Common variable immunodeficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mohsen Basiri M.D.

Synonyms and Keywords: CVID; common variable hypogammaglobulinaemia; non-familial hypogammaglobulinaemia; acquired hypogammaglobulinemia; immunodeficiency, common variable; late-onset immunoglobulin deficiency

Overview

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder. CVID is the most common antibody deficiency affecting both children and adults. The characteristic immunological defect in CVID is impaired B cell differentiation with defective production of immunoglobulin. Impaired B cell differentiation leads to low serum concentrations of immunoglobulin G (IgG), as well as low immunoglobulin A (IgA) and/or immunoglobulin M (IgM), as well poor or absent response to immunization. The majority of patients are diagnosed between the ages of 20 and 40 years. Recurrent bacterial infections of the sino-pulmonary tract (sinusitis and pneumonia) are most common manifestations of patients with CVID. Opportunistic and unusual infections are uncommon, but can occur. In addition to recurrent infections, patients with CVID have evidence of immune dysregulation leading to autoimmunity. Patients may suffer from chronic lung disease, gastrointestinal and liver disorders, granulomatous infiltrations, lymphoid hyperplasia, splenomegaly, or malignancy. Various forms of primary and secondary hypogammaglobulinemia must be excluded before the diagnosis of CVID. The diagnosis of CVID requires a suggestive clinical history, a reduced total serum concentration of IgG, plus low IgA or IgM, and poor responses to both protein- and polysaccharide-based vaccines.

Historical Perspective

  • In 1953, Charles Janeway was the first to describe CVID as a separate entity.
  • In 1990, the European Society for Immunodeficiency (ESID) and Pan-American Group for Immunodeficiency (PAGID) determined the diagnostic criteria, including minimum age of diagnosis and the need to rule out other diseases, to determine CVID.[1]

Classification

Common variable immunodeficiency (CVID) is a heterogeneous immune disorder characterized by recurrent sinopulmonary infections, autoimmune diseases, and granulomatous disease. A phenotypic approach to classify CVID has been suggested, based upon the type of complications the patient demonstrates. Five phenotypic categories were proposed:[2]

Pathophysiology

Type Gene Immunoglobulin Deficiency Phenotype
ICOS deficiency ICOS Low IgG and IgA Recurrent infections, autoimmunity, gastroenteritis.
CD19 deficiency CD19 Low IgG and IgA Recurrent infections.

May be associated with glomerulonephritis.

CD81 deficiency CD81 Low IgG, low or normal IgA and IgM Recurrent infections.

May be associated with glomerulonephritis.

CD20 deficiency CD20 Low IgG, normal or elevated IgM, and IgA Recurrent infections.
CD21 deficiency CD21 Low IgG; impaired antipneumococcal response Recurrent infections.
TACI deficiency TNFRSF13B Low IgG and IgA and/or IgM Variable clinical expression
BAFF-receptor

deficiency

TNFRSF13C Low IgG and IgM Variable clinical expression
TWEAK deficiency TWEAK Low IgM and IgA; lack of antipneumococcal antibody Recurrent infections such as Pneumonia, bacterial infections, warts;

and thrombocytopenia; neutropenia

NF-kappa-B2

deficiency

NFKB2 Low IgG and IgA and IgM; very low B cells in some Recurrent infections; adrenal insufficiency;

ACTH deficiency; alopecia

NF-kappa-B1

deficiency

NFKB1 Low IgG and IgA and IgM; low B cells in some Recurrent infections
IKAROS IKZF1 Low IgG and IgA and IgM, very low B cells Recurrent infections

Causes

The cause of common variable immunodeficiency has not been identified. Genetic mutations can be recognized as the cause of CVID in about 10% of patients, and familial inheritance accounts for 10-25% of the affected population. Rather than arising from a single genetic mutation, CVID is due to numerous mutations that all are associated with dysfunction in antibody regulation and production.[7]

Differentiating Common Variable Immunodeficiency from other Diseases

CVID should be differentiated from diseases which hypogammaglobulinemia is their primary laboratory feature include:

In addition to primary causes of hypogammaglobulinemia a large number of conditions are associated with secondary hypogammaglobulinemia and should be excluded:

