Common Variable Immune Deficiency Syndromes - CVID

Diagnosis

Indications for Testing

  • Chronic or recurrent infections

Criteria for Diagnosis

  • Current criteria for diagnosis of common variable immune deficiency (CVID) – European Society of Immunodeficiencies and Pan American Group for Immunodeficiency, 1999

    Criteria for Diagnosis of CVID (European Society of Immunodeficiencies and

    Pan American Group for Immunodeficiency, 1999)

    Probable Diagnosis of CVID

    Male or female with marked decrease (≥2 standard deviations (SD) below mean for age) in serum IgG AND IgA PLUS all below criteria

    • Onset of immunodeficiency >2 years of age
    • Absent antibodies and/or poor response to vaccines
    • Other defined causes of hypogammaglobulinemia have been excluded

    Possible Diagnosis of CVID

    Male or female with marked decrease (≥2 SD below the mean for age) in ONE of the major antibodies (IgA, IgG, and IgM) and all below criteria

    • Onset of immunodeficiency >2 years of age
    • Absent antibodies and/or poor response to vaccines
    • Other defined causes of hypogammaglobulinemia have been excluded
  • Clinical criteria for probable diagnosis of CVID (European Society for Immunodeficiencies [ESID], 2015)

    Clinical Criteria for Probable Diagnosis (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; <2SD of the normal levels for age)

    AND at least one of the following:

    • Poor antibody response to vaccines and/or absent isohemagglutinins (eg, absence of protective levels despite vaccination where defined)
    • Low switched memory B cells (<70% of age-related normal value)

    AND secondary causes of hypogammaglobulinemia excluded

    AND diagnosis established after 4th year of life (symptoms may be present before)

    AND no evidence of profound T cell deficiency, defined as two of the following:

    • CD4 numbers/microliter
      • 2-6 years of age – <300
      • 6-12 years of age – <250
      • >12 years of age – <200
    • Naïve CD4 percent
      • 2-6 years – <25%
      • 6-16 years – <20%
      • >16 years – <10%
    • T cell proliferation absent
    CVID
    Proposed criteria for diagnosis (Ameratunga, 2013)

    Proposed Criteria for Diagnosis (Ameratunga, 2013)

    Must meet all major criteria

    • >4 years of age
    • Hypogammaglobulinemia (IgG <5g/L for adults)
    • No other cause identified for immune defect

    Clinical symptoms directly attributable to in vivo failure of immune system (≥1 criteria)

    • Recurrent, severe, or unusual infections
    • Poor response to antibiotics
    • Breakthrough bacterial infections despite prophylactic antibiotics
    • Infections despite immunization with appropriate vaccine
    • Bronchiectasis and/or chronic sinus disease
    • Inflammatory disorders or autoimmunity

    Supportive laboratory evidence (≥3 criteria)

    • Concomitant deficiency or reduction of IgA (<0.8 g/L) and/or IgM (<0.4 g/L)
    • Presence of B cells but reduced memory B cell subsets and/or increased CD21 low subsets by flow cytometry
    • IgG3 deficiency (<0.2 g/L)
    • Impaired vaccine responses compared to age-matched controls
    • Absent antibodies (if not blood group AB)
    • Serological support for autoimmunity in section B (eg, positive Coombs’ test)
    • Sequence variations of genes predisposing to CVID (eg, TACI, BAFFR, MAH5)

    Presence of any one of relatively specific histological markers of CVID (not required for diagnosis but presence increases diagnostic certainty)

    • Lymphoid interstitial pneumonitis
    • Granulomatous disorder
    • Nodular regenerative hyperplasia of liver
    • Nodular lymphoid hyperplasia of gut
    • Absence of plasma cells on gut biopsy

Laboratory Testing

  • CVID is a diagnosis of exclusion
  • Consider the following based on clinical presentation
    • Quantitative immunoglobulin levels by nephelometry
      • Reduced concentrations required to define CVID
    • B-cell memory and naïve panel
      • May be helpful in ruling out other diseases associated with recurrent infections
    • 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
    • Vaccination response – pre- and postvaccination IgG titers
      • Pneumococcal, diphtheria, tetanus, Haemophilus influenzae may be used
      • Defective antibody production after vaccination supports diagnosis of CVID – may be low-normal in some patients with CVID
      • Unnecessary if severe immunoglobulin deficiency already detected on quantitative immunoglobulin testing
    • Monoclonal protein detection, characterization, and quantitation – includes quantitative IgG, IgA, and IgM, along with serum protein electrophoresis and immunofixation electrophoresis
      • Rule out monoclonal gammopathy
      • Recommended in all patients >15 years with symptoms of hypogammaglobulinemia
  • Genetic testing
    • TACI gene
      • Most common genetic variant
        • Low yield (≤10% clinical sensitivity)
    • Primary antibody deficiency gene panel testing
      • 20% clinical sensitivity
      • Includes CD19, CD81, CR2, ICOS, LRBA, MS4A1, NFKB2, PRKCD, TNFRSF13B, TNFRSF13C, VAV1 genes

Differential Diagnosis

Clinical Background

Common variable immune deficiency (CVID), the most common immunodeficiency disease, is characterized by recurrent or chronic infections resulting from defective antibody production and hypogammaglobulinemia.

