Immunodeficiency

Definition

Immunodeficiency disorders are a group of disorders in which part of the immune system is missing or defective. The body's ability to fight infections is, therefore, impaired. As a result, a child with an immunodeficiency disorder has frequent infections that are generally more severe and last longer than in a healthy child.

Description

The immune system is the body's main defense against infections. Any defect in the immune system decreases a person's ability to fight infections. A person with an immunodeficiency disorder may get more frequent infections, heal more slowly, and have a higher incidence of some cancers.

The normal immune system involves a complex interaction of certain types of cells that can recognize and attack foreign invaders, such as bacteria, viruses, and fungi. It also plays a role in fighting cancer . The immune system has both innate and adaptive components. Innate immunity is made up of immune protections people are born with. Adaptive immunity develops throughout life. It adapts to fight off specific invading organisms. Adaptive immunity is divided into two components: humoral immunity and cellular immunity.

The innate immune system is made up of the skin (which acts as a barrier to prevent organisms from entering the body); white blood cells called phagocytes; a system of proteins called the complement system; and chemicals called interferons. When phagocytes encounter an invading organism, they surround and engulf it in order to destroy it. The complement system also attacks bacteria. The elements in the complement system create a hole in the outer layer of the target cell, which leads to the death of the cell.

The adaptive component of the immune system is extremely complex and is as of the early 2000s still not entirely understood. Basically, it has the ability to recognize an organism or tumor cell as not being a normal part of the body and to develop a response to attempt to eliminate it.

The humoral response of adaptive immunity involves a type of cell called B lymphocytes. B lymphocytes manufacture proteins called antibodies (which are sometimes also called immunoglobulins). The terms antibody and immunoglobulin are often used interchangeably, although immunoglobulin refers to the larger classification system for antibodies. There are five types or classes of immunoglobulin that antibodies fit into, and each has a slightly different role in response against bacteria and viruses. Antibodies attach themselves to the invading foreign substance. This allows the phagocytes to begin engulfing and destroying the organism. The action of antibodies also activates the complement system. The humoral response is particularly useful for attacking bacteria.

The cellular response of adaptive immunity is useful for attacking viruses, some parasites, and possibly cancer cells. The main type of cell in the cellular response is the T lymphocyte. There are helper T lymphocytes and killer T lymphocytes. The helper T lymphocytes play a role in recognizing invading organisms, and they also help killer T lymphocytes to multiply. As the name suggests, killer T lymphocytes act to destroy the target organism.

Defects can occur in any component of the immune system or in more than one component (combined immunodeficiency). Different immunodeficiency diseases involve different components of the immune system. The defects can be inherited (congenital) or acquired.

Congenital immunodeficiency disorders

Congenital immunodeficiency is present at the time of birth and is the result of genetic defects. These immunodeficiency disorders are also called primary immunodeficiencies. Even though more than 70 different types of congenital immunodeficiency disorders have been identified, they rarely occur. Congenital immunodeficiencies may occur as a result of defects in B lymphocytes, T lymphocytes, or both. They also can occur in the innate immune system.

HUMORAL IMMUNITY DISORDERS The congenital immunodeficiency disorder, Bruton's agammaglobulinemia , also known as X-linked agammaglobulinemia, results in a decrease or absence of B lymphocytes and, therefore, a decreased ability to make antibodies. People with this disorder are particularly susceptible to infections of the throat, skin, middle ear, and lungs. It is seen only in males because it is caused by a genetic defect on the X chromosome. Since males have only one X chromosome, they always have the defect if the gene is present. Females can have the defective gene, but since they have two X chromosomes, there will be a normal gene on the other X chromosome to counter it. Women may pass the defective gene on to their sons.

B LYMPHOCYTE DEFICIENCIES If there is an abnormality in either the development or function of B lymphocytes, the ability to make antibodies will be impaired. This deficit makes the body susceptible to recurrent infections.

A type of B lymphocyte deficiency involves a group of disorders called selective immunoglobulin deficiency syndromes . The five different types of immunoglobulins are called IgA, IgG, IgM, IgD, and IgE. The most common type of immunoglobulin deficiency is selective IgA deficiency, occurring in about one in every 500 white persons. The amounts of the other antibody types are normal. Some patients with selective IgA deficiency experience no symptoms, while others have occasional lung infections and diarrhea . In another immunoglobulin disorder, IgG and IgA antibodies are deficient, and there is increased IgM. People with this disorder tend to get severe bacterial infections.

Common variable immunodeficiency (CVID) is another type of B lymphocyte deficiency. In this disorder, the production of one or more of the immunoglobulin types is decreased, and the antibody response to infections is impaired. It generally develops in people between the ages of ten and 20. The symptoms vary among affected people. Most people with this disorder have frequent infections, and some also experience auto-immune phenomena, such as autoimmune hemolytic anemia or rheumatoid arthritis. Persons with CVID develop cancer at a higher rate than the general population, particularly lymphomas.