Epidemiology and Demographics

Prevalence

CVID has an estimated prevalence ranging from a low of 2 per 100,000 to a high of 4 per 100,000 with an average of 3 per 100,000.[11]

Age

  • The typical patient is after puberty and between 20 and 40 years age.
  • About 20% of patients are diagnosed in childhood.
  • In an analysis of the CVID data from the ESID about 35 percent of patients were diagnosed before 10 years of age; and in studies from United States centers, 20 percent of patients are diagnosed before the age of 20 years. The majority of patients are diagnosed between the ages of 20 and 45. [12] [13]

Gender

There is no gender predilection to common variable immunodeficiency.

Race

Race is not associated with an increased risk of common variable immunodeficiency. However, there is some evidence of higher prevalence among individuals of northern European descent.[14]

Natural History, Complications and Prognosis

Natural History

All patients have several histories of acute and recurrent infections. The majority of patients with CVID have evidence of immune dysregulation leading to autoimmunity, inflammatory disorders, and malignant disease. Accordingly, CVID Patients may suffer from chronic lung disease, gastrointestinal and liver disorders, granulomatous infiltrations of several organs, lymphoid hyperplasia, splenomegaly, or malignancy.[15]The clinical manifestations of CVID affect multiple organ systems, and patients often have the history of several specialists visits by the time they are recognized. It may be partly for this reason, delayed diagnosis of this condition is common. in the European Society for Immunodeficiencies (ESID) database, and other studies, there was an average of five to seven years between the beginning of symptoms and diagnosis[16][17]

Complications

Numerous complications are possible in CVID. They include:[18][19][20]

Prognosis

Prognosis with the advent of immune globulin treatment is generally good, and the incidence of death associated with acute bacterial infection in CVID decreased dramatically.[21] Afterwards, the leading causes of death are owing to complications of chronic lung disease and malignancies.

In the several large series of following patients with CVID, the leading causes of death were respiratory failure due to bronchiectasis, lymphoma, and liver disease.[22][23]

Diagnosis

History and Symptoms

Symptoms of CVID are:[24][25]

Physical Examination

Physical examination of patients with longstanding immune defects may be remarkable for:

Laboratory Findings

Patients with CVID do not usually present abnormalities in routine laboratories, such as complete blood counts, serum chemistries, and electrolytes. In the presence of infection and associated condition some abnormalities which may develop include:

Laboratory findings consistent with the diagnosis of CVID are reduced concentrations of serum immunoglobulins levels and include:[26]

  • IgG of 258 mg/dL
  • IgA of 28 mg/dL
  • IgM of 40 mg/dL

Evaluation of vaccine response to both protein and polysaccharide-based vaccines is part of the diagnosis and should be evaluated. IgG responsiveness to tetanus and diphtheria and polysaccharide pneumococcal vaccine provide an estimate of the patient's responsiveness.[27]

Diagnosis is often delayed,and diagnosis is often made in the second or third decade of life after referral to an immunologist. As with several other immune cell disorders, CVID may predispose to lymphoma or possibly stomach cancer. There also appears to be a predilection for autoimmune diseases, with a risk of up to 25%. Autoimmune destruction of platelets or red blood cells are the commonest of these.

Treatment

Medical Therapy

The mainstay of treatment for CVID is immune globulin replacement therapy. In addition, management also includes monitoring and screening for other associated conditions, such as sinopulmonary, granulomatous, gastrointestinal, and autoimmune diseases, and malignancy.

