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Overview of Immunodeficiency Disorders

By James Fernandez, MD, PhD, RJ Fasenmyer Center for Clinical Immunology

Immunodeficiency disorders involve malfunction of the immune system, resulting in infections that develop and recur more frequently, are more severe, and last longer than usual.

  • Immunodeficiency disorders usually result from use of a drug or from a long-lasting serious disorder (such as cancer) but occasionally are inherited.

  • People usually have frequent, unusual, or unusually severe or prolonged infections and may develop an autoimmune disorder or cancer.

  • Doctors suspect immunodeficiency based on symptoms and do blood tests to identify the particular disorder.

  • People may be given antimicrobial drugs (such as antibiotics) to prevent and treat infections.

  • Immune globulin may be given if there are too few antibodies (immunoglobulins) or they are not functioning normally.

  • If the disorder is severe, stem cell transplantation is sometimes done.

Immunodeficiency disorders impair the immune system’s ability to defend the body against foreign or abnormal cells that invade or attack it (such as bacteria, viruses, fungi, and cancer cells). As a result, unusual bacterial, viral, or fungal infections or lymphomas or other cancers may develop.

Another problem is that up to 25% of people who have an immunodeficiency disorder also have an autoimmune disorder (such as immune thrombocytopenia). In an autoimmune disorder, the immune system attacks the body's own tissues. Sometimes the autoimmune disorder develops before the immunodeficiency causes any symptoms.

There are two types of immunodeficiency disorders:

  • Primary: These disorders are usually present at birth and are usually hereditary. They typically become evident during infancy or childhood. However, some primary immunodeficiency disorders (such as common variable immunodeficiency) are not recognized until adulthood. There are more than 100 primary immunodeficiency disorders. All are relatively rare.

  • Secondary: These disorders generally develop later in life and often result from use of certain drugs or from another disorder, such as diabetes or human immunodeficiency virus (HIV) infection. They are more common than primary immunodeficiency disorders.

Some immunodeficiency disorders shorten life span. Others persist throughout life but do not affect life span, and a few resolve with or without treatment.

Causes

Primary immunodeficiency

Primary immunodeficiency disorders may be caused by mutations, sometimes in a specific gene. If the mutated gene is on the X (sex) chromosome, the resulting disorder is called an X-linked disorder. X-linked disorders occur more often in boys. About 60% of people with primary immunodeficiency disorders are male.

Primary immunodeficiency disorders are classified by which part of the immune system is affected:

  • Humoral immunity, which involves B cells (lymphocytes), a type of white blood cell that produces antibodies (immunoglobulins)

  • Cellular immunity, which involves T cells (lymphocytes), a type of white blood cell that helps identify and destroy foreign or abnormal cells

  • Both humoral and cellular immunity (B cells and T cells)

  • Phagocytes (cells that ingest and kill microorganisms)

  • Complement proteins (proteins with various immune functions, such as killing bacteria and other foreign cells and making foreign cells easier for other immune cells to identify and ingest)

The affected component of the immune system may be missing, reduced in number, or abnormal and malfunctioning.

Problems with B cells are the most common primary immunodeficiency disorders, accounting for more than half.

Some Primary Immunodeficiency Disorders

Part of the Immune System That Is Affected

Disorder

Humoral immunity:Problems with B cells (lymphocytes) and their production of antibodies

Deficiency of a specific antibody ( selective immunoglobulin deficiency), such as IgA deficiency

Cellular immunity: Problems with T cells (lymphocytes)

Combined humoral and cellular immunity: Problems with B and T cells

Wiskott-Aldrich syndrome

Phagocytes: Problems with the movement or killing activity of these cells

Cyclic neutropenia

Complement proteins: Deficiency of complement proteins

Complement component 1 (C1) inhibitor deficiency (hereditary angioedema)

C3 deficiency

C4 deficiency

C5, C6, C7, C8, and/or C9 deficiency

Secondary immunodeficiency disorders

These disorders can result from

  • Prolonged (chronic) and/or serious disorders such as diabetes or cancer

  • Drugs

  • Rarely, radiation therapy

Immunodeficiency disorders may result from almost any prolonged serious disorder. For example, diabetescan result in an immunodeficiency disorder because white blood cells do not function well when the blood sugar level is high. Human immunodeficiency virus (HIV) infection results in acquired immunodeficiency syndrome (AIDS), the most common severe acquired immunodeficiency disorder.