T LYMPHOCYTE DEFICIENCIES Severe defects in the ability of T lymphocytes to mature result in impaired immune responses to infections with viruses, fungi, and certain types of bacteria. These infections are usually severe and can be fatal.

DiGeorge syndrome is a genetic syndrome most frequently associated with a chromosomal deletion (22q11.2). This syndrome is often associated with T lymphocyte deficiencies. Children with DiGeorge syndrome either do not have a thymus or have an underdeveloped thymus. Since the thymus is a major organ that directs the production of T lymphocytes, these patients have low numbers of T lymphocytes. If the T cell count is very low the patients are susceptible to recurrent infections. The syndrome can be associated with other physical abnormalities. For example, these individuals may have distinctive facial features such as thin upper lip and flattened nasal bridge, and they may have low calcium from hypoparathyroidism or cardiac defects. If the entire syndrome is not present (as is the usual case), the syndrome is called incomplete DiGeorge, and if all elements are present and the thymus is absent, the syndrome is called complete. Children with complete DiGeorge are particularly susceptible to viral and fungal infections.

In some cases, no treatment is required for DiGeorge syndrome because T lymphocyte production improves. Either an underdeveloped thymus begins to produce more T lymphocytes, or organ sites other than the thymus compensate by producing more T lymphocytes.

COMBINED IMMUNODEFICIENCIES Some types of immunodeficiency disorders affect both B lymphocytes and T lymphocytes. For example, severe combined immunodeficiency disease (SCID) is caused by the defective development or function of these two types of lymphocytes. It results in impaired humoral and cellular immune responses. SCID usually is recognized during the first year of life. It tends to cause fungal infections, including severe thrush that does not respond to usual treatment; severe diarrhea; and serious bacterial infections. If the deficiency is not treated (usually by bone marrow transplant), a person with SCID usually dies from infection before the age of two years. The most common form of SCID is X-linked, i.e. the defect is on the X chromosome and, therefore, occurs only in boys. In the early 2000s new genetic defects leading to SCID are being identified each year.

DISORDERS OF INNATE IMMUNITY Disorders of innate immunity affect phagocytes or the complement system. These disorders also result in recurrent infections.

Acquired immunodeficiency disorders

Acquired immunodeficiency is more common than congenital immunodeficiency. It is the result of an infectious process or other disease. For example, the human immunodeficiency virus (HIV) is the virus that causes acquired immunodeficiency syndrome ( AIDS ). HIV, however, is not the most common cause of acquired immunodeficiency.

Acquired immunodeficiency often occurs as a complication of other conditions and diseases. For example, the most common causes of acquired immunodeficiency are malnutrition , some types of cancer, and infections. People who weigh less than 70 percent of the average weight of persons of the same age and gender are considered to be malnourished. Examples of types of infections that can lead to immunodeficiency are chickenpox , cytomegalovirus, German measles ( rubella ), measles, tuberculosis , infectious mononucleosis (Epstein-Barr virus), chronic hepatitis, lupus, and bacterial and fungal infections.

In some cases, acquired immunodeficiency is brought on by drugs used to treat another condition. For example, patients who have an organ transplant are given drugs to suppress the immune system so the body will not reject the organ. Also, some chemotherapy drugs that are given to treat cancer have the side effect of killing cells of the immune system. During the period of time that these drugs are being taken, the risk of infection increases. It usually returns to normal after the person stops taking the drugs.

Demographics

About 50,000 new cases of congenital immunodeficiencies are diagnosed in the United States each year. The frequency of severe combined immunodeficiency is estimated to be one out of every 50,000 to 500,000 births, and of combined variable immunodeficiency, one out of every 10,000 to 50,000 births. As of 2004 HIV is estimated to affect approximately 4.4 million children worldwide.

Causes and symptoms

Congenital immunodeficiency is caused by genetic defects that generally occur while the fetus is developing in the uterus. These defects affect the development and/or function of one or more of the components of the immune system. Acquired immunodeficiency is the result of a disease process, and it occurs later in life. The causes can be diseases, infections, or the side effects of drugs given to treat other conditions.

People with an immunodeficiency disorder tend to become infected by organisms that do not usually cause disease in healthy persons. The major symptoms of most immunodeficiency disorders are repeated infections that heal slowly. These chronic infections cause symptoms that persist for long periods of time. People with chronic infection tend to be pale and thin. They may have skin rashes . Their lymph nodes may be absent or larger than usual, and in some types of immune deficiency the spleen and liver may be enlarged. (The lymph nodes are small organs that house antibodies and lymphocytes.) This can result in black-and-blue marks in the skin. The person may lose hair from their head. Sometimes, a red inflammation of the lining of the eye ( conjunctivitis ) is present. They may have a crusty appearance in and on the nose from chronic nasal dripping.

