Common Variable Immune Deficiency

Common Variable Immune Deficiency

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Common Variable Immune Deficiency is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • CVI
  • CVID
  • Acquired Hypogammaglobulinemia
  • common variable hypogammaglobulinemia
  • late-onset immunoglobulin deficiency
  • common variable immunodeficiency
  • immunodeficiency, common variable

Disorder Subdivisions

  • None

General Discussion

Common Variable Immune Deficiency (CVID) is a type of primary immunodeficiency, which is defined as an immune system dysfunction typically caused by a mutation in a gene or genes. The World Health Organization (WHO) recognizes more than 150 primary immunodeficiencies ranging from relatively common to quite rare.



CVID is one of the most prevalent of primary immunodeficiencies and manifests a wide variability of symptoms and range of severity. It is considered a diverse group of diseases of unknown cause (etiology) as many different immune system defects have been reported. CVID is characterized by a low level of specific proteins (antibodies, also called immunoglobulins) in the fluid portion of the blood which results in a decreasedability to fight invading microorganisms, toxins, or other foreign substances. These immunoglobulins are produced by specialized white blood cells (B cells) as they mature.



The cause of CVID is unknown in 75-80% of cases, and a genetic cause has been identified in 10-20%. Sporadic cases, with no apparent history of the disorder in their family, may be caused by a complex interaction of environmental and genetic components (multifactorial inheritance), but genes that are involved in the development and function of B cells are believed to be the primary cause.

Symptoms

The clinical course and symptoms of CVID vary widely from mild to severe. The immunoglobulins affected also vary. For example, some patients have a deficiency in all three major types of immumoglobulins: immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) while others have a shortage of just IgG and IgA.



Onset of symptoms, including frequent and unusual infections, may first occur during childhood and adolescence; however, in the majority of patients, the diagnosis is not made until the third to fourth decade of life.



People with CVID have trouble fighting off infections because of a lack of antibodies which are normally made to resist invading microbes. As antibody production is impaired, vaccines often are not effective in people with CVID. Recurrent bacterial infections, particularly affecting the upper and lower respiratory tracts, such as in the lungs, sinuses, or ears, are common. Recurrent lung infections can lead to chronic lung disease and potentially life-threatening complications.



Gastrointestinal complications, such as infections or inflammation, are also prevalent. Some patients report abdominal pain, bloating, nausea, vomiting, diarrhea and weight loss. Affected individuals may also have an impaired ability to absorb nutrients such as vitamins, minerals, fat and certain sugars from the digestive tract. Individuals with CVID may also experience recurrent or chronic infections (giardiasis) of the small intestine caused by the single-celled parasite called Giardia lamblia. (For more information on giardiasis, choose "giardiasis" as your search term in the Rare Disease Database.)



Individuals with CVID also have an increased susceptibility to certain bacterial gastrointestinal infections (e.g., Campylobacter, etc.) that may cause symptoms similar to those associated with giardiasis.



Due to abnormalities in the maturation of B cells, and dysregulation of theimmune system, some individuals with CVID may have abnormal accumulations of lymphocytes in lymphoid tissues such as lymph nodes (lymphadenopathy) or spleen (splenomegaly). In some cases, abnormal growth of small nodules of lymphoid tissue in the gastrointestinal tract (nodular lymphoid hyperplasia) may occur. In addition, an increased percent of individuals with CVID are more prone to developing certain forms of cancer than the general population such as malignancies of lymphatic tissue (lymphoma) and possibly stomach cancer). The risk of gastric carcinoma is almost 50 times greater in patients with CVID than in other individuals.



In addition, in some cases, individuals with CVID may develop granular, inflammatory nodules (noncaseating granulomas) within tissue of the skin, lungs, spleen, and/or liver.



Twenty to twenty-five percent of patients with CVID are prone to developing certain autoimmune disorders. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) anemia are the most frequently diagnosed ones. (For more information on these disorders, choose "Idiopathic Thrombocytopenic Purpura" and "Anemia, Hemolytic, Acquired Autoimmune" as your search terms in the Rare Disease Database.)



