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Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults

Authors
Sam Ahn, MD
Charlotte Cunningham-Rundles, MD, PhD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Anna M Feldweg, MD

INTRODUCTION

Common variable immunodeficiency (CVID, MIM# 240500) is a primary immunodeficiency disorder characterized by impaired B cell differentiation with defective immunoglobulin production. It is the most prevalent form of severe antibody deficiency affecting both children and adults. "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent infections, chronic lung disease, autoimmune disorders, gastrointestinal disease, and a heightened susceptibility to lymphoma.

CVID is not a single disease, but rather a collection of hypogammaglobulinemia syndromes resulting from many genetic defects. In a small subset of patients, specific molecular defects have been identified, although in most cases these causes are, as of yet, unknown.

The clinical manifestations, epidemiology, evaluation, and diagnosis of CVID will be discussed here, with a focus on presentation in adult patients. Issues that are particularly relevant to the clinical manifestations and diagnosis in children are reviewed separately. The pathogenesis and treatment in adults are also presented separately. (See "Common variable immunodeficiency in children" and "Pathogenesis of common variable immunodeficiency" and "Treatment and prognosis of common variable immunodeficiency".)

DEFINITION

Common variable immunodeficiency (CVID) is defined by the following [1]:

Markedly reduced serum concentrations of immunoglobulin G (IgG), in combination with low levels of immunoglobulin A (IgA) and/or immunoglobulin M (IgM)

                                        