Many types of cancer can cause an immunodeficiency disorder. For example, any cancer that affects the bone marrow (such as leukemia and lymphoma) can prevent the bone marrow from producing normal white blood cells (B cells and T cells), which are part of the immune system.

Undernutrition—whether of all nutrients or only one—can impair the immune system. When undernutrition causes weight to decrease to less than 80% of recommended weight, the immune system is often impaired. A decrease to less than 70% usually results in severe impairment.

Secondary immunodeficiency disorders also occur in older people and people who are hospitalized.

Disorders That Can Cause Immunodeficiency

Type

Examples

Blood

Multiple myeloma (a cancer)

Cancer

Many other types of cancers

Chromosomal

Down syndrome

Infections

Chickenpox (varicella)

Some bacterial infections

Hormonal

Kidney

Build up of toxic substances in the blood (uremia)

Liver

Musculoskeletal

Spleen

Removal of spleen

Other

Immunosuppressants are used to intentionally suppress the immune system. For example, some are used to prevent rejection of a transplanted organ or tissue (see Table: Drugs Used to Prevent Transplant Rejection). They may be given to people with an autoimmune disorder to suppress the body's attack against its own tissues.

Corticosteroids, a type of immunosuppressant, are used to suppress inflammation due to various disorders, such as rheumatoid arthritis. However, immunosuppressants also suppress the body’s ability to fight infections and perhaps to destroy cancer cells.

Chemotherapy and radiation therapy can also suppress the immune system, sometimes leading to immunodeficiency disorders.

Some Drugs That Can Cause Immunodeficiency

Type

Examples

Anticonvulsants (used to treat seizures)

Lamotrigine

Phenytoin

Valproate

Immunosuppressants (drugs that suppress the immune system)

Azathioprine

Cyclosporine

Mycophenolate mofetil

Sirolimus

Tacrolimus

Corticosteroids

Methylprednisolone

Prednisone

Chemotherapy drugs

Alemtuzumab

Busulfan

Cyclophosphamide

Melphalan

Other drugs such as antibodies that target and suppress specific parts of the immune system

Adalimumab

Etanercept

Infliximab

Muromonab (OKT3)

Rituximab

Tocilizumab

Spotlight On Aging: Immunodeficiency

As people age, the immune system becomes less effective in several ways (see Effects of Aging on the Immune System). For example, as people age, they produce fewer T cells. T cells help the body recognize and fight foreign or abnormal cells.

Undernutrition, which is common among older people, impairs the immune system. Undernutrition is usually thought of as a deficiency of calories, but it may also be a deficiency of one or more essential nutrients. Two nutrients that are particularly important to immunity—calcium and zinc—may be deficient in older people. Calcium deficiency becomes more common among older people, partly because as people age, the intestine becomes less able to absorb calcium. Also, older people may not get enough calcium in their diet. Zinc deficiency is very common among older people who are institutionalized or homebound.

Certain disorders (such as diabetes and chronic kidney disease), which are more common among older people, and certain therapies (such as immunosuppressants), which older people are more likely to use, can also impair the immune system.

Symptoms

People with an immunodeficiency disorder tend to have one infection after another. Usually, respiratory infections (such as sinus and lung infections) develop first and recur often. Most people eventually develop severe bacterial infections that persist, recur, or lead to complications. For example, sore throats and head colds may progress to pneumonia. However, having many colds does not necessarily suggest an immunodeficiency disorder. For example, a more likely cause of frequent infections in children is repeated exposure to infection at day care or school.

Infections of the mouth, eyes, and digestive tract are common. Thrush, a fungal infection of the mouth, may be an early sign of an immunodeficiency disorder. Sores may form in the mouth. People may have chronic gum disease (gingivitis) and frequent ear and skin infections. Bacterial infections (for example, with staphylococci) may cause pus-filled sores to form (pyoderma). People with certain immunodeficiency disorders may have many large, noticeable warts (caused by viruses).

Many people have fevers and chills and lose their appetite and/or weight.

Abdominal pain may develop, possibly because the liver or spleen is enlarged.

Infants or young children may have chronic diarrhea and may not grow and develop as expected (called failure to thrive). Immunodeficiency may be more severe if symptoms develop in early childhood than if they develop later.

Other symptoms vary depending on the severity and duration of the infections.

Primary immunodeficiencies may occur as part of a syndrome with other symptoms. These other symptoms are often more easily recognized than those of the immunodeficiency. For example, doctors may recognize DiGeorge syndrome because affected infants have low-set ears, a small jawbone that recedes, and wide-set eyes.