Immune Globulin Replacement Therapy

  • Human antibodies harvested from blood donations are administered either intravenously or subcutaneously.
  • Immune globulin replacement therapy reduces the number of infections and decreases antibiotic use and hospitalizations.[28]
  • This therapy is not a cure, but it strengthens immunity in hypogammaglobulinemic patients, which helps to prevent recurrent upper respiratory infections, and fewer serious infections and days of hospitalization among patients with primary immunodeficiency . However, immune globulin therapy does not completely eliminate infections in most patients, and the sinopulmonary and gastrointestinal systems, in particular, remain susceptible.[29]
  • IG therapy should not be used if the patient has anti-IgA antibodies but in these cases, products low in IgA can be used; subcutaneous delivery also is a means of permitting such patients to have adequate antibody replacement.
  • IVIG treatment can be received by patients with a complete IgA deficiency if the IgA is completely removed from the treatment.
  • Preferred regimen : Intravenous immunoglobulin 300 to 600 mg/kg every three to four weeks.
  • Alternative regimen (1) :Subcutaneous immunoglobulin G administered weekly or every other week. Dose depends on body weight and immune globulin requirements.
  • Alternative regimen (2) : Intramuscular immunoglobulin (IMIG, less effective, painful).

Adverse reactions

Some CVID patients may experience reactions to immune globulin replacement therapies; reactions may include:

Reactions can be minimized by taking an antihistamine and/or hydrocortisone and some paracetamol/acetaminophen/anti-inflammatory (naproxen, advil, aspirin) prior to treatment; patients should also be thoroughly hydrated and continue to drink water before, after and during treatment (if possible).

Antimicrobial Therapy

Antibiotics may be administered prophylactically, as well as for the treatment of acute infections or exacerbations of chronic infections.

  • Prophylactic antibiotics do not routinely administer to all patients with CVID. In CVID patients with ongoing lung disease, and with recurrent sinopulmonary infections, this approach is helpful. Evidence in support of this approach is largely derived from benefits observed in retrospective studies of children with this and similar antibody deficiencies.[30]
  • Antibiotics are required for management of acute infections among patients with immunodeficiency. CVID patients typically do not clear common infections without the use of proper antibiotics. Thus, immediate recognition and treatment with antibiotics can help prevent chronic infections and infectious complications. It is important to ensure that the infection has treated completely at the end of a course of antibiotics, as patients with immunodeficiency sometimes necessitate longer duration of therapy. Antibiotic resistance does not seem to be a serious problem in patients with CVID, for causes which are not clearly understood, then the same antibiotics continue to be useful, regardless of prolonged or frequent exposure.[31]

Prevention

  • There are no primary preventive measures available for common variable immunodeficiency.
  • Secondary and tertiary prevention strategies following CVID include avoidance measures, vaccination, prophylactic antibiotics, immune globulin therapy, and when infections do occur, broader spectrum and more prolonged antibiotics are often recommended.
    • Avoidance to reduce exposure to others with potentially contagious illnesses: proper hand-washing and use of alcohol-based disinfectants should be provided to patients and their families; Co-sleeping among family members should be minimized, and immunization of family members and close contacts is required.
    • Careful attention should be paid to patient's oral hygiene and dental health.
    • The efficiency of killed or inactivated vaccines in patients with CVID is not fully understood because of the impaired responses to of patients to vaccination due to dysregulated , however, vaccination might augment T cell immunity to viral agents, in addition to inducing the formation of specific antibodies. Certain live vaccines i.e. oral polio, smallpox, live-attenuated influenza vaccine, yellow fever, or live oral typhoid vaccines should not be given to patients with CVID , particularly those with significantly impaired T cell function.[32]

