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Primary Immunodeficiency

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Contents

NICHD Publications

Introduction

What is Primary Immunodeficiency?

The Immune Defenses

Genes and PI

Signs and Symptoms

Diagnosing PI

Treatments for PI

Important Precautions

Primary Immunodeficiency Diseases: Some Examples

Research in Progress

Future Research Challenges

Resources

Glossary


Introduction

Most of us are no strangers to infections. Just about everybody has had colds and coughs and infected cuts, the flu or chicken pox. Some people have had first-hand experience with infections that are even more serious—pneumonia and meningitis.

Usually, we expect to recover quickly from an infection. We count on our body's immune defenses (sometimes with the help of antibiotics) to get rid of any germs that cause infection, and to protect us against new germs in the future.

Some people, however, are born with an immune defense system that is faulty. They are missing some or, in the worst cases, almost all of the body's immune defense weapons. Such people are said to have a primary immunodeficiency (PI).

There are over 70 different types of PIs. Each type has somewhat different symptoms, depending on which parts of the immune defense system are deficient. Some deficiencies are deadly, while some are mild. But they all have one thing in common: they may open the door to multiple infections.

Individuals with PI—many of them infants and children—get one infection after another. Ear, sinus, and other infections may not improve with treatment as expected, but keep coming back or occurring with less common but severe infections, such as recurrent pneumonia. Besides being painful, frightening, and frustrating, these constant infections can cause permanent damage to the ears or to the lungs.

In the more severe forms of PI, germs which cause only mild infections in people with healthy immune systems may cause severe or life-threatening infections.

Although infections are the hallmark of PIs, they are not always the only health problem, or even the main one. Some PIs are associated with other immune system disorders, such as anemia, arthritis, or autoimmune diseases. Other PIs involve more than the immune system; some, for instance, are associated with symptoms involving the heart, digestive tract, or the nervous system. Some PIs retard growth and increase the risk of cancer.

Today, thanks to rapid advances in medicine, many PI diseases can be successfully treated or even cured. With proper treatment, most people with PIs are not only surviving once-deadly diseases, they are usually able to lead normal lives. Children usually can go to school, mix with playmates, and take part in sports. Most adults with PI are leading productive lives in their communities.

Successfully combatting PI, however, depends on prompt detection. Physicians, parents, and adult patients alike need to recognize when infections are more than "ordinary," so that treatment can be started in time to prevent permanent damage or life-threatening complications.

This booklet is designed to make PIs easier to recognize, and to cope with, by making them more familiar. It describes how these diseases arise, how they affect health, and how they can be treated. It also reports on promising areas of research, and suggests sources of help for patients and their families. It is not intended as a substitute for professional medical care. You should consult your pediatrician or family physician for specific information on the diagnosis, treatment, and clinical care of patients with PI.

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What Is Primary Immunodeficiency?

A PI disease results whenever one or more essential parts of the immune system is missing or not working properly at birth because of a genetic defect. Since the immune system is tremendously complex, hundreds of things can go wrong during development and sometimes the backup systems cannot compensate for the defects. (See section on The Immune Defenses)

A variety of developmental errors in the immune system create different types of PIs. They make people susceptible to different kinds of germs and create different sets of symptoms.

THE IMMUNE DEFENSE SYSTEM IS A BODY-WIDE NETWORK OF ORGANS, TISSUES, CELLS, AND PROTEIN SUBSTANCES THAT WORK TOGETHER TO DEFEND THE BODY AGAINST ATTACKS BY "FOREIGN" INVADERS.

PI diseases were once thought to be rare, mostly because only the more severe forms were recognized. Today physicians realize that PIs are not uncommon. They are sometimes relatively mild, and they can occur in teenagers and adults as often as in infants and children.

Very serious inherited immunodeficiencies become apparent almost as soon as a baby is born. Many more are discovered during the baby's first year of life. Others—usually the milder forms—may not show up until people reach their twenties and thirties. There are even some inherited immune deficiencies that never produce symptoms.

The exact number of persons with PI is not known. It is estimated that each year about 400 children are born in the United States with a serious PI. The number of Americans now living with a primary immunodeficiency is estimated to be between 25,000 and 50,000.

As new laboratory tests become more widely available, more cases of PIs are being recognized. At the same time, new types of PI are being discovered and described.

Currently, the World Health Organization lists over 70 PIs and the numbers are increasing.

