Common Variable Immune Deficiency - CVID

Diagnosis

Indications for Testing

  • Chronic or recurrent infections

Criteria for Diagnosis (European Society of Immunodeficiencies and Pan American Group for Immunodeficiency 1999)

  • Significantly decreased levels of immunoglobulin G, A, or M – ≥2 standard deviations below mean
  • Poor or absent antibody production – impaired vaccine responses
  • Exclusion of other causes of hypogammaglobulinemia
  • Age of onset >2 years

Laboratory Testing

  • Common variable immune deficiency (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
    • Consider 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
  • Molecular genetic testing
    • TACI gene sequencing – low yield (10% clinical sensitivity), but it can provide positive evidence for CVID if mutations are detected
    • Panel testing for primary antibody deficiency
      • 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 1/25,000-50,000
  • Age – bimodal peaks
    • Childhood (<10 years)
    • 10-29 years
  • Sex – M:F, equal

Risk Factors

  • Genetic defect – molecular defects have been identified in only 20% of cases
    • Genes include ICD19, CD81, CR2, ICOS, LRBA, MS4A1, NFKB2, PRKCD, TNFRSF13B, TNFRSF13C, VAV1

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-)

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 for suspected primary immune deficiency  

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 accessing primary B-cell immunodeficiency disorders

Panel measures B cells (CD19+); total memory B cells (CD19+CD27+); class-switched memory B cells (CD19+CD27+IgD-); nonswitched/marginal-zone memory B cells (CD19+CD27+IgD+); and naïve 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 enumerates the percent and absolute cell count of lymphocyte subsets in whole blood 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
  • 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

Clinical sensitivity – 10%

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

Preferred test for individuals with clinical phenotype of antibody deficiency (eg, agammaglobulinemia, common variable immunodeficiency) 

Genes sequenced –  ADA, AICDA, ATM, BLNK, BTK, CD19, CD40, CD40LG, CD79A, CD79B, CD81, CR2, ICOS, IGHM, IGLL1, IKBKG, LRBA, LRRC8A, MRE11A, MS4A1, NBN/NBS1, NFKB2, NFKBIA, PIK3CD, PIK3R1, PLCG2, PRKCD, PTPRC, RAG2, SH2D1A, TNFRSF13B, TNFRSF13C, UNG, VAV1, XIAP/BIRC4

Genes analyzed for deletions/duplications – ADA, AICDA, ATM, BLNK, BTK, CD19, CD40, CD40LG, CD79A, CD79B, CD81, CR2, ICOS, IGHM, IGLL1, MRE11A, MS4A1, NBN/NBS1, NFKB2, NFKBIA, PTPRC, RAG2, TNFRSF13B, TNFRSF13C, UNG, VAV1

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

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
B-Cell Immunodeficiency Profile 0095940
Method: Quantitative Flow Cytometry

Useful in supporting diagnosis of primary B-cell immunodeficiency disorders, including bare lymphocyte syndrome and agammaglobulinemia

Measures circulating B-cells (CD19), their surface immunoglobulins (Total Ig, IgG, IgD, IgM, and IgA) and a common HLA class II antigen