When to call the doctor

In an undiagnosed child, parents should inquire about immune deficiency if there are frequent infections, prolonged infections, unusual infections, unusual complications of usual infections, or if there is a family history of immune deficiency. If a child is known to have an immunodeficiency disorder, a healthcare provider should be contacted if the child shows signs of having an infection, such as fever , vomiting , diarrhea, swelling of the lymph nodes, or unusual fatigue.

Diagnosis

Usually, the first sign that individuals may have an immunodeficiency disorder is that they do not improve rapidly when given antibiotics to treat an infection. An immunodeficiency disorder is likely to be present when rare diseases occur or the patient gets ill from organisms that do not normally cause diseases, especially if the patient gets repeatedly infected. When this happens in very young children, a genetic defect may be causing an immunodeficiency disorder. When this situation occurs in older children or young adults, their medical history may indicate that childhood diseases may have caused an immunodeficiency disorder. Other possibilities also exist, such as recently acquired infections (e.g. HIV, hepatitis, tuberculosis, etc.).

Laboratory tests are used to determine the exact nature of the immunodeficiency. Most tests are performed on blood samples. Blood contains antibodies, lymphocytes, phagocytes, and complement components, all of the major immune components that might cause immunodeficiency. A blood cell count determines if the number of phagocytic cells or lymphocytes is below normal. Lower than normal counts of either of these two cell types correlates with immunodeficiency. The blood cells also are checked for their appearance. Sometimes a person may have normal cell counts, but the cells are structurally defective. If the lymphocyte cell count is low, further testing is usually done to determine whether any particular type of lymphocyte is lower than normal. A lymphocyte proliferation test is done to determine if the lymphocytes can respond to stimuli. The failure to respond to stimulants correlates with immunodeficiency. Antibody levels can be measured. Complement levels can be determined by immunodiagnostic tests.

Treatment

There is no cure for congenital immunodeficiency disorders. Therapy is aimed at controlling infections (such as with antibiotics) and, for some disorders, replacing defective or absent components.

Patients with Bruton's agammaglobulinemia must be given periodic infusions of pooled immunoglobulin from multiple donors. The product is called intravenous immunoglobulin (IVIG). The infusions are given approximately once a month for life to compensate for the patients' inability to make these proteins.

Common variable immunodeficiency also is treated with periodic infusions of IVIG throughout life. Additionally, antibiotics are given when necessary to treat infections.

Patients with selective IgA deficiency usually do not require any treatment. Antibiotics can be given for frequent infections.

In some cases, no treatment is required for DiGeorge syndrome because T lymphocyte production improves on its own. In some severe cases, a bone marrow transplant or thymus transplant can be performed to correct the problem.

For most patients with SCID, bone marrow transplantation is necessary. In this procedure, healthy bone marrow from a donor who has a similar type of tissue (usually a relative, such as a brother or sister) is removed. The bone marrow, a substance that is found in the cavity of bones, is the factory that produces blood cells, including some of the white blood cells that make up the immune system. The bone marrow of the person receiving the transplant is destroyed and is then replaced with marrow from the donor. One type of SCID called adenosine deaminase (ADA) deficiency is treated with infusion of the deficient enzyme on a regular basis, and another type of SCID due to an absence of an interleukin, a protein that is important in directing the immune response, is also treated by infusions of the missing protein.

Treatment of the HIV infection that causes AIDS consists of drugs called antiretrovirals. These drugs interrupt the virus replication cycle and, therefore, spare the T cells. Several of these drugs used in various combinations with one another can treat but not cure the disease. Decreasing the viral in the blood to very low levels allows the immune system to remain in tact. Other treatments for people with AIDS are aimed at the particular infections and conditions that arise as a result of the impaired immune system.

For people being treated for cancer, periodic relief from chemotherapy drugs can restore the function of the immune system. In some cases, IVIG is utilized to boost the immune system.

Alternative treatment

For some individuals, alternative treatments such as acupuncture therapy to ease infection-related symptoms or homeopathic medicines to boost immunity may be used in conjunction with traditional medicine as part of a patient's treatment plan.

Nutritional concerns

In most cases, immunodeficiency caused by malnutrition is reversible. The health of the immune system is directly linked to the nutritional status of the patient. Among the essential nutrients required by the immune system are proteins, vitamins , iron, and zinc.