It is not fully understood why CVID patients are at risk for autoimmune disorders. CVID suppresses the immune response, whereas autoimmunity involves an overactive immune system that attack the body's healthy tissues and organs. This phenomenon suggests that more complex defects in the immune system, beyond qualitative and quantitative defects in antibodies production, underlie the diverse clinical manifestations of CVID.

Causes

The cause of CVID is unknown in 95% of cases and a genetic cause has been identified in less than 5%. Autosomal dominant and autosomal recessive inheritance has been reported in some families with CVID. More commonly, sporadic cases, with no apparent history of the disorder in their family, may be caused by either rare autosomal defects or complex interactions of environmental and genetic causes (multifactorial inheritance), but mutations in genes that are involved in the development and function of B cells are believed to be the primary cause.



B cells are specialized white blood cells that, as they mature into their final stage of plasma cells, produce special proteins called antibodies (immunoglobulins). These antibodies help protect the body against infection by attaching to specific invading microorganisms, toxins, or other foreign substances (antigens), marking them for destruction. Individuals with CVID usually have a deficiency of all major immunoglobulin classes (panhypogammaglobulinemia). However, in some cases, affected individuals may have severely reduced levels of some immunoglobulins (i.e., IgG and IgA) and relatively normal levels of IgM.



Researchers have found that, in addition to defective B cells, errors in other immune cells (the T cell system) may either contribute to or be responsible for the irregularities in immunoglobulin production. Lack of T cell maturational influence on the developing B cell may lead to poor B cell development.



Some researchers suggest that, in certain cases, CVID and Selective IgA Deficiency may be inherited in connection with a common disease gene or genes (i.e., in or near the major histocompatibility complex [MHC] class III gene region on chromosome 6) and may represent opposite ends of the spectrum of the same disorder. This is supported by reports in the medical literature in which some individuals in some multigenerational families (kindreds) have CVID while other members of the same families have Selective IgA Deficiency. (For more information on Selective IgA Deficiency, refer to the Related Disorders section below.)



Dominant genetic disorders occur when a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.



Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.



Mutations in at least five genes have been associated with CVID. Approximately 10 percent of affected individuals have mutations in the TNFRSF13B gene but as the same gene can be found in normal relatives and blood bank normal donors, it is not considered a cause of CVID. Other genes that have been associated with a very small percentage of cases include: CD19, CD81, ICOS, and TNFRSF13C. The identification in 2009 of a mutation in the ICOS gene in nine CVID patients in one large family showed that what had previously been perceived as a B-cell disease might in fact have its genetic origin in human T cells.

Affected Populations

CVID equally affects males and females. The prevalence of CVID is approximately 1 in 30,000 people. The diagnosis of CVID is not made in children under the age of 4, because until that time, it may be confused with other genetic defects that must be excluded. However, most patients have symptoms later and are not diagnosed until ages 20-40.

Standard Therapies

Diagnosis

In most cases, Common Variable Immune Deficiency is diagnosed based upon a thorough clinical evaluation, identification of characteristic symptoms and physical findings, a detailed patient and family history, and a pattern of immune system defects confirmed by laboratory testing.



Confirmation of certain immunologic abnormalities plays an essential role in establishing the diagnosis of CVID. The diagnosis of CVID is primarily established by testing for low blood (serum) IgG immunoglobulin concentrations ranging from severely reduced (<100 mg/dL) to just below adult normal range (500-1200 mg/dL). In addition, laboratory testing may reveal normal or, in some cases, reduced numbers of circulating B cells. Failure of certain B cells to appropriately mature into antibody-producing plasma cells may also be detected. Specialized laboratory tests may also help to determine the exact nature of the immune defect (e.g., B cell, helper T cell, suppressor T cell, or B and T cell defects).



