Common variable immunodeficiency

Definition

Common variable immunodeficiency (CVID) is a disorder of the immune system characterized by low levels of specific immunoglobulins, antibodies produced by the immune system to fight infection or disease. In CVID, immunoglobulin G (IgG) antibodies, one of several classes of antibodies, are either absent or produced in lower than normal numbers. Children who have this disorder are subject to recurring infections and may not respond appropriately to immunization. In some children, levels of the four types of IgG may be out of balance, a condition that has been associated with autoimmune diseases.

Description

The function of the immune system is to respond to organisms and substances that invade the body, such as bacteria, viruses, fungi, parasites, and toxins, by producing antibodies against them. Antibodies are specific proteins (immunoglobulins) manufactured by the immune system to bind to corresponding molecules (antigens) on the cell surfaces of foreign organisms in an attempt to make them harmless. This antigen/antibody reaction is the body's way of protecting itself from invasion and possible illness. Immunodeficiency means that the immune system is deficient in one or more of its components and is unable to respond effectively to disease-producing organisms that invade the body. IgG antibodies, the specific immunoglobulins absent or reduced in CVID, are targeted at bacterial organisms, viruses, and certain toxins.

Individuals with CVID will typically have frequent infections, especially repeat infections caused by the same organism. Recurring infections are an indication that the immune system is not responding normally and that immunity to reinfection has not developed. Surprisingly, people with CVID will usually have a normal number of B cells, the type of white blood cells (B-cell lymphocytes) that make antibodies to fight infection. However, the B cells will either be lacking one of the necessary IgG antibodies (IgG subclasses IgG1, IgG2, IgG3, and IgG4) on their surfaces or will have reduced amounts of one or more subclasses, making the B cells incapable of responding appropriately to microorganisms. Although the total IgG level may be normal, the imbalance in the types of IgG antibodies makes the B cells unprepared to fight all types of infection. The toxin associated with tetanus , for example, is attacked by IgG1 and IgG3 antibodies; reduced percentages of either immunoglobulin subclass on a child's cells will leave the child unprotected against that specific toxin. Similarly, frequent sinus infections may result from deficiencies of IgG2 and IgG3.

CVID may include deficiencies in other immunoglobulins as well, such as IgA and IgM deficiencies, although these deficiencies are more frequently associated with a group of other primary immunoglobulin deficiencies (agammaglobulinemia, severe combined immunodeficiency , and others). Other components of the immune system may be normal in CVID. T-cell lymphocytes, the type of white cells responsible for cellular immunity, are usually manufactured at normal levels in the same individuals who have CVID, although certain cell signal components may be lacking.

Autoimmune diseases such as autoimmune hemolytic anemia (AIHA), immune thrombocytopenia purpura (ITP), rheumatoid arthritis, autoimmune thyroiditis, and systemic lupus erythematosus are sometimes associated with CVID. These conditions develop in CVID as a result of the production of autoantibodies (antibodies directed against the body's own tissue). The term variable applies to this range of possible complications, which also includes gastrointestinal disorders as well as certain cancers, such as lymphomas and leukemias.

Demographics

Common variable immunodeficiency is believed to affect one in 50,000 to 200,000 individuals although it is not always diagnosed, and exact numbers of cases in the population cannot be accurately determined.

Causes and symptoms

The cause of common variable immunodeficiency was as of 2004 not known, although some forms seem to be inherited. The group of deficiencies is believed to be heterogeneous, that is, having widely varying characteristics among those affected.

CVID usually appears in children after the age of ten. The primary symptom is the presence of recurring infections that tend to be chronic rather than acute. Most children have had at least one episode of pneumonia caused by Streptococcus pneumoniae . Some children may also have frequent digestive disturbances and diarrhea that can lead to improper absorption of nutrients and malnourishment, occurring most commonly in IgA deficiency.

When to call the doctor

Young children and teenagers who are having recurrent infections, particularly infections of the same type such as frequent upper respiratory infection or chronic chest symptoms, ear infections, sinusitis, asthma , or pneumonia should be evaluated by a pediatrician or family practitioner.

Diagnosis

Children are typically diagnosed after age ten, but some immunoglobulin subclass deficiencies appear between ages one and three and are diagnosed after repeat cases of sinusitis, pneumonia, bacteremia, bronchiectasis, or diarrhea and malabsorption. A history of the child's illnesses and immunizations will be obtained, and the doctor will determine the child's general pattern of growth and development. Diagnostic testing may include routine blood tests such as a complete blood count (CBC) and differential (peripheral blood smear) to evaluate overall health and determine the type and number of red cells, white cells, and platelets in the blood. B lymphocytes and T lymphocytes may be quantified. An erythrocyte sedimentation rate (ESR) may be done to determine if inflammation is present. Blood chemistries may be performed to evaluate overall organ system functioning. If immunodeficiency is suspected, the primary diagnostic test that will distinguish common variable immunodeficiency from other types of immune system dysfunction is a reduced level of IgG immunoglobulins or IgG antibody subclasses, despite a relatively normal number of B cells. Serum immunoglobulin levels are measured in the clinical laboratory by a procedure called electrophoresis. This procedure both quantifies the amount of each antibody present and identifies the various classes and subclasses of antibodies. Deficiencies may be noted in one class or subclass or in combinations of IgG, IgM and IgA antibodies. Genetic testing may be done to rule out other types of immunodeficiency disease.