Epidemiology

  • Incidence – estimates vary from 1/25,000-60,000
  • Age – bimodal peaks
    • Childhood (<10 years)
    • 10-29 years
  • Sex – M:F, equal

Genetics

  •  
    Common variable immune deficiency (CVID) syndrome genes

    Common Variable Immune Deficiency (CVID) Syndrome Genes

    Gene

    Inheritance*

    CVID Designation

    CD19

    AR

    CVID3

    CD81

    AR

    CVID6

    CR2 (CD21)

    AR

    CVID7

    IL21

    AR

    CVID11

    ICOS

    AR

    CVID1

    MS4A1 (CD20)

    AR

    CVID5

    LRBA

    AR

    CVID8

    NFKB2

    AR

    CVID10

    PRKCD

    AR

    ALPS3 (formerly CVID9)

    TNFRSF13B (TACI)

    AD or AR

    CVID2

    TNFRSF13C

    AD or AR

    CVID4

    VAV1

    AD

    CVID with T-cell dysfunction

    *AR = autosomal recessive; AD = autosomal dominant

Pathophysiology

  • Most individuals with CVID have normal number of peripheral blood B cells
    • B cells appear immature
    • Reduced number of memory B cells
      • Identified by surface marker CD27
  • 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

  • Frequent delay in diagnosis – median 2-5 years
  • Two main disease phenotypes
    • Infectious presentation
    • Infectious presentation combined with inflammatory and/or autoimmune disorders
  • Recurrent infection is hallmark of CVID
    • Pyogenic bacteria – encapsulated organisms are frequent pathogens
    • Sinusitis
    • Respiratory tract infections
  • Malabsorption, diarrhea
  • Increased incidence of malignancy – 10- to 20-fold increased risk
  • Increased incidence of autoimmune disease – 20% of patients
  • Benign lymphoid proliferation
    • 10-25% develop lymphadenopathy, splenomegaly
    • Must be differentiated from lymphoproliferative disorders

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry
Initial test in the 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) or suspected hypogammaglobulinemia

B-Cell Memory and Naive Panel 2008901
Method: Flow Cytometry

Useful for assessing primary B-cell immunodeficiency disorders

Panel  measures B cells (CD19+), total memory B cells (CD19+ CD27+), class switched memory B cells (CD19+ CD27+ IgD-), non-switched/marginal zone memory B cells (CD19+ CD27+ IgD+), and naive B cells (CD19+ CD27-IgD+)

   
Lymphocyte Subset Panel 6 - Total Lymphocyte Enumeration with CD45RA and CD45RO 0095862
Method: Quantitative Flow Cytometry

Useful for assessing primary T-cell immunodeficiency disorders

Test enumerates the 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

   
Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899
Method: Quantitative Flow Cytometry

Acceptable lymphocyte subset panel for the 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

   
Streptococcus pneumoniae Antibodies, IgG (14 Serotypes) 0050725
Method: Quantitative Multiplex Bead Assay
Confirm antibody production with pre- and postvaccination testing if severe immunoglobulin deficiency is not detected on quantitative immunoglobulin testing    
Diphtheria & Tetanus Antibodies, IgG 0050595
Method: Quantitative Multiplex Bead Assay
Confirm antibody production with pre- and postvaccination testing if severe immunoglobulin deficiency is not detected on quantitative immunoglobulin testing    
Monoclonal Protein Detection Quantitation and Characterization, SPEP, IFE, IgA, IgG, IgM, Serum 0050615
Method: Qualitative Immunofixation Electrophoresis/Quantitative Capillary Electrophoresis/Quantitative Nephelometry

Use to detect and quantify serum monoclonal protein to rule out plasma cell dyscrasia in patients with recurrent infection 

Components include serum protein electrophoresis, immunofixation electrophoresis, IgA, IgG, and IgM

   
TACI-Associated Common Variable Immunodeficiency (TNFRSF13B) Sequencing 2007569
Method: Polymerase Chain Reaction/Sequencing

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

Clinical sensitivity – ≤10%

No detection/identification of deep intronic mutations, regulatory region mutations, large deletions and/or duplications

May detect variants of unknown significance

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

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

 
Primary Antibody Deficiency Panel, Sequencing (35 Genes) and Deletion/Duplication (26 Genes)  2011156
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Preferred test for individuals with clinical phenotype of antibody deficiency (eg, agammaglobulinemia, CVID)

Refer to Additional Technical Information document for list of genes tested

Not determined or evaluated – mutations in genes not included on the panel; deep intronic and regulatory region mutations; breakpoints for large deletions/duplications; translocations

Deletions/duplications will not be detected in IKBKG, LRBA, LRRC8A, PIK3CD, PIK3R1, PLCG2, PRKCD, SH2D1A, or XIAP/BIRC4 gene

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of primary antibody deficiency