References

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  3. C. Cunningham-Rundles & C. Bodian (1999). "Common variable immunodeficiency: clinical and immunological features of 248 patients". Clinical immunology (Orlando, Fla.). 92 (1): 34–48. PMID 10413651. doi:10.1006/clim.1999.4725. 
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  12. C. Cunningham-Rundles & C. Bodian (1999). "Common variable immunodeficiency: clinical and immunological features of 248 patients". Clinical immunology (Orlando, Fla.). 92 (1): 34–48. PMID 10413651. doi:10.1006/clim.1999.4725. 
  13. R. A. Hermaszewski & A. D. Webster (1993). "Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications". The Quarterly journal of medicine. 86 (1): 31–42. PMID 8438047. 
  14. L. Hammarstrom, I. Vorechovsky & D. Webster (2000). "Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)". Clinical and experimental immunology. 120 (2): 225–231. PMID 10792368. 
  15. L. Hammarstrom, I. Vorechovsky & D. Webster (2000). "Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)". Clinical and experimental immunology. 120 (2): 225–231. PMID 10792368. 
  16. C. Cunningham-Rundles & C. Bodian (1999). "Common variable immunodeficiency: clinical and immunological features of 248 patients". Clinical immunology (Orlando, Fla.). 92 (1): 34–48. PMID 10413651. doi:10.1006/clim.1999.4725. 
  17. Benjamin Gathmann, Nizar Mahlaoui, Laurence Gerard, Eric Oksenhendler, Klaus Warnatz, Ilka Schulze, Gerhard Kindle, Taco W. Kuijpers, Rachel T. van Beem, David Guzman, Sarita Workman, Pere Soler-Palacin, Javier De Gracia, Torsten Witte, Reinhold E. Schmidt, Jiri Litzman, Eva Hlavackova, Vojtech Thon, Michael Borte, Stephan Borte, Dinakantha Kumararatne, Conleth Feighery, Hilary Longhurst, Matthew Helbert, Anna Szaflarska, Anna Sediva, Bernd H. Belohradsky, Alison Jones, Ulrich Baumann, Isabelle Meyts, Necil Kutukculer, Per Wagstrom, Nermeen Mouftah Galal, Joachim Roesler, Evangelia Farmaki, Natalia Zinovieva, Peter Ciznar, Efimia Papadopoulou-Alataki, Kirsten Bienemann, Sirje Velbri, Zoya Panahloo & Bodo Grimbacher (2014). "Clinical picture and treatment of 2212 patients with common variable immunodeficiency". The Journal of allergy and clinical immunology. 134 (1): 116–126. PMID 24582312. doi:10.1016/j.jaci.2013.12.1077. 
  18. L. Hammarstrom, I. Vorechovsky & D. Webster (2000). "Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)". Clinical and experimental immunology. 120 (2): 225–231. PMID 10792368. 
  19. R. A. Hermaszewski & A. D. Webster (1993). "Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications". The Quarterly journal of medicine. 86 (1): 31–42. PMID 8438047. 
  20. Elena S. Resnick, Erin L. Moshier, James H. Godbold & Charlotte Cunningham-Rundles (2012). "Morbidity and mortality in common variable immune deficiency over 4 decades". Blood. 119 (7): 1650–1657. PMID 22180439. doi:10.1182/blood-2011-09-377945. 
  21. Elena S. Resnick, Erin L. Moshier, James H. Godbold & Charlotte Cunningham-Rundles (2012). "Morbidity and mortality in common variable immune deficiency over 4 decades". Blood. 119 (7): 1650–1657. PMID 22180439. doi:10.1182/blood-2011-09-377945. 
  22. Helen Chapel, Mary Lucas, Martin Lee, Janne Bjorkander, David Webster, Bodo Grimbacher, Claire Fieschi, Vojtech Thon, Mohammad R. Abedi & Lennart Hammarstrom (2008). "Common variable immunodeficiency disorders: division into distinct clinical phenotypes". Blood. 112 (2): 277–286. PMID 18319398. doi:10.1182/blood-2007-11-124545. 
  23. Isabella Quinti, Carlo Agostini, Stefano Tabolli, Grazia Brunetti, Francesco Cinetto, Antonio Pecoraro & Giuseppe Spadaro (2012). "Malignancies are the major cause of death in patients with adult onset common variable immunodeficiency". Blood. 120 (9): 1953–1954. PMID 22936739. doi:10.1182/blood-2012-05-431064. 