Diagnosis

  • Blood tests

  • Skin tests

  • A biopsy

  • Sometimes genetic testing

Doctors must first suspect that an immunodeficiency exists. Then they do tests to identify the specific immune system abnormality.

Doctors suspect immunodeficiency when one or more of the following occur:

  • A person has many recurrent infections (typically sinusitis, bronchitis, middle ear infections, or pneumonia).

  • Infections are severe or unusual.

  • A severe infection is caused by an organism that normally does not cause severe infection (such as Pneumocystis, fungi, or cytomegalovirus).

  • Recurring infections do not respond to treatment.

  • Family members also have recurring infections.

Physical examination

Results of a physical examination may suggest immunodeficiency and sometimes the type of immunodeficiency disorder. For example, doctors suspect certain types of immunodeficiency disorders when the following are found:

  • The spleen is enlarged.

  • There are problems with the lymph nodes and tonsils.

In some types of immunodeficiency disorders, the lymph nodes are extremely small. In some other types, lymph nodes and tonsils are swollen and tender.

History

To help identify the type of immunodeficiency disorder, doctors ask at what age the person began to have recurring or unusual infections or other characteristic symptoms. Different types of immunodeficiency disorders are more likely depending on the age at which infections starts, as in the following:

  • Younger than 6 months: Usually an abnormality in T cells

  • Age 6 to 12 months: Possibly a problem with both B cells and T cells or with B cells

  • Older than 12 months: Usually an abnormality in B cells and antibody production

The type of infection may also help doctors identify the type of immunodeficiency disorder. For example, knowing which organ (ear, lung, brain, or bladder) is affected, what the infecting organism is (bacteria, fungus, or virus), and what the organism's species is can help.

Doctors ask the person about risk factors, such as diabetes, use of certain drugs, exposure to toxic substances, and the possibility of having close relatives with immunodeficiency disorders (family history). The person may also be asked about past and current sexual activity, use of intravenous drugs, and previous blood transfusions to determine whether HIV infection could be the cause.

Tests

Laboratory tests are needed to confirm the diagnosis of immunodeficiency and to identify the type of immunodeficiency disorder.

Blood tests, including a complete blood count (CBC), are done. CBC can detect abnormalities in blood cells that are characteristic of specific immunodeficiency disorders. A blood sample is taken and analyzed to determine the total number of white blood cells and the percentages of each main type of white blood cell. The white blood cells are examined under a microscope for abnormalities. Doctors also determine immunoglobulin levels, the number of red blood cells and platelets, and the levels of certain specific antibodies produced after the person is given vaccines. If any results are abnormal, additional tests are usually done.

Skin tests may be done if the immunodeficiency is thought to be due to a T-cell abnormality. The skin test resembles the tuberculin skin test, which is used to screen for tuberculosis. Small amounts of proteins from common infectious organisms such as yeast are injected under the skin. If a reaction (redness, warmth, and swelling) occurs within 48 hours, the T cells are functioning normally. No reaction could suggest a T-cell abnormality. To confirm a T-cell abnormality, doctors do additional blood tests to determine the number of T cells and to evaluate T-cell function.

A biopsy may be done to help doctors identify which specific immunodeficiency disorder is causing the symptoms. For the biopsy, doctors take a sample of tissue from the lymph nodes, lungs, and/or bone marrow. The sample is tested to determine whether certain immune cells are present.

Genetic testing may be done if doctors suspect a problem with the immune system. The gene mutation or mutations that cause many immunodeficiency disorders have been identified. Thus, genetic testing can sometimes help identify the specific immunodeficiency disorder.

Screening

Genetic testing, usually blood tests, may also be done in people whose families are known to carry a gene for a hereditary immunodeficiency disorder. These people may wish to be tested to learn whether they carry the gene for the disorder and what their chances of having an affected child are. Talking with a genetic counselor before testing is helpful.

Several immunodeficiency disorders, such as X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, severe combined immunodeficiency, and chronic granulomatous disease, can be detected in a fetus by testing a sample of the fluid around the fetus (amniotic fluid) or the fetus’s blood ( prenatal testing). Such testing may be recommended for people with a family history of an immunodeficiency disorder when the mutation has been identified in the family.

Some experts recommend screening all newborns with a blood test that determines whether they have abnormal T cells or too few T cells—called the T-cell receptor excision circle (TREC) test. This test can identify cellular immunity deficiencies, such as severe combined immunodeficiency. Identifying infants with severe combined immunodeficiency early can help prevent their death at a young age. TREC testing of all newborns is now required in many U.S. states.