Among the rarest forms of immune deficiency is Severe Combined Immune Deficiency (SCID). SCID has been reported in small numbers, while some deficiencies, like DiGeorge Anomaly, are diagnosed more commonly.

At the other extreme, an immune disorder called Selective IgA Deficiency may occur in as many as one in every 300 persons. This figure is an estimate, based on studies of blood from blood donors, since most people with IgA deficiency are healthy and never realize they have this disorder.

Where Do Primary Immunodeficiency Diseases Come From?

PI diseases are usually inherited. Like anything that is inherited, these diseases are the result of altered or mutated genes that can be passed on from parent to child or can arise as genes are being copied. (See box on DNA, Genes and Chromosomes.)

One or both parents, usually healthy themselves, may carry a gene (or genes) that is somehow defective or mutated, so that it no longer produces the right protein product. If their child inherits a defective gene and does not have a normal gene to compensate, the child may show signs of immunodeficiency. The loss of just one small molecule, if it is an important one, can impair the body's immune system.

Sometimes close relatives—brothers, sisters, cousins—also inherit the defective gene. If they do not inherit a normal gene copy they may also have immunodeficiency. In some PIs, some relatives may have only mild symptoms, while others may have no symptoms at all.

It is also possible to develop, or acquire, an immunodeficiency disorder during one's lifetime. This can be the result of immune system damage due to an infection, as is the case with AIDS—the acquired immune deficiency syndrome. AIDS is caused by infection with HIV, the human immunodeficiency virus, which infects immune cells and destroys the immune system. When HIV is transmitted from the mother to the baby, congenital AIDS may occur; but the disease is viral and not inherited.

An immunodeficiency can also develop as the unintended side-effect of certain drug or radiation treatments, such as those given to cancer or transplant patients.

The focus of this booklet is primary immunodeficiency disease that is heritable. It is carried through the genes; you cannot "catch it" like a cold.

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The Immune Defenses

The immune defense system is a body-wide network of organs, tissues, cells, and protein substances that work together to defend the body against attacks by "foreign" invaders. Those invaders are primarily germs—tiny, infection-causing organisms such as bacteria and viruses, parasites and fungi. (See box on Germs)

The immune system is amazingly complex. It can recognize millions of different enemies, and it can enlist specialized cells and secretions to seek out and destroy each of them. (Substances recognized as foreign that provoke an immune response are called antigens.)

The organs of the immune system are known as lymphoid organs because they are home to lymphocytes, small white blood cells that are key components of the immune defenses. Bone marrow is soft tissue in the hollow center of bones, and it is the original source of all blood cells. The thymus is an organ that lies behind the breastbone; that is where some lymphocytes mature. The spleen, located in the upper left of the abdomen, serves as headquarters for many immune system activities.

Types Of White Blood Cells

Immune cells, once alerted to danger, undergo important changes. They begin to produce powerful chemicals that allow the cells to grow and multiply, and to attract and direct their fellow cells.

To work well, most immune cells need the help of other immune cells. Sometimes immune cells communicate with one another by direct physical contact, sometimes by releasing chemical messengers.

Each type of immune cell has its special role. B cells work chiefly by making plasma cells that secrete antibodies. Antibodies are large molecules that attach to invading germs (and other foreign particles) and mark them for destruction.

T cells contribute to the immune defenses in two major ways. Helper T cells and cytotoxic T cells secrete powerful chemicals (cytokines) that allow them to control the immune responses, including the work of B cells. Natural killer cells directly attack cells that have been infected by viruses.

Phagocytes are large white blood cells that act as scavengers. They roam through the body, engulfing germs and destroying them. Neutrophils and monocytes are phagocytes that contain bags of potent chemicals that help destroy the germs they engulf.

Antibodies are blood proteins known as immunoglobulins. They are produced by B cells. Different types, or classes, of immunoglobulins play different roles in immune defenses. As an immune response unfolds, B cells gradually switch from making one type of immunoglobulin to another.

  • Immunoglobulin M (IgM) is the first to respond to an invading germ. IgM antibodies tend to stay in the bloodstream, where they aid in killing bacteria.
  • Immunoglobulin G (IgG) follows on the heels of IgM. It is the main immunoglobulin working in the blood and tissues. IgG antibodies coat germs so that immune cells have an easier time of engulfing them.
  • Immunoglobulin A (IgA) is produced along surface linings of the body and secreted in body fluids such as tears, saliva, and mucus, where it protects the entrances to the body—mouth, nose, lungs, and intestines. It is also present in breast milk and provides important protection against bacteria in the intestines of newborns.
  • Immunoglobulin E (IgE) which is normally present only in trace amounts, is an important component of allergic reactions.