  24. Elena S. Resnick, Erin L. Moshier, James H. Godbold & Charlotte Cunningham-Rundles (2012). "Morbidity and mortality in common variable immune deficiency over 4 decades". Blood. 119 (7): 1650–1657. PMID 22180439. doi:10.1182/blood-2011-09-377945. 
  25. Simon Urschel, Lale Kayikci, Uwe Wintergerst, Gundula Notheis, Annette Jansson & Bernd H. Belohradsky (2009). "Common variable immunodeficiency disorders in children: delayed diagnosis despite typical clinical presentation". The Journal of pediatrics. 154 (6): 888–894. PMID 19230900. doi:10.1016/j.jpeds.2008.12.020. 
  26. Isabella Quinti, Annarosa Soresina, Giuseppe Spadaro, Silvana Martino, Simona Donnanno, Carlo Agostini, Pignata Claudio, Dammacco Franco, Anna Maria Pesce, Federica Borghese, Andrea Guerra, Roberto Rondelli & Alessandro Plebani (2007). "Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency". Journal of clinical immunology. 27 (3): 308–316. PMID 17510807. doi:10.1007/s10875-007-9075-1. 
  27. Jordan S. Orange, Mark Ballow, E. Richard Stiehm, Zuhair K. Ballas, Javier Chinen, Maite De La Morena, Dinakantha Kumararatne, Terry O. Harville, Paul Hesterberg, Majed Koleilat, Sean McGhee, Elena E. Perez, Jason Raasch, Rebecca Scherzer, Harry Schroeder, Christine Seroogy, Aarnoud Huissoon, Ricardo U. Sorensen & Rohit Katial (2012). "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". The Journal of allergy and clinical immunology. 130 (3 Suppl): S1–24. PMID 22935624. doi:10.1016/j.jaci.2012.07.002. 
  28. Paula Jane Busse, Samiya Razvi & Charlotte Cunningham-Rundles (2002). "Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency". The Journal of allergy and clinical immunology. 109 (6): 1001–1004. PMID 12063531. 
  29. Benjamin Gathmann, Nizar Mahlaoui, Laurence Gerard, Eric Oksenhendler, Klaus Warnatz, Ilka Schulze, Gerhard Kindle, Taco W. Kuijpers, Rachel T. van Beem, David Guzman, Sarita Workman, Pere Soler-Palacin, Javier De Gracia, Torsten Witte, Reinhold E. Schmidt, Jiri Litzman, Eva Hlavackova, Vojtech Thon, Michael Borte, Stephan Borte, Dinakantha Kumararatne, Conleth Feighery, Hilary Longhurst, Matthew Helbert, Anna Szaflarska, Anna Sediva, Bernd H. Belohradsky, Alison Jones, Ulrich Baumann, Isabelle Meyts, Necil Kutukculer, Per Wagstrom, Nermeen Mouftah Galal, Joachim Roesler, Evangelia Farmaki, Natalia Zinovieva, Peter Ciznar, Efimia Papadopoulou-Alataki, Kirsten Bienemann, Sirje Velbri, Zoya Panahloo & Bodo Grimbacher (2014). "Clinical picture and treatment of 2212 patients with common variable immunodeficiency". The Journal of allergy and clinical immunology. 134 (1): 116–126. PMID 24582312. doi:10.1016/j.jaci.2013.12.1077. 
  30. Julie Wang & Charlotte Cunningham-Rundles (2005). "Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID)". Journal of autoimmunity. 25 (1): 57–62. PMID 15994061. doi:10.1016/j.jaut.2005.04.006. 
  31. A. Samuelson, S. Borrelli, R. Gustafson, L. Hammarstrom, C. I. Smith, J. Jonasson & A. A. Lindberg (1995). "Characterization of Haemophilus influenzae isolates from the respiratory tract of patients with primary antibody deficiencies: evidence for persistent colonizations". Scandinavian journal of infectious diseases. 27 (4): 303–313. PMID 8658061. 
  32. William T. Shearer, Thomas A. Fleisher, Rebecca H. Buckley, Zuhair Ballas, Mark Ballow, R. Michael Blaese, Francisco A. Bonilla, Mary Ellen Conley, Charlotte Cunningham-Rundles, Alexandra H. Filipovich, Ramsay Fuleihan, Erwin W. Gelfand, Vivian Hernandez-Trujillo, Steven M. Holland, Richard Hong, Howard M. Lederman, Harry L. Malech, Stephen Miles, Luigi D. Notarangelo, Hans D. Ochs, Jordan S. Orange, Jennifer M. Puck, John M. Routes, E. Richard Stiehm, Kathleen Sullivan, Troy Torgerson & Jerry Winkelstein (2014). "Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts". The Journal of allergy and clinical immunology. 133 (4): 961–966. PMID 24582311. doi:10.1016/j.jaci.2013.11.043. 

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