AR

Infancy

CVID5

CD27a

AR

Infancy to childhood

CD27 deficiency

IL21a

AR

Infancy

CVID11, IL-21 deficiency

IL21Ra

AD, AR

Infancy to childhood

IL-21 deficiency

LRBAa

AR

Infancy to childhood

CVID8, LRBA deficiency

CTLA4a

AD

Infancy to adulthood

CTLA-4 deficiency

Genes Encoding Intracellular Signaling Molecules

PRKCDa

AR

Infancy to early childhood

ALPS3 (formerly CVID9), PKCδ deficiency

PLCG2a

AD

Infancy to childhood

PLAID

NFKB2a

AD

Infancy to childhood

CVID10, NF-κB1 deficiency

NFKB1a

AD

Early childhood to adulthood

CVID12, NF-κB2 deficiency

PIK3CDa

AD

Infancy to early childhood

APDS

PIK3R1a

AD, AR

Infancy to childhood

APDS-like

VAV1a

AD

Adulthood

CVID with T-cell dysfunction, Vav1 deficiency

RAC2a

AD

Infancy to childhood

RAC2 deficiency

BLK

AD

Infancy

CVID13

IKZF1a

AD

Early childhood to late adulthood

CVID

IRF2BP2a

AD

Early childhood to childhood

CVID

aGenes included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication, ARUP test code 2011156

AD, autosomal dominant; AR,& autosomal recessive

Source: Adapted from Bogaert, 2016

Pathophysiology

  • Most individuals with CVID have a normal number of peripheral blood B cells
    • Reduced number of memory B cells identified by surface marker CD2​7
  • Low serum immunoglobulins associated with reduction of class-switched memory B cells (CD27+IgD-)
  • T-cell defects are rare in most cases of CVID

Clinical Presentation

  • Recurrent infection
    • Pyogenic bacteria – encapsulated organisms are frequent pathogens
      • Fungal, viral pathogens uncommon
    • Sinusitis
    • Otitis media
    • Respiratory tract infections
      • Pneumonia
      • Chronic bronchitis
      • Bronchiectasis
  • Pulmonary disease, including obstructive, restrictive, and granulomatous disease
  • Impaired ability to produce antibodies after vaccination
  • Gastrointestinal manifestations, including malabsorption and intermittent or chronic diarrhea
  • Increased incidence of malignancy – 10- to 20-fold increased risk
  • Autoimmune disease occurs at increased rate
  • Lymphoid proliferation
    • Lymphadenopathy, splenomegaly, interstitial lung disease
    • Must be differentiated from lymphoproliferative disorders

ARUP Laboratory Tests

Primary 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

Assess B-cell subsets in immunodeficiencies

Supports diagnosis of common variable immune deficiency (CVID) 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+)

Detect presence of isohemagglutinins

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

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

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

Evaluate NK cells in patients with suspected immune deficiency

Identify pathogenic TNFRSF13B variants in individuals with CVID clinical phenotype or symptomatic selective IgA deficiency

Deep intronic variants, regulatory region variants, and large deletions and/or duplications are not detected

May detect variants of unknown significance

Rare diagnostic errors may occur due to primer- or probe-site variants

Variants in CD19, CD81, ICOS, MS4A1, TNFRSF13C, or other genes implicated in CVID will not be evaluated

Preferred genetic test for individual with clinical phenotype of primary antibody deficiency (eg, agammaglobulinemia, hyper-IgM syndrome, or CVID)

Refer to Test Fact Sheet for complete list of genes tested

Refer to Test Fact Sheet for complete list of limitations

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

Evaluate patients with suspected immunodeficiency diseases, including severe combined immunodeficiency

Primarily for evaluating T-cell 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

Not a first-level test; order after lymphocyte proliferation, mitogen induced, by flow cytometry has been performed

Evaluate ability of patient to produce antibody to pure polysaccharide vaccines (Pneumovax) or protein conjugated vaccines (Prevnar)

Evaluate the ability of a patient to produce antibody to pure protein vaccines after vaccination to rule out antibody deficiency

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

Related Tests

Detect presence of isohemaglutinins

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

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

Determine if fibrinogen deficiency is a potential cause of bleeding

Aid in diagnosis of iron deficiency anemia and iron overload

Monitor treatment of hemochromatosis

Medical Experts

Contributor

Delgado

Julio Delgado, MD, MS
Executive Vice President, ARUP Laboratories
Division Chief of Clinical Pathology, University of Utah and ARUP Laboratories
Professor of Clinical Pathology, University of Utah
Medical Director, Protein Immunology and Immunologic Flow Laboratories, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®