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Literature review current through: Nov 2016. | This topic last updated: Mon Apr 25 00:00:00 GMT+00:00 2016.
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References
Top
  1. 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; 93:190.
  2. Hammarström L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 2000; 120:225.
  3. Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med 1993; 86:31.
  4. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 1999; 92:34.
  5. Oksenhendler E, Gérard L, Fieschi C, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis 2008; 46:1547.
  6. Gathmann B, Grimbacher B, Beauté J, et al. The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008. Clin Exp Immunol 2009; 157 Suppl 1:3.
  7. Gathmann B, Goldacker S, Klima M, et al. The German national registry for primary immunodeficiencies (PID). Clin Exp Immunol 2013; 173:372.
  8. Gathmann B, Mahlaoui N, CEREDIH, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol 2014; 134:116.
  9. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 2012; 119:1650.
  10. Urschel S, Kayikci L, Wintergerst U, et al. Common variable immunodeficiency disorders in children: delayed diagnosis despite typical clinical presentation. J Pediatr 2009; 154:888.
  11. Spickett GP, Farrant J, North ME, et al. Common variable immunodeficiency: how many diseases? Immunol Today 1997; 18:325.
  12. Cunningham-Rundles C. Clinical and immunologic analyses of 103 patients with common variable immunodeficiency. J Clin Immunol 1989; 9:22.
  13. Sneller MC, Strober W, Eisenstein E, et al. NIH conference. New insights into common variable immunodeficiency. Ann Intern Med 1993; 118:720.
  14. JANEWAY CA, APT L, GITLIN D. Agammaglobulinemia. Trans Assoc Am Physicians 1953; 66:200.
  15. Webster ADB. Common Variable Immunodeficiency. Immunol Allergy Clin North Am 2001; 21:1.
  16. Esolen LM, Fasano MB, Flynn J, et al. Pneumocystis carinii osteomyelitis in a patient with common variable immunodeficiency. N Engl J Med 1992; 326:999.
  17. Kaczmarski RS, Webster AD, Moxham J, et al. CD4+ lymphocytopenia due to common variable immunodeficiency mimicking AIDS. J Clin Pathol 1994; 47:364.
  18. Webster AD, Taylor-Robinson D, Furr PM, Asherson GL. Mycoplasmal (ureaplasma) septic arthritis in hypogammaglobulinaemia. Br Med J 1978; 1:478.
  19. Roifman CM, Rao CP, Lederman HM, et al. Increased susceptibility to Mycoplasma infection in patients with hypogammaglobulinemia. Am J Med 1986; 80:590.
  20. Busse PJ, Farzan S, Cunningham-Rundles C. Pulmonary complications of common variable immunodeficiency. Ann Allergy Asthma Immunol 2007; 98:1.
  21. Kainulainen L, Suonpää J, Nikoskelainen J, et al. Bacteria and viruses in maxillary sinuses of patients with primary hypogammaglobulinemia. Arch Otolaryngol Head Neck Surg 2007; 133:597.
  22. Onbaşi K, Günşar F, Sin AZ, et al. Common variable immunodeficiency (CVID) presenting with malabsorption due to giardiasis. Turk J Gastroenterol 2005; 16:111.
  23. Sawatzki M, Peter S, Hess C. Therapy-resistant diarrhea due to Giardia lamblia in a patient with common variable immunodeficiency disease. Digestion 2007; 75:101.
  24. Washington K, Stenzel TT, Buckley RH, Gottfried MR. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol 1996; 20:1240.
  25. Lai Ping So A, Mayer L. Gastrointestinal manifestations of primary immunodeficiency disorders. Semin Gastrointest Dis 1997; 8:22.
  26. Khodadad A, Aghamohammadi A, Parvaneh N, et al. Gastrointestinal manifestations in patients with common variable immunodeficiency. Dig Dis Sci 2007; 52:2977.
  27. van de Ven AA, Douma JW, Rademaker C, et al. Pleconaril-resistant chronic parechovirus-associated enteropathy in agammaglobulinaemia. Antivir Ther 2011; 16:611.
  28. Woodward JM, Gkrania-Klotsas E, Cordero-Ng AY, et al. The role of chronic norovirus infection in the enteropathy associated with common variable immunodeficiency. Am J Gastroenterol 2015; 110:320.
  29. Franz A, Webster AD, Furr PM, Taylor-Robinson D. Mycoplasmal arthritis in patients with primary immunoglobulin deficiency: clinical features and outcome in 18 patients. Br J Rheumatol 1997; 36:661.
  30. Hill LE. Hypogammaglobulinaemia in the United Kingdom. 3. Clinical features of hypogammaglobulinaemia. Spec Rep Ser Med Res Counc (G B) 1971; 310:9.
  31. Kainulainen L, Varpula M, Liippo K, et al. Pulmonary abnormalities in patients with primary hypogammaglobulinemia. J Allergy Clin Immunol 1999; 104:1031.
  32. Cadranel J, Bouvry D, Wislez M. [Respiratory manifestations of common variable immunodeficiency in adults]. Rev Mal Respir 2003; 20:126.
  33. Quinti I, Soresina A, Spadaro G, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol 2007; 27:308.
  34. Thickett KM, Kumararatne DS, Banerjee AK, et al. Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings. QJM 2002; 95:655.
  35. Aghamohammadi A, Allahverdi A, Abolhassani H, et al. Comparison of pulmonary diseases in common variable immunodeficiency and X-linked agammaglobulinaemia. Respirology 2010; 15:289.
  36. Agondi RC, Barros MT, Rizzo LV, et al. Allergic asthma in patients with common variable immunodeficiency. Allergy 2010; 65:510.
  37. Bates CA, Ellison MC, Lynch DA, et al. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol 2004; 114:415.
  38. Park JH, Levinson AI. Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID). Clin Immunol 2010; 134:97.
  39. Park JE, Beal I, Dilworth JP, et al. The HRCT appearances of granulomatous pulmonary disease in common variable immune deficiency. Eur J Radiol 2005; 54:359.
  40. Wheat WH, Cool CD, Morimoto Y, et al. Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency. J Exp Med 2005; 202:479.
  41. Zullo A, Romiti A, Rinaldi V, et al. Gastric pathology in patients with common variable immunodeficiency. Gut 1999; 45:77.
  42. Agarwal S, Mayer L. Pathogenesis and treatment of gastrointestinal disease in antibody deficiency syndromes. J Allergy Clin Immunol 2009; 124:658.
  43. Guo BC, Saxon A. B cell lines from a subset of patients with common variable immunodeficiency undergo enhanced apoptosis associated with an increased display of CD95 (Apo-1/fas), diminished CD38 expression, and decreased IgG and IgA production. Cell Immunol 1995; 166:83.
  44. Maarschalk-Ellerbroek LJ, Oldenburg B, Mombers IM, et al. Outcome of screening endoscopy in common variable immunodeficiency disorder and X-linked agammaglobulinemia. Endoscopy 2013; 45:320.
