Common Variable Immune Deficiency - CVID

Diagnosis

Indications for Testing

  • Chronic or recurrent infections

Criteria for Diagnosis

  • Significantly decreased levels of immunoglobulin G, A, or M with poor or absent antibody production
  • Exclusion of other causes of hypogammaglobulinemia

Laboratory Testing

  • Quantitative immunoglobulin levels by nephelometry
    • IgG, IgA – low, usually ≥2 standard deviations below age-related norms
    • IgM – sometimes low
    • B-cell memory and naïve panel
      • May be helpful in screening common variable immune deficiency (CVID)
  • T-cell and B-cell immunodeficiency profile testing (lymphocyte testing)
    • T-cell testing at minimum should include CD4, CD45RA, CD45RO, CD8, CD4:8 ratio, CD3, CD19, and NK cell
    • Severe deficiencies in T cells or B cells should initiate differential workup based on deficiency
  • Pneumococcal, diphtheria, tetanus vaccination – pre- and postvaccination IgG titers
    • Defective antibody production after vaccination supports diagnosis of CVID
    • Not necessary if severe immunoglobulin deficiency already detected on quantitative immunoglobulin testing
  • TACI sequencing – low yield (10% clinical sensitivity), but it can provide positive evidence for CVID that is diagnosed mainly as an exclusion
  • Other testing to consider in adults
    • 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

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 to 1/50,000
  • 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 ICOS, CD19, TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B), TNFRSF13C (BAFF-R)

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-)
    • Most individuals with high risk for splenomegaly and granulomatous disease show marked reduction of class-switched memory B cells

Clinical Presentation

  • Frequent delay in diagnosis – median 2-5 years
  • Individuals with CVID can be classified into two main disease phenotypes
    • Individuals presenting with infections
    • Individuals presenting with infections in addition to inflammatory and/or autoimmune disorders
  • Recurrent infection is hallmark
    • Pyogenic bacteria – encapsulated organisms are frequent pathogens
    • Sinusitis
    • Respiratory tract infections
  • Malabsorption, diarrhea
  • Increased incidence of malignancy
    • Predominantly lymphoreticular – especially B-cell lymphomas
    • 10-fold to 20-fold increased incidence
  • Increased incidence of autoimmune disease – 20% of patients
  • Benign lymphoid proliferation
    • 10-25% develop lymphadenopathy, splenomegaly
    • Must be differentiated from lymphoproliferative disorders
  • Individuals with CVID can be classified into two main disease phenotypes
    • Individuals presenting with infections
    • Individuals presenting with infections in addition to inflammatory and/or autoimmune disorders

Treatment

  • Intravenous immunoglobulin

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

Screen for CVID

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 (suppressor T cells), CD4: CD8 ratio, CD3 (total T cells), CD19 (B cells), NK cells

   
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

   
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
 

Severe deficiencies in T cells should initiate differential workup based on deficiency

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

Not necessary if immunoglobulin deficiency has already been detected

   
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

Not necessary if immunoglobulin deficiency has already been detected

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

Identify pathogenic TNFRSF13B mutations

Clinical sensitivity – 10%

   
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