Common Variable Immune Deficiency Syndromes - CVID

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

Indications for Testing

Chronic or recurrent infections occurring at 2 or more sites or severe in nature

Criteria for Diagnosis

  • Several systems of diagnostic criteria are in use for common variable immune deficiency (CVID) syndromes
    • Basis has remained relatively unchanged – delayed onset hypogammaglobulinemia with recurrent infections and poor antibody response to vaccines, unexplained by other diagnosis

Laboratory Testing

  • CVID is largely a diagnosis of exclusion
    • Defined causes of hypogammaglobulinemia should be excluded
  • Initial testing
    • CBC with differential
      • CVID is often associated with granulocytopenia, lymphocytopenia, small platelets, thrombocytopenia
      • May indicate need to test for other immunodeficiency syndromes
    • Immunoglobulin (IgG, IgA, IgM) concentrations
      • IgG <4.5-5.0 g/L suggestive of CVID
      • Must be accompanied by low IgA  (<2 standard deviations below normal level), with or without low IgM
      • Elevated IgM suggests other syndromes
      • Reference ranges must be age matched
    • B-cell memory and naive panel
      • Low cell numbers of switched memory B cells used as alternate criterion to low antibody response to vaccines  (ESID, 2015)
      • Cell numbers may be helpful in ruling out other diseases associated with recurrent infections
    • Vaccination response
      • Evaluate pre- and postvaccination IgG titers
      • Pneumococcal, diphtheria, tetanus, Haemophilus influenzae are commonly  used
      • Limitations to each test type are known (eg, poorly immunogenetic, residual antibody after childhood immunization)
      • Evaluation of both protein (eg, tetanus) and polysaccharide (eg, pneumococcal polysaccharide) vaccines is recommended
    • 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
  • Associated testing – may help identify alternate diagnosis
    • Monoclonal protein detection, characterization, and quantitation
      • Includes quantitative IgG, IgA, and IgM, along with serum protein and immunofixation electrophoresis
      • Rule out monoclonal gammopathy
      • Recommended in all patients >15 years with symptoms of hypogammaglobulinemia
    • Chemistries
    • Ferritin – elevated concentrations may suggest hereditary hemochromocytosis
    • Fibrinogen​

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, lipopolysaccharide-responsive, beige-like anchor protein [LRBA] deficiency)
    • Currently, monogenic cause can be identified in approximately 10% of patients
  • Useful for establishing diagnosis and supporting need for intravenous immune globulin therapy
  • Primary antibody deficiency gene panel testing
    • Includes tests for CVID-like conditions, as well as other antibody deficiency syndromes
    • 20% clinical sensitivity for CVID

Differential Diagnosis

  • Agammaglobulinemia or hypogammaglobulinemia
    • X-linked agammaglobulinemia
    • Autosomal recessive agammaglobulinemias
      • µ heavy-chain deficiency
      • Ig-alpha deficiency
      • Ig-beta deficiency
  • Other primary immunodeficiency disorders (International Union of Immunological Societies [IUIS], 2014)
    • B-cell and T-cell deficiency
    • Other defined immunodeficiency syndromes
    • Defects of innate immunity
    • Autoinflammatory disorders
    • Complement deficiencies
    • Diseases of immune dysregulation
    • Congenital defects of phagocyte numbers, function, or both
    • Immunodeficiency associated with autoantibodies
  • Secondary immunodeficiency syndromes
    • Human immunodeficiency syndrome
    • Chemotherapy/immunotherapy
    • Burns
    • Malnutrition
  • Malignancy

There is no standard consensus statement to define the indication for screening for common variable immune deficiency (CVID) or other primary immune deficiency syndromes; however, clinicians should maintain a high level of suspicion for these disorders in individuals with increased susceptibility to infection.