  45. Bayraktar Y, Ersoy O, Sokmensuer C. The findings of capsule endoscopy in patients with common variable immunodeficiency syndrome. Hepatogastroenterology 2007; 54:1034.
  46. Kalha I, Sellin JH. Common variable immunodeficiency and the gastrointestinal tract. Curr Gastroenterol Rep 2004; 6:377.
  47. Daniels JA, Lederman HM, Maitra A, Montgomery EA. Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol 2007; 31:1800.
  48. Detková D, de Gracia J, Lopes-da-Silva S, et al. Common variable immunodeficiency: association between memory B cells and lung diseases. Chest 2007; 131:1883.
  49. Wang J, Cunningham-Rundles C. Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). J Autoimmun 2005; 25:57.
  50. Boileau J, Mouillot G, Gérard L, et al. Autoimmunity in common variable immunodeficiency: correlation with lymphocyte phenotype in the French DEFI study. J Autoimmun 2011; 36:25.
  51. Cunningham-Rundles C. Autoimmune manifestations in common variable immunodeficiency. J Clin Immunol 2008; 28 Suppl 1:S42.
  52. Agarwal S, Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep 2009; 9:347.
  53. Michel M, Chanet V, Galicier L, et al. Autoimmune thrombocytopenic purpura and common variable immunodeficiency: analysis of 21 cases and review of the literature. Medicine (Baltimore) 2004; 83:254.
  54. Sève P, Bourdillon L, Sarrot-Reynauld F, et al. Autoimmune hemolytic anemia and common variable immunodeficiency: a case-control study of 18 patients. Medicine (Baltimore) 2008; 87:177.
  55. Giannouli S, Anagnostou D, Soliotis F, Voulgarelis M. Autoimmune manifestations in common variable immunodeficiency. Clin Rheumatol 2004; 23:449.
  56. Chapel H, Lucas M, Lee M, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood 2008; 112:277.
  57. Sarmiento E, Mora R, Rodríguez-Mahou M, et al. [Autoimmune disease in primary antibody deficiencies]. Allergol Immunopathol (Madr) 2005; 33:69.
  58. Arunachalam M, Sanzo M, Lotti T, et al. Common variable immunodeficiency in vitiligo. G Ital Dermatol Venereol 2010; 145:783.
  59. Fernández-Castro M, Mellor-Pita S, Citores MJ, et al. Common variable immunodeficiency in systemic lupus erythematosus. Semin Arthritis Rheum 2007; 36:238.
  60. Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med 1997; 127:613.
  61. Ardeniz O, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Clin Immunol 2009; 133:198.
  62. Artac H, Bozkurt B, Talim B, Reisli I. Sarcoid-like granulomas in common variable immunodeficiency. Rheumatol Int 2009; 30:109.
  63. Boursiquot JN, Gérard L, Malphettes M, et al. Granulomatous disease in CVID: retrospective analysis of clinical characteristics and treatment efficacy in a cohort of 59 patients. J Clin Immunol 2013; 33:84.
  64. Pasquet F, Kodjikian L, Mura F, et al. Uveitis and common variable immunodeficiency: data from the DEF-I study and literature review. Ocul Immunol Inflamm 2012; 20:163.
  65. Wehr C, Kivioja T, Schmitt C, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 2008; 111:77.
  66. Fasano MB, Sullivan KE, Sarpong SB, et al. Sarcoidosis and common variable immunodeficiency. Report of 8 cases and review of the literature. Medicine (Baltimore) 1996; 75:251.
  67. Kanathur N, Byrd RP Jr, Fields CL, Roy TM. Noncaseating granulomatous disease in common variable immunodeficiency. South Med J 2000; 93:631.
  68. Arnold DF, Wiggins J, Cunningham-Rundles C, et al. Granulomatous disease: distinguishing primary antibody disease from sarcoidosis. Clin Immunol 2008; 128:18.
  69. Marashi SM, Raeiszadeh M, Workman S, et al. Inflammation in common variable immunodeficiency is associated with a distinct CD8(+) response to cytomegalovirus. J Allergy Clin Immunol 2011; 127:1385.
  70. Agondi RC, Barros MT, Kokron CM, et al. Can patients with common variable immunodeficiency have allergic rhinitis? Am J Rhinol Allergy 2013; 27:79.
  71. Ward C, Lucas M, Piris J, et al. Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia. Clin Exp Immunol 2008; 153:331.
  72. Malamut G, Ziol M, Suarez F, et al. Nodular regenerative hyperplasia: the main liver disease in patients with primary hypogammaglobulinemia and hepatic abnormalities. J Hepatol 2008; 48:74.
  73. Mellemkjaer L, Hammarstrom L, Andersen V, et al. Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study. Clin Exp Immunol 2002; 130:495.
  74. Vajdic CM, Mao L, van Leeuwen MT, et al. Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency? Blood 2010; 116:1228.
  75. Cunningham-Rundles C, Siegal FP, Cunningham-Rundles S, Lieberman P. Incidence of cancer in 98 patients with common varied immunodeficiency. J Clin Immunol 1987; 7:294.
  76. Aghamohammadi A, Rezaei N, Gharagozlou M, et al. Hodgkin lymphoma in two siblings with common variable immunodeficiency. Pediatr Hematol Oncol 2007; 24:337.
  77. Vorechovský I, Cullen M, Carrington M, et al. Fine mapping of IGAD1 in IgA deficiency and common variable immunodeficiency: identification and characterization of haplotypes shared by affected members of 101 multiple-case families. J Immunol 2000; 164:4408.
  78. Dhalla F, da Silva SP, Lucas M, et al. Review of gastric cancer risk factors in patients with common variable immunodeficiency disorders, resulting in a proposal for a surveillance programme. Clin Exp Immunol 2011; 165:1.
  79. Cunningham-Rundles C. How I treat common variable immune deficiency. Blood 2010; 116:7.
  80. Orange JS, Glessner JT, Resnick E, et al. Genome-wide association identifies diverse causes of common variable immunodeficiency. J Allergy Clin Immunol 2011; 127:1360.
  81. International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies, Notarangelo LD, Fischer A, et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol 2009; 124:1161.
  82. 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; 145:709.
  83. Hunter ZR, Manning RJ, Hanzis C, et al. IgA and IgG hypogammaglobulinemia in Waldenström's macroglobulinemia. Haematologica 2010; 95:470.
  84. Kelesidis T, Yang O. Good's syndrome remains a mystery after 55 years: A systematic review of the scientific evidence. Clin Immunol 2010; 135:347.
  85. Patient information about specific disorders is available at: http://primaryimmune.org/about-primary-immunodeficiency-diseases/types-of-pidd (Accessed on January 19, 2012).
  86. Patient information about specific immunodeficiencies can be found at: http://www.info4pi.org/aboutPI/index.cfm?section=aboutPI&content=defects (Accessed on January 19, 2012).