In many cases, x-ray, examination of the small intestine (enteroscopy), or surgical removal (biopsy) of small samples of tissue from lymph nodes may reveal certain abnormalities (e.g., nodular lymphoid hyperplasia). In addition, in some cases, specialized imaging tests followed by biopsy and microscopic examination may confirm the presence of granular, inflammatory nodules (noncaseating granulomas) within tissue of the skin, lungs, spleen, and/or liver.



Treatment

The treatment of Common Variable Immune Deficiency requires the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected individual's treatment. Such specialists may include physicians who diagnose and treat disorders of the blood (hematologists), the digestive tract (gastroenterologists), and/or the lungs (pulmonologists); specialists in the treatment of immune system disorders (immunologists); and/or other health care professionals.



The primary treatment for CVID consists of regular immunoglobulin (gammaglobulin) therapy, which is administered by intravenous or subcutaneous infusion with antibodies obtained from the fluid portion of the blood (gammaglobulin). Such therapy may help to prevent the recurrent infections characteristic of CVID as well as treat the disorder's associated symptoms.



Individuals with CVID who experience adverse reactions to intravenous gammaglobulin may benefit from administration of medications that block the effects of the chemical histamine (antihistamines), which is released during allergic reactions, or nonsteroidal anti-inflammatory agents (NSAIDs). Rarely, hydrocortisone, a corticosteroid medication, may be needed prior to gammaglobulin therapy. Because corticosteroids may actually suppress an already weakened immune system, NSAIDs may be helpful in controlling autoimmune-like symptoms while avoiding the use of corticosteroids.



Some researchers have recommended that when a patient is diagnosed with an autoimmune disease, the possibility of an underlying CVID should be evaluated before the administration of immunosuppressive drugs for the autoimmune disease.



Antibiotic medications often prove beneficial for the treatment of various bacterial infections associated with CVID. Patients with irregularities involving the malabsorption of vitamin B12 may also benefit from monthly B12 injections.



Affected individuals with severely low levels of circulating platelets may be cautioned to avoid the use of aspirin, since this medication may interfere with the ability of platelets to assist in the blood-clotting process. In addition, as is the case with individuals affected by many other primary immunodeficiency disorders, individuals with CVID should not receive live virus vaccines since there is the remote possibility that the vaccine strains of virus may cause disease as a result of their defective immune systems.



Surveillance for complications include periodic complete blood count (CBC), and differential white blood counts to detect lymphoma, annual thyroid examination and thyroid function testing, annual lung (pulmonary) function testing beginning about age eight to ten years, biopsy of enlarged lymphoid tissue, and other imaging techniques for assessment of granulomatous disease and gastrointestinal complications.



Genetic counseling is recommended for affected individuals and their family members if a rare autosomal recessive type of CVID is suspected or confirmed. Other treatment is symptomatic and supportive.

Investigational Therapies

The Immune Deficiency Foundation is conducting studies to determine the prevalence, treatment, costs, and health insurance coverage of individuals with primary immunodeficiency diseases. For more information, contact the Immune Deficiency Foundation, which is listed in the Resources section of this report.



The Jeffrey Modell Centers Network (JMCN) is comprised of over 50 Diagnostic & Research Centers worldwide and more than 300 referral physicians at 138 academic teaching hospitals and medical schools in 39 countries and 120 cities, spanning 6 continents. For information on additional research concerning primary immunodeficiency diseases, contact the Jeffrey Modell Foundation, which is listed in the Resources section below.



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Contact for additional information about common variable immune deficiency:



Charlotte Cunningham-Rundles, MD, PhD

Departments of Medicine, Pediatrics

The Immunology Institute

Mount Sinai School of Medicine

1425 Madison Avenue,

New York City, New York, 10029

212 659 9268 (phone)

212 987 5593 (fax)

References

TEXTBOOKS

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Scriver CR, et al, eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:3887.



Frank MM, et al. Samter's Immunologic Diseases, 5th ed. Boston, MA: Little, Brown and Company; 1995:407-11.



