NORD gratefully acknowledges Charlotte Cunningham-Rundles, MD, PhD, Departments of Medicine, Pediatrics, The Immunology Institute, Mount Sinai School of Medicine, for assistance in the preparation of this report.
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 180 primary immunodeficiencies ranging from relatively common to quite rare.
CVID is one of the most prevalent of the symptomatic primary immunodeficiencies and manifests a wide variability of symptoms and range of severity. It is considered a diverse group of diseases due to a number of causes, most of which are still unknown. . CVID is characterized by a low level of specific proteins (called immunoglobulins) in the fluid portion of the blood. This results in a loss of antibodies, and a decreased ability to fight invading microorganisms, toxins, or other foreign substances. These immunoglobulins are produced by specialized white blood cells (B cells) as they mature into plasma cells.
The cause of CVID is unknown in at least 90% of affected individuals, as a genetic cause has been identified in about 10%. Sporadic cases, with no apparent history of the disorder in the family, are the commonest form. These 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 immune cells are believed to be the primary cause.
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. The diagnosis is made by finding that functional antibodies are very low or absent.
Onset of symptoms, including frequent and unusual infections, may first occur during childhood and adolescence; however, for many patients, the diagnosis may not be 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 are not effective. 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 the immune 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, some 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.
The cause of CVID is unknown for most patients but a genetic cause has been identified in about 10%. Autosomal dominant and autosomal recessive inheritance has been reported in a few families with CVID. More commonly, sporadic cases, with no apparent history of the disorder in their family, may still 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, similar to 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 direct cause of CVID. Other genes that have been associated with a very small percentage of cases include: CD19, CD81, ICOS CD20, CD21, 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.
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. In addition, it can be confused with physiologic immaturity. However, most patients have symptoms later and are not diagnosed until ages 20-40.
In most patients, 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.
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. However, after being immunoglobulin therapy for several months, most patients no longer require any premedications.
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.
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: [email protected]
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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)
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., immune deficiency, autoimmune disorders affecting certain elements of the blood, etc.].)
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