Common Variable Immune Deficiency Syndromes - CVID

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • Chronic or recurrent infections

Criteria for Diagnosis

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
    • TNFRSF13B gene
      • Most common genetic variant
        • Low yield (≤10% clinical sensitivity for CVID)
    • Primary antibody deficiency gene panel testing
      • 20% clinical sensitivity for CVID

Differential Diagnosis

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
    • 1/25,000-60,000 Caucasians
    • 1/100,000 Japanese
  • Age – bimodal peaks
    • Childhood (<10 years)
    • 10-29 years
  • Sex – M:F, equal

Genetics

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
  • Hypogammaglobulinemia with impaired ability to produce antibodies after vaccination
  • Malabsorption, intermittent or chronic 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

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.

Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Follow Up

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

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

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

Streptococcus pneumoniae Antibodies, IgG (14 Serotypes) 0050725
Method: Quantitative Multiplex Bead Assay

Streptococcus pneumoniae Antibodies, IgG (23 Serotypes) 2005779
Method: Quantitative Multiplex Bead Assay

Streptococcus pneumoniae Antibodies, IgG (9 Serotypes) 2008919
Method: Quantitative Multiplex Bead Assay

Diphtheria & Tetanus Antibodies, IgG 0050595
Method: Quantitative Multiplex Bead Assay

Monoclonal Protein Detection Quantitation and Characterization, SPEP, IFE, IgA, IgG, IgM, Serum 0050615
Method: Qualitative Immunofixation Electrophoresis/Quantitative Capillary Electrophoresis/Quantitative Nephelometry

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

Limitations

Deep intronic mutations, regulatory region mutations, 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 mutations

Mutations in CD19, CD81, ICOS, MS4A1, TNFRSF13C, 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

Limitations

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

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley MEllen, Cunningham-Rundles C, Etzioni A, Franco JLuis, Gaspar B, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML K. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

General References

Ameratunga R, Woon S, Gillis D, Koopmans W, Steele R. New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin. Clin Exp Immunol. 2013; 174(2): 203-11. PubMed

Aslam A, Chapel H. Dissecting the group of common variable immunodeficiency disorders. Clin Infect Dis. 2009; 49(9): 1339-40. PubMed

Bonilla FA, Geha RS. Common variable immunodeficiency. Pediatr Res. 2009; 65(5 Pt 2): 13R-19R. PubMed

Brandt D, Gershwin E. Common variable immune deficiency and autoimmunity. Autoimmun Rev. 2006; 5(7): 465-70. PubMed

Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999; 93(3): 190-7. PubMed

Cunningham-Rundles C. The many faces of common variable immunodeficiency Hematology Am Soc Hematol Educ Program. 2012; 2012: 301-5. PubMed

ESID Registry Steering Committee. New clinical diagnosis criteria for the ESID Registry. European Society for Immunodeficiencies (ESID). Geneva, Switzerland [Last Revision May 2015; Accessed: Nov 2015]

Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014; 46(2): 154-68. PubMed

Ogershok PR, Hogan MBeth, Welch JE, Corder T, Wilson NW. Spectrum of illness in pediatric common variable immunodeficiency Ann Allergy Asthma Immunol. 2006; 97(5): 653-6. PubMed

Seidel MG. Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment. Blood. 2014; 124(15): 2337-44. PubMed

Urschel S, Kayikci L, Wintergerst U, Notheis G, Jansson A, Belohradsky BH. Common variable immunodeficiency disorders in children: delayed diagnosis despite typical clinical presentation J Pediatr. 2009; 154(6): 888-94. PubMed

Wilmott RW. Delayed diagnosis in common variable immunodeficiency. J Pediatr. 2009; 154(6): A1. PubMed

Wood PM. Primary antibody deficiency syndromes. Curr Opin Hematol. 2010; 17(4): 356-61. PubMed

Yong PL, Orange JS, Sullivan KE. Pediatric common variable immunodeficiency: immunologic and phenotypic associations with switched memory B cells Pediatr Allergy Immunol. 2010; 21(5): 852-8. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Chen K, Coonrod EM, Kumánovics A, Franks ZF, Durtschi JD, Margraf RL, Wu W, Heikal NM, Augustine NH, Ridge PG, Hill HR, Jorde LB, Weyrich AS, Zimmerman GA, Gundlapalli AV, Bohnsack JF, Voelkerding KV. Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet. 2013; 93(5): 812-24. PubMed

Gundlapalli AV, Scalchunes C, Boyle M, Hill HR. Fertility, pregnancies and outcomes reported by females with common variable immune deficiency and hypogammaglobulinemia: results from an internet-based survey J Clin Immunol. 2015; 35(2): 125-34. PubMed

Kuehn HSun, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW, Maffucci P, Pierce KR, Abbott JK, Voelkerding KV, South ST, Augustine NH, Bush JS, Dolen WK, Wray BB, Itan Y, Cobat A, Sorte HSørmo, Ganesan S, Prader S, Martins TB, Lawrence MG, Orange JS, Calvo KR, Niemela JE, Casanova J, Fleisher TA, Hill HR, Kumánovics A, Conley MEllen, Rosenzweig SD. Loss of B Cells in Patients with Heterozygous Mutations in IKAROS N Engl J Med. 2016; 374(11): 1032-43. PubMed

Margraf RL, Coonrod EM, Durtschi JD, Augustine NH, Voelkerding KV, Hill HR, Kumánovics A. TACI mutation p.Lys154Ter identified in Good Syndrome. Clin Immunol. 2013; 146(1): 10-2. PubMed

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Last Update: June 2016