Prevention

Some of the disorders that can cause immunodeficiency can be prevented and/or treated, thus helping prevent immunodeficiency from developing. The following are examples:

  • HIV infection: Measures to prevent HIV infection such as following safe sex guidelines and not sharing needles to inject drugs can reduce the spread of this infection. Also, antiretroviral drugs can usually treat HIV infection effectively.

  • Cancer: Successful treatment usually restores the function of the immune system unless people need to continue taking immunosuppressants.

  • Diabetes: Good control of blood sugar levels can help white blood cells function better and thus prevent infections.

Treatment

  • General measures and vaccines to prevent infections

  • Antibiotics and antivirals when needed

  • Sometimes immune globulin

  • Sometimes stem cell transplantation

Treatment of immunodeficiency disorders usually involves preventing infections, treating infections when they occur, and replacing parts of the immune system that are missing when possible.

With appropriate treatment, many people with an immunodeficiency disorder have a normal life span. However, some require intensive and frequent treatments throughout life. Others, such as those with severe combined immunodeficiency, die during infancy unless they are given a stem cell transplant.

Preventing infections

Strategies for preventing and treating infections depend on the type of immunodeficiency disorder. For example, people who have an immunodeficiency disorder due to a deficiency of antibodies are at risk of bacterial infections. The following can help reduce the risk:

  • Being treated periodically with immune globulin (antibodies obtained from the blood of people with a normal immune system) given intravenously or under the skin

  • Practicing good personal hygiene (including conscientious dental care)

  • Not eating undercooked food

  • Not drinking water that may be contaminated

  • Avoiding contact with people who have infections

Vaccines are given if the specific immunodeficiency disorder does not affect antibody production. Vaccines are given to stimulate the body to produce antibodies that recognize and attack specific bacteria or viruses. If the person's immune system cannot make antibodies, giving a vaccine does not result in the production of antibodies and can even result in illness. For example, if a disorder does not affect production of antibodies, people with that disorder are given the influenza vaccine once a year. Doctors may also give this vaccine to the person's immediate family members and to people who have close contact with the person.

Generally, vaccines that contain live but weakened organisms (viruses or bacteria) are not given to people who have a B- or T-cell abnormality because these vaccines may cause an infection in such people. These vaccines include rotavirus vaccines, measles-mumps-rubella vaccine, chickenpox (varicella) vaccine, varicella-zoster (shingles) vaccine, bacille Calmette-Guérin (BCG) vaccine, influenza vaccine given as a nasal spray, and oral poliovirus vaccine. The oral poliovirus vaccine is no longer used in the United States but is used in some other parts of the world.

Treating infections

Antibiotics are given as soon as a fever or another sign of an infection develops and before surgical and dental procedures, which may introduce bacteria into the bloodstream. If a disorder (such as severe combined immunodeficiency) increases the risk of developing serious infections or particular infections, people may be given antibiotics to prevent these infections.

Antiviral drugsare given at the first sign of infection if people have an immunodeficiency disorder that increases the risk of viral infections (such as immunodeficiency due to a T-cell abnormality). These drugs include amantadine for influenza and acyclovir for herpes or chickenpox.

Replacing missing parts of the immune system

Immune globulin can effectively replace missing antibodies (immunoglobulins) in people with an immunodeficiency that affects antibody production by B cells. Immune globulin may be injected into a vein (intravenously) once a month or under the skin (subcutaneously) once a week or once a month. Subcutaneous immune globulin can be given at home, often by the person with the disorder.

Stem cell transplantation can correct some immunodeficiency disorders, particularly severe combined immunodeficiency. Stem cells may be obtained from bone marrow or blood (including umbilical cord blood). Stem cell transplantation, which is available at some major medical centers, is usually reserved for severe disorders.

Transplantation of thymus tissue is sometimes helpful.

Gene therapy for severe combined immunodeficiency has been successful, but it is rarely used because some people who received it developed leukemia.

Resources In This Article

Drugs Mentioned In This Article

  • Generic Name
    Select Brand Names
  • No US brand name
  • IMURAN
  • NEORAL, SANDIMMUNE
  • CYTOXAN (LYOPHILIZED)
  • DILANTIN
  • RAYOS
  • RITUXAN
  • ACTEMRA
  • ZOVIRAX
  • RAPAMUNE
  • MYLERAN
  • PROGRAF
  • CAMPATH
  • ALKERAN
  • LAMICTAL
  • MEDROL
  • REMICADE
  • HUMIRA
  • ENBREL

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