Another important component of the immune defenses is the complement system. The complement system is composed of a series of more than 20 blood proteins that, when activated, work closely together in a step-wise fashion. Complement helps antibodies and phagocytes destroy bacteria and acts as a signal for recruiting phagocytes to sites of infections.

Although the immune system is designed to recognize and attack foreign invaders, its recognition program sometimes breaks down. Then the body begins to make T cells and antibodies directed against its own cells and organs. These misguided T cells and these autoantibodies, as they are known, contribute to "autoimmune" diseases. For instance, T cells that attack pancreatic islet cells contribute to diabetes, while certain autoantibodies are common in persons with rheumatoid arthritis.

Lymphocytes can travel throughout the body, using the blood vessels or a system of lymphatic vessels. The lymphatic vessels carry a clear fluid known as lymph. Scattered along the lymphatic vessels are small, bean-shaped lymph nodes, where immune cells gather and interact.

Clumps of lymphoid tissue are found in many parts of the body, especially in the linings of the digestive tract and the airways and lungs—areas that protect gateways into the body. These tissues include the tonsils, adenoids, and appendix.

The immune system makes use of many types of white blood cells. These include two main kinds of lymphocytes, T lymphocytes (T cells) and B lymphocytes (B cells); and a class of cytotoxic lymphocytes called natural killer (NK) cells. Additionally, there are large white blood cells known as phagocytes (neutrophil and monocyte).

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Genes and PI

In the past few years, scientists have succeeded in identifying the genes that are responsible for many PI diseases. These include X-Linked Agammaglobulinemia, X-linked Hyper-IgM Syndrome, Wiskott-Aldrich Syndrome, Ataxia Telangiectasia, four forms of Chronic Granulomatous Disease, and several forms of SCID. The search for other genes that cause PI is under way and more are being discovered.

Sometimes the same, or nearly the same, symptoms can be the product of different defective genes on different chromosomes. For example, SCID can be caused by mutations in different genes. One genetic defect blocks activation of B cells and T cells. Another genetic defect prevents immune cells from getting rid of toxic chemicals. In every case, however, the end result is the same: major immune defenses are non-functional.

Once researchers have identified the defective gene, they try to find out what it normally does, what protein it makes, and how that protein contributes to the immune response. Some proteins, for example, relay signals that tell immune cells to multiply and mature. Other proteins help the immune system to eliminate excess or unwanted cells.

The next step is to ascertain what happens when the protein is missing or distorted and how the faulty protein causes disease.

Learning about a disease-causing gene and its protein product raises the exciting prospect of finding a cure for the disease.

Germs

  • Bacteria are tiny living organisms. Each bacterium consists of a single cell, but bacteria often live in colonies. Most are harmless or even beneficial, but some can cause illness and death.

Bacteria are responsible for many respiratory, skin, and bone infections. Examples of infection-causing bacteria include "strep" ( Streptococcus) and "staph" ( Staphylococcus).

  • Viruses consist of the barest essentials: a strand of genetic material, either DNA or RNA, surrounded by a protein coat. Some viruses also have an outer envelope. Viruses are so simple that, in order to reproduce, they need to invade a living cell and use the cell's machinery.

Different types of viruses target different types of cells. Some viruses kill the cell they invade. Others permanently change the way the cell behaves.

Viruses cause the flu (or influenza, a highly contagious respiratory infection), colds, polio, hepatitis (liver inflammation), and measles. A single virus family, Herpes viruses, causes everything from cold sores to chicken pox.

  • Parasites live, grow, and feed on other organisms, which serve as their "hosts." Parasites come in many shapes and sizes, and they cause a wide range of diseases.

Microscopic one-cell parasites known as Cryptosporidium and Giardia lamblia cause diarrhea and inflammation of the digestive system. Pneumocystis carinii can cause pneumonia, and Toxoplasma gondii can produce brain inflammation.

  • Mycoplasma are simpler than bacteria but more complex than viruses. They are the smallest known organisms that can live without a host. Mycoplasma can cause pneumonia and a type of arthritis.
  • Fungi, which are primitive plant forms, include yeasts and molds. As a cause of disease, they are especially dangerous for persons with impaired immunity.

A fungus called Candida albicans causes thrush, which commonly forms a white mat coating on the inside of the mouth in severely immunodeficient