  • Monitoring for autoimmune disorders and malignancy is recommended every 6-12 months for individuals with a diagnosis of common variable immune deficiency (CVID)
  • Monitoring on IgG therapy
    • Monitor IgG yearly
      • Collect trough level immediately before scheduled infusion
      • Monthly monitoring may be indicated at initiation of therapy to identify optimal dose
    • Yearly screening for hepatitis C in patients on IgG therapy is standard of care in European Union; testing for hepatitis A and B may be indicated periodically
    • Serum creatinine and liver tests are recommended every 6-12 months

Common variable immune deficiency (CVID) is the most common clinically significant primary immunodeficiency disease (PID). Clinically, it is characterized by recurrent or chronic infections, especially of the sinopulmonary system, and carries an increased risk of autoimmune manifestations and malignancy. It is due to defective antibody production and hypogammaglobulinemia, with a late onset due to delayed antibody failure. There are a multitude of PIDs, and diagnosis of CVID depends on using the patient’s infection history, physical examination findings, family history, and laboratory data to differentiate it from other immune disorders. Early identification and initiation of treatment with intravenous and subcutaneous immunoglobulin can prevent major organ dysfunction.

Advances in genetic testing have made it possible to identify many monogenic forms of CVID-like conditions. Despite these advances, the genetic basis of CVID has not been completely identified, making it a diagnosis of exclusion and suggesting that it may be a polygenic condition in many patients.

Classification

While several phenotypes have been identified and discussed, a clinically relevant phenotype classification does not appear to have been established.

Epidemiology

  • Prevalence
    • 1:30,000-1:200,000 (Chapel, 2009; Park, 2008)
  • Age – bimodal peaks
    • Childhood – 6-10 years (Urschel, 2009)
    • 10-29 years
  • Sex – M:F, equal

Genetics

Pathophysiology

  • Most individuals with CVID have a normal number of peripheral blood B cells
    • Reduced number of memory B cells identified by surface marker CD2​7
  • 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

  • Recurrent infection
    • Pyogenic bacteria – encapsulated organisms are frequent pathogens
      • Fungal, viral pathogens uncommon
    • Sinusitis
    • Otitis media
    • Respiratory tract infections
  • Pulmonary disease, including obstructive, restrictive, and granulomatous disease
  • Impaired ability to produce antibodies after vaccination
  • Gastrointestinal manifestations, including malabsorption and intermittent or chronic diarrhea
  • Increased incidence of malignancy – 10- to 20-fold increased risk
  • Autoimmune disease occurs at increased rate
  • Lymphoid proliferation
    • Lymphadenopathy, splenomegaly, interstitial lung disease
    • 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) with 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

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 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 diagnosis of primary antibody deficiency

Guidelines

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

Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, Nelson RP, Orange JS, Routes JM, Shearer WT, Sorensen RU, Verbsky JW, Bernstein DI, Blessing-Moore J, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller D, Spector SL, Tilles S, Wallace D, Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136(5): 1186-205.e1-78. PubMed

Borte S, von Döbeln U, Hammarström L. Guidelines for newborn screening of primary immunodeficiency diseases. Curr Opin Hematol. 2013; 20(1): 48-54. PubMed

de Vries E, European Society for Immunodeficiencies (ESID) members. Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update. Clin Exp Immunol. 2012; 167(1): 108-19. PubMed

Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases. Third Edition. Immune Deficiency Foundation. Towson, MD [Accessed: Oct 2017]

Orange JS, Ballow M, Stiehm R, Ballas ZK, Chinen J, De La Morena M, Kumararatne D, Harville TO, Hesterberg P, Koleilat M, McGhee S, Perez EE, Raasch J, Scherzer R, Schroeder H, Seroogy C, Huissoon A, Sorensen RU, Katial R. Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2012; 130(3 Suppl): S1-24. PubMed

Picard C, Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Puck JM, Sullivan KE, Tang ML, Franco JL, Gaspar B. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015; 35(8): 696-726. PubMed

General References

Abolhassani H, Sagvand BT, Shokuhfar T, Mirminachi B, Rezaei N, Aghamohammadi A. A review on guidelines for management and treatment of common variable immunodeficiency. Expert Rev Clin Immunol. 2013; 9(6): 561-74; quiz 575. PubMed

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

Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br J Haematol. 2009; 145(6): 709-27. 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

Park MA, Li JT, Hagan JB, Maddox DE, Abraham RS. Common variable immunodeficiency: a new look at an old disease. Lancet. 2008; 372(9637): 489-502. 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

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Content Reviewed: 
August 2017

Last Update: August 2017