text: Home / For Patients and Families / Rare Disease Information / Common Variable Immune Deficiency
  NORD gratefully acknowledges Charlotte Cunningham-Rundles, MD, PhD, Departments of Medicine, Pediatrics, The Prism Immunology Institute, The Icahn School of Medicine at Mount Sinai, for assistance in the preparation of this report.
  Synonyms of Common Variable Immune Deficiency
  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 400 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. While considered a genetic condition, the syndrome consists of a group of diseases, and most of the causes are still unknown. CVID is characterized by low levels of specific proteins (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 80% of affected individuals, as a genetic cause has been identified in about 20%. 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 have now been shown 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 immunoglobulins: 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.
  Individuals with CVID also have an increased susceptibility to certain bacterial gastrointestinal infections (e.g., Campylobacter, etc.) or more recently, norovirus that causes 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 "ITP" 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. While one would assume that CVID suppresses the immune response, in fact, loss of normal controls in CVID leads to autoimmunity due to an overactive or unrestrained portion of the immune system. This then leads to an attack on the body's healthy tissues and organs. This phenomenon has long shown that more complex defects in the immune system, beyond qualitative and quantitative defects in antibody 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 20%. Autosomal dominant (mostly) and autosomal recessive inheritance has been reported in 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). Mutations in genes that are involved in the development and function of B cells are only a small part of the genes that lead to CVID, as most the causal genes identified are those that are involved in regulation of immune responses.
  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.
  Previous research suggested that, in certain cases, CVID and selective IgA deficiency are somewhat related conditions. In multigenerational families (kindreds) some 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 many genes have now been associated with CVID. Approximately 8% of affected individuals have mutations in the TNFRSF13B gene but since mutations in this gene can be found in unaffected relatives and blood bank normal donors, it is not considered a direct cause of CVID. The second most common gene associated with CVID is an autosomal dominant gene, NFKB1, but not all family members with a mutation in this gene are affected. Other dominant genes associated with CVID include: NFKB2, CLTA4, PI3KCD, IKZF1 and STAT3. As for recessive genes, mutations in LRBA are common in some groups. Much more rarely, mutations in CD19, CD81, ICOS CD20, CD21, and TNFRSF13C have been identified.
  Symptoms of the following disorders may be similar to those of common variable immunodeficiency. Comparisons may be useful for a differential diagnosis:
  Agammaglobulinemia is a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes (B cells) in the blood and lymph. The types of agammaglobulinemia are: X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia. All of these disorders are characterized by a weakened immune system that must be strengthened by the administration of gammaglobulin in order to fight off infections. (For more information on this disorder, choose "agammaglobulinemia" as your search term in the Rare Disease Database.)
  Hyper-IgM Syndrome (HIGM) is a rare primary immunodeficiency disorder that is usually inherited as an X-linked recessive condition. People with this disorder have low levels of IgG, IgA and IgE antibodies. Levels of IgM antibodies may be high or in the normal range. Symptoms and physical findings usually become apparent in the first or second year of life. HIGM is characterized by recurrent bacterial infections of the middle ear, sinuses, lungs, the membrane that lines the eyelid and the white portion of the eyes, the skin, and/or other areas. Affected children may have an impaired absorption of nutrients, chronic diarrhea and failure to gain weight (failure to thrive) and enlargement of the tonsils and/or enlargement of the liver and spleen (hepatosplenomegaly). In addition, affected individuals are prone to the development of autoimmune disorders of the blood such as neutropenia, in which there is a decreased level of certain white blood cells. Because approximately 70 percent of reported cases of HIGM are X-linked, the vast majority of affected individuals are male. However, autosomal recessive and autosomal dominant forms of the disorder have also been described. (For more information on this disorder, choose "Hyper IgM" as your search term in the Rare Disease Database.)
  X-linked lymphoproliferative (XLP) syndrome is an extremely rare inherited primary immunodeficiency disorder characterized by a defective immune response to infection with the Epstein-Barr virus (EBV). This virus is common among the general population and is relatively well-known because it is the cause of infectious mononucleosis (IM), usually with no long-lasting effects. However, in individuals with XLP, exposure to EBV may result in severe, life-threatening fulminant hepatitis; abnormally low levels of antibodies in the blood and body secretions (hypogammaglobulinemia), resulting in increased susceptibility to various infections; malignancies of certain types of lymphoid tissue (B-cell lymphomas); and/or other abnormalities. The range of symptoms and findings associated with XLP may vary considerably from person to person. In addition, the range of effects may change in an affected individual over time. In most cases, individuals with XLP experience an onset of symptoms anytime from ages about 6 months to 10 years of age. XLP is caused by mutations in the SH2D1A and XIAP genes.
  The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia. The WAS gene abnormality results in a deficiency in the WASP protein that leads to a low platelet count (thrombocytopenia). WAS-related disorders usually present in infancy and are characterized by bloody diarrhea, recurrent infections, scaling, itchy, skin rashes (eczema), and the appearance of small purple spots on the skin (petechia). The development of Pneumocystis carinii pneumonia (PCP) and intracranial bleeding are possible early, life-threatening complications. Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis and kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family. (For more information on this disorder, choose "WAS related disorders" as your search term in the Rare Disease Database.)
  In most patients, CVIDis 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 CVID 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 the subcutaneous delivery of this medication. In some, the administration of medications that block the effects of the chemical histamine (antihistamines), which is released during allergic reactions, or nonsteroidal anti-inflammatory agents (NSAIDs) are used. 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 premedication.
  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 genetic 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.
  Contact for additional information about common variable immune deficiency:
  The Prism Immunology Institute
  1425 Madison Avenue,
  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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