Prognosis

The prognosis depends on the type of immunodeficiency disorder. People with Bruton's agammaglobulinemia who are given IVIG infusions generally live into their 30s or 40s. They often die from chronic infections, usually of the lung. People with selective IgA deficiency generally live normal lives. They may experience problems if given a blood transfusion, and therefore they should wear a Medic Alert bracelet or have some other way of alerting any physician who treats them that they have this disorder.

SCID is the most serious of the immunodeficiency disorders. If a bone marrow transplant is not successfully performed, the child usually may not live beyond two years of age.

People with HIV/AIDS are living longer than in the past because of the antiretroviral drugs that became available in the mid-1990s. In the early 2000s HIV is still a potentially fatal illness, but medications have changed the face of the disease for those who have access to them. If medical treatment is timely and successful, T cells do not become depleted and opportunistic infections do not occur.

Prevention

Primary or congenital immunodeficiencies are genetic and are not preventable by avoidance of exposures or by dietary measures. However, someone with a congenital immunodeficiency disorder might want to consider getting genetic counseling before having children in order to find out if there is a chance they will pass the defect on to their children.

Some of the infections associated with acquired immunodeficiency can be prevented or treated before they cause problems. For example, there are effective treatments for tuberculosis and most bacterial and fungal infections. HIV infection can be prevented by practicing safe sex (e.g. using a condom ) and by not using illegal intravenous drugs. These are the primary routes of transmitting the virus.

Nutritional concerns

In general, people with immunodeficiency disorders should maintain a healthy diet because malnutrition can aggravate immunodeficiencies. People can prevent malnutrition by getting adequate nutrition . They also should avoid being near others who have colds or are sick because they can easily acquire new infections. For the same reason, they should practice good personal hygiene, especially dental care. People with immunodeficiency disorders also should avoid eating undercooked food because it might contain bacteria that could cause infection. While this food might not cause infection in others, it is a potential source of infectious organisms for someone with an immunodeficiency.

Parental concerns

If a child has been diagnosed with an immunodeficiency disorder, the parents may be instructed to refrain from having normal childhood vaccinations that contain live viruses, since even weakened versions of the virus may cause serious disease. In some cases, the immuno-deficient child needs to be encouraged to wear a mask when in public or around family members who are sick in order to reduce the risk of developing an infection.

Resources

BOOKS

Doan, Thao. Concise Medical Immunology. Hagerstown, MD: Lippincott Williams & Wilkins, 2005.

Fireman, Philip. Atlas of Allergies and Clinical Immunology. St. Louis, MO: Mosby, 2005.

Mahon, Connie. Clinical Immunology. Paramus, NJ: Prentice Hall PTR, 2005.

Playfair, J. H., et al. Immunology at a Glance. Oxford, UK: Blackwell Publishing, 2005.

PERIODICALS

Bonilla, Francisco A., and Raif S. Geha. "Primary Immunodeficiency Disorders." Journal of Allergy and Clinical Immunology 112, no. 2 (February 1, 2003): S571–81.

Cooper, Megan A., Thomas L. Pommering, and Katalin Koranyi. "Primary Immunodeficiencies." American Family Physician (November 15, 2003): 2001.

Fischer, Alain. "Have We Seen the Last Variant of Severe Combined Immunodeficiency?" The New England Journal of Medicine (November 6, 2003): 1789.

ORGANIZATIONS

Children Affected by AIDS Foundation. 6033 W. Century Blvd., Suite 280, Los Angeles, CA 90045. Web site: http://www.caaf4kids.org.

Immune Deficiency Foundation. 40 W. Chesapeake Ave., Suite 308, Towson, MD 21204. Web site: http://www.primaryimmune.org.

WEB SITES

Frye, Richard E., and Delia M. Rivera-Hernandez. "Human Immunodeficiency Virus Infection." eMedicine , December 14, 2004. Available online at http://www.emedicine.com/ped/topic1027.htm (accessed January 7, 2005).

Makhoul, Hanan, et al. "Combined B-Cell and T-Cell Disorders." eMedicine , June 29, 2003. Available online at http://www.emedicine.com/med/topic3538.htm (accessed January 7, 2005).

Park, C. Lucy. "Common Variable Immunodeficiency." eMedicine. May 26, 2004. Available online at http://www.emedicine.com/ped/topic444.htm (accessed January 7, 2005).

Trigg, Michael. "Severe Combined Immunodeficiency Syndrome." Nemours Foundation , August 2002. Available online at http://kidshealth.org/parent/medical/allergies/severe_immunodeficiency.html (accessed January 7, 2005).

Wong, Henry, and Clarissa Yang. "Severe Combined Immunodeficiency." eMedicine , November 12, 2002. Available online at http://www.emedicine.com/derm/topic879.htm (accessed January 7, 2005).

John T. Lohr, PhD Teresa G. Odle Stephanie Dionne Sherk