Buyse ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:952-53.



JOURNAL ARTICLES

Yong PF, Salzer U, Grimbacher B. The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency. Immunol Rev. 2009;229(1):101-13.



Lopes-da-Silva S, Rizzo LV. Autoimmunity in common variable immunodeficiency. J Clin Immunol. 2008;28(suppl 1):S46-S55.



Cunningham-Rundles C, Knight AK. Common variable immune deficiency: reviews, continued puzzles, and a new registry. Immunol. Res. 2007;38(1-3):78-86.



Nijenhuis T, Klasen I, Weemaes CM, Preijers F, de Vries E, van der Meer JW. Common variable immunodeficiency (CVID) in a family: an autosomal dominant mode of inheritance. Neth J Med. 2001;59(3):134-9.



Reichenbach J, et al. Antioxidative capacity in patients with common variable immunodeficiency. J Clin Immunol. 2000;20:221-26.



Zhang JG, et al. The effects of vitamin a derivatives on in vitro antibody production by peripheral blood mononuclear cells (PBMC) from normal blood donors and patients with common variable immunodeficiency (CVID). Clin Exp Immunol. 1997;107:57-60.



Mechanic LJ, et al. Granulomatous disease in common variable immunodeficiency. Ann Intern Med. 1997;127:613-17.



Johnson ML, et al. Age-related changes in serum immunoglobulins in patients with familial IgA deficiency and common variable immunodeficiency (CVID). Clin Exp Immunol. 1997;108:477-83.



Kondratenko I, et al. Lack of specific antibody response in common variable immunodeficiency (CVID) associated with failure in production of antigen-specific memory T cells. MRC immunodeficiency group. Clin Exp Immunol. 1997;108: 9-13.



Thon V, et al. Antigen presentation by common variable immunodeficiency (CVID) B cells and monocytes is unimpaired. Clin Exp Immunol. 1997;108:1-8.



Oliva A, et al. IL-10 production and CD40L expression in patients with common variable immunodeficiency. Scand J Immunol. 1997;46:86-90.



Silvestris N, et al. Common variable immunodeficiency. Recenti Prog Med. 1996;87:616-22.



Ardiles A, et al. Unexplained remission of common variable immunodeficiency: analysis of a clinical case. Rev Med Chil. 1996;124:725-31.



Silvestris N, et al. Common variable immunodeficiency. The authors' personal cases from the last 5 years. Recenti Prog Med. 1996;87:594-96.



Litzman J, et al. Orally administered bacterial lysate broncho-vaxom for the treatment of common variable immunodeficiency. Allerg Immunol. 1996;28:81-85.



Litzman J, et al. Progression of selective IgA deficiency to common variable immunodeficiency in a 16 year old boy. Allergol Immunopathol. 1996;24:174-76.



de Asis ML, et al. Analysis of a family containing three members with common variable immunodeficiency. Ann Allergy Asthma Immunol. 1996;76:527-29.



Eibl MM, et al. Common variable immunodeficiency: clinical aspects and recent progress in identifying the immunological defect(s). Folia Microbiol. 1995;40:360-66.



Fischer MB, et al., A defect in the early phase of T-cell receptor-mediated t-cell activation in patients with common variable immunodeficiency. Blood. 1994;84:4234-41.



Eisenstein EM, et al. Common variable immunodeficiency: diagnosis and management. Ann Allergy. 1994;73:285-92.



Sneller MC, et al. NIH conference. New insights into common variable immunodeficiency. Ann Intern Med. 1993;118:720-30. Comment in: Ann Intern Med. 1993;119:862.



Saxon A, et al. Long-term administration of 13-CIS retinoic acid in common variable immunodeficiency: circulating interleukin-6 levels, B-cell surface molecule display, and in vitro and in vivo B-cell antibody production. Immunology. 1993;80:477-87.



Volanakis JE, et al. Major histocompatibility complex class III genes and susceptibility to immunoglobulin a deficiency and common variable immunodeficiency. J Clin Invest. 1992;89:1914.



Adelman DC, et al. 13-CIS retinoic acid enhances in vivo B-lymphocyte differentiation in patients with common variable immunodeficiency. J Allergy Clin Immunol. 1991;88:705-12.



Cunningham-Rundles C, et al. Clinical and immunologic analyses of 103 patients with common variable immunodeficiency. J Clin Immunol. 1989;9:22-33.



Sherr E, et al. Retinoic acid induces the differentiation of B cell hybridomas from patients with common variable immunodeficiency. J Exp Med. 1988;168:55-71.



Cunningham-Rundles C, et al. Incidence of cancer in 98 patients with common varied immunodeficiency. J Clin Immunol. 1987;7:294-99.



Rosen FS, et al. Primary immunodeficiency diseases. Clin Immunol Immunopathol. 1986;40:166.



Provisor AJ, et al. Acquired agammaglobulinemia after a life-threatening illness with clinical and laboratory features of infectious mononucleosis in three related male children. N Engl J Med. 1975;293:62-65.



INTERNET

Genetics Home Reference. Common variable immune deficiency. http://ghr.nlm.nih.gov/condition/common-variable-immune-deficiency/. Accessed: 2/8/11.



Scharenberg AM, Hannibal MC, Torgerson T, Ochs HD, Rawlings DJ. (Updated 7/5/06). Common Variable Immune Deficiency Overview. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). 2011. University of Washington, Seattle. 1997-2011. Available at: http://www.genetests.org.. Accessed: 2/8/11.



Immune Deficiency Foundation. Common Variable Immune Deficiency. http://www.primaryimmune.org/publications/book_pats/e_ch02.pdf. Accessed: 2/8/11.



Immune Deficiency Foundation. What is a Primary Immunodeficiency Disease? http://www.primaryimmune.org/about_pi/about_pi.htm. Accessed: 2/8/11.



Park CL, Common variable immunodeficiency. eMedicine. Updated: 9/28/10. http://emedicine.medscape.com/article/885935-overview Accessed: 2/8/11.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 240500; Last Update: 7/27/2010. Available at: http://www.ncbi.nlm.nih.gov/omim/240500 Accessed: 2/8/11.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 607594; Last Update: 7/27/2010. Available at: http://www.ncbi.nlm.nih.gov/omim/607594 Accessed: 2/7/11.



Schwartz RA, Modak RM, Modak P. Common variable immunodeficiency. eMedicine. Updated: 3/16/10. http://emedicine.medscape.com/article/1051103-overview. Accessed: 2/8/11.

Resources

March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



Immune Deficiency Foundation

40 W. Chesapeake Avenue

Suite 308

Towson, MD 21204

Tel: (410)321-6647

Fax: (410)321-9165

Tel: (800)296-4433

Email: idf@primaryimmune.org

Internet: http://www.primaryimmune.org



NIH/National Heart, Lung and Blood Institute

P.O. Box 30105

Bethesda, MD 20892-0105

Tel: (301)592-8573

Fax: (301)251-1223

Email: nhlbiinfo@rover.nhlbi.nih.gov

Internet: http://www.nhlbi.nih.gov/



International Patient Organization for Primary Immunodeficiencies

Firside Main Road

Downderry

Cornwall, PL11 3LE

United Kingdom

Tel: 441503250668

Fax: 441503250961

Email: info@ipopi.org

Internet: http://www.ipopi.org/



Jeffrey Modell Foundation

780 Third Avenue

New York, NY 10017

USA

Tel: (212)819-0200

Fax: (212)764-4180

Tel: (866)469-6474

Email: info@jmfworld.org

Internet: http://www.info4pi.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



European Society for Immunodeficiencies

1-3 rue de Chantepoulet

Geneva, CH 1211

Switzerland

Tel: 410229080484

Fax: 41229069140

Email: esid@kenes.com

Internet: http://www.esid.org



For a Complete Report

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