Common Variable Immune Deficiency Syndromes - CVID

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  • Pediatrics
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Indications for Testing

  • Chronic or recurrent infections

Criteria for Diagnosis

Laboratory Testing

  • CVID is largely a diagnosis of exclusion
  • Consider the following based on clinical presentation
    • Quantitative immunoglobulin levels
      • Reduced concentrations required to define CVID
    • B-cell memory and naive panel
      • One of the diagnostic criteria (ESID, 2015)
      • 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
      • May be omitted if severe immunoglobulin deficiency already detected on quantitative immunoglobulin testing (<100 mg/dL) and delaying IgG therapy would be harmful
      • Evaluation of both protein (eg, tetanus) and polysaccharide (eg, pneumococcal) vaccines is recommended
    • 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
    • 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, LRBA deficiency)
    • TNFRSF13B (TACI) 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 primary immunodeficiency disease, is characterized by recurrent or chronic infections resulting from defective antibody production and hypogammaglobulinemia.


  • Prevalence
    • 1:10,000-1:100,000
  • Age – bimodal peaks
    • Childhood – 6-10 years (Urschel, 2009)
    • 10-29 years
  • Sex – M:F, equal



  • Most individuals with CVID have normal number of peripheral blood B cells
    • 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 about 5 years
  • Two main disease phenotypes
    • Infectious presentation
    • Infectious presentation combined with inflammatory and/or autoimmune/granulomatous/malignant disorders
  • Recurrent infection
    • Pyogenic bacteria – encapsulated organisms are frequent pathogens
      • Fungal, viral pathogens uncommon
    • Sinusitis
    • Otitis media
    • Respiratory tract infections
  • Pulmonary – includes obstructive, restrictive, and granulomatous disease
  • 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
  • Benign lymphoid proliferation
    • Lymphadenopathy and splenomegaly
    • Must be differentiated from lymphoproliferative disorders


Indications for Testing

  • Refer to Diagnosis section

Criteria for Diagnosis

  • Refer to Diagnosis section

Laboratory Testing

  • Refer to Diagnosis section

Differential Diagnosis



  • Prevalence
    • Less common in children than adults
  • Age – bimodal peaks
    • Childhood – 6-10 years (Urschel, 2009)
    • 10-29 years
  • Sex – M:F, equal

Clinical Presentation

  • Often have delayed diagnosis (just like adults)
  • Most commonly appear chronically ill with failure to thrive
  • Pulmonary
    • Chronic cough
    • Bronchiectasis
    • Granulomatous lung disease
  • Recurrent infections
    • Pyogenic
    • Upper and lower respiratory tract
      • Sinusitis, otitis media, pneumonia
    • Gastrointestinal – G. lamblia, H. pylori, salmonella spp
    • Meningitis
    • Pyelonephritis
  • Allergic disease
    • Asthma
    • Eczema
  • Autoimmune disease
  • Malignancy
    • Unclear if associated with increased risk of developing malignancy
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


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

Isohemagglutinin Titer, IgG and IgM 2000280
Method: Hemagglutination

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

Natural Killer Cell and Natural Killer T-Cell Panel 2013805
Method: Semi-Quantitative Flow Cytometry

Natural Killer Cells Enumeration 0092404
Method: Quantitative Flow Cytometry

Lymphocyte Antigen and Mitogen Proliferation Panel 0096056
Method: Cell Culture

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


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


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


Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar B, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML. 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

Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena T, Espinosa-Rosales FJ, Hammarström L, Nonoyama S, Quinti I, Routes JM, Tang ML, Warnatz K. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders J Allergy Clin Immunol Pract. 2016; 4(1): 38-59. PubMed

General References

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

Bogaert DJ, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016; 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, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients Clin Immunol. 1999; 92(1): 34-48. 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 [Latest Version Aug 2016; Accessed: Jan 2017]

Gathmann B, Mahlaoui N, CEREDIH, Gérard L, Oksenhendler E, Warnatz K, Schulze I, Kindle G, Kuijpers TW, Dutch WID, van Beem RT, Guzman D, Workman S, Soler-Palacín P, De Gracia J, Witte T, Schmidt RE, Litzman J, Hlavackova E, Thon V, Borte M, Borte S, Kumararatne D, Feighery C, Longhurst H, Helbert M, Szaflarska A, Sediva A, Belohradsky BH, Jones A, Baumann U, Meyts I, Kutukculer N, Wågström P, Galal NM, Roesler J, Farmaki E, Zinovieva N, Ciznar P, Papadopoulou-Alataki E, Bienemann K, Velbri S, Panahloo Z, Grimbacher B, European Society for Immunodeficiencies Registry Working Party. Clinical picture and treatment of 2212 patients with common variable immunodeficiency J Allergy Clin Immunol. 2014; 134(1): 116-26. PubMed

Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, Zhang Y, Liu Z, Fritz JM, Marsh R, Husami A, Kissell D, Nortman S, Chaturvedi V, Haines H, Young LR, Mo J, Filipovich AH, Bleesing JJ, Mustillo P, Stephens M, Rueda CM, Chougnet CA, Hoebe K, McElwee J, Hughes JD, Karakoc-Aydiner E, Matthews HF, Price S, Su HC, Rao K, Lenardo MJ, Jordan MB. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy Science. 2015; 349(6246): 436-40. PubMed

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

Ogershok PR, Hogan MB, 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®

Buchbinder D, Baker R, Lee YN, Ravell J, Zhang Y, McElwee J, Nugent D, Coonrod EM, Durtschi JD, Augustine NH, Voelkerding KV, Csomos K, Rosen L, Browne S, Walter JE, Notarangelo LD, Hill HR, Kumánovics A. Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders J Clin Immunol. 2015; 35(2): 119-24. PubMed

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 HS, 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 HS, Ganesan S, Prader S, Martins TB, Lawrence MG, Orange JS, Calvo KR, Niemela JE, Casanova J, Fleisher TA, Hill HR, Kumánovics A, Conley ME, 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

Medical Reviewers

Last Update: March 2017