Not all children who have repeat infections are immunodeficient. Doctors tell the difference by evaluating the child's history and development. A normal child who most likely does not need further examination or diagnostic testing will have the following characteristics:

• no history of deep infection at multiple sites, even though repeat upper respiratory infections or ear infections may occur
• overall normal growth and body functions
• generally good health and normal functioning between infections
• no known family history of immune system deficiencies

The type of organism causing repeat infection can be a clue to which immunoglobulins are deficient. Therefore, when infection is present in suspected cases of common variable immunodeficiency, it may be important to identify the bacteria or virus causing the illness. Diagnostic tests may include performing a culture on material from the nose, throat, a wound, blood, or urine of the affected child.

Treatment

As of 2004 no specific treatment cured common variable immunodeficiency; each child is treated according to the individual clinical condition, the symptoms presented, and the antibody subclasses shown to be absent or deficient. Treatment is aimed generally at boosting the body's immune response and preventing or controlling infections. Immune serum, obtained from donated blood that contains adequate levels of IgG antibodies, may sometimes be transfused as a source of antibodies to boost the immune response, even though it may not contain all the antibodies the child needs and may lack antibodies specific for some of the recurring infections. The preferred treatment is to give immunoglobulins intravenously (immunoglobulin intravenous therapy or IVIG) or intramuscularly (IMIG) if specific antibody deficiencies are found; this is not usually done to boost IgA levels, however, because of the possible presence of anti-IgA antibodies that could cause an unwanted reaction. Immunization against frequent infection can be achieved in some children by administering polysaccaride-protein conjugate vaccines shown to improve immune response in certain types of infection. Antibiotics are used routinely at the first sign of an infection to help eliminate infectious organisms.

Alternative treatment

Several nutritional supplements are reported to help build the immune system. These include garlic (contains the essential trace element germanium), essential fatty acids (abundant in flax seed oil, evening primrose oil, and fish oils), sea vegetables such as kelp, acidophilus to supply natural bacteria in the digestive tract, and vitamins A and C, both powerful antioxidants that improve immune function and increase resistance to infection. Zinc is another nutrient essential to immune system functioning. Green drinks made with young barley are believed to cleanse the blood and supply chlorophyll and nutrients for tissue repair. Alcohol, medications, drugs, coffee, and other caffeine drinks should be avoided. Stress is known to produce biochemicals that reduce white blood cell functioning; therefore, it is important for the child to get sufficient sleep and reduce stress to help improve immune system functioning. Therapeutic massage, yoga , and other types of stress reduction programs are available in most communities.

Prognosis

Regular medical observation, treatment of symptoms, and appropriate immune system boosting usually produces a good result in children with common variable immunodeficiency. In some children, delayed maturation of certain IgG subclasses will make the condition a temporary one that corrects itself as more typical levels of the IgG antibodies develop. In other children, prognosis is related to the immune system's ability to produce specific antibodies. Individuals with common variable immunodeficiency usually have a normal life span although a variety of complications can occur, including autoimmune, gastrointestinal, granulomatous, and malignant conditions as a result of progressive immune deficiency.

Prevention

The disorder cannot be prevented, but parents can take precautions to prevent the recurrent infections commonly associated with immunodeficiency. For example, practicing good hygiene and providing optimum nutrition are important for helping children avoid contact with infectious organisms and to develop resistance against them. Avoiding crowds and staying away from other children or relatives who have active infections is another important way to avoid challenges to the immune system.

Nutritional concerns

Maintaining a healthy immune system requires essential nutrients that can be provided through a good diet and regular supplementation. A diet to improve immune system functioning includes fresh fruits and vegetables, as many eaten raw as possible to provide necessary enzymes; whole grain cereals, brown rice, and whole grain pasta for essential vitamins, minerals , and fiber; and non-meat sources of protein such as nuts, seeds, tofu, legumes (beans), and eggs. Fish, fowl, and lean meats can be consumed in small amounts. Sweets, especially if sweetened with refined sugars, should be reduced or avoided altogether. Vitamin supplements should include vitamins A, C, and E, which are all valuable parts of the body's defense system, helping to increase the production of healthy white blood cells and to fight infection.

Parental concerns

Parents are aware that school-age children and teenagers are in frequent contact with their peers in school and at play , and infections commonly spread. In this situation, when infection occurs frequently, it is important to remember that not all children or teens who have repeat infections are immunodeficient and that the pediatrician or family practitioner will have specific criteria and diagnostic tests to rule out common variable immunodeficiency.

See also Immunodeficiency syndromes; HIV infection and AIDS .

Resources

BOOKS

Sompayrac, Lauren. How the Immune System Works. Oxford, UK: Blackwell, 2003.

ORGANIZATIONS

Centers for Disease Control and Prevention. 1600 Clifton Road, Atlanta, GA 30333. Web site: http://www.cdc.gov.

WEB SITES

"Understanding the Immune System." Science behind the News. Available online at http://press2.nci.nih.gov/sciencebehind/immune/immune.00htm (accessed December 8, 2004).

L. Lee Culvert John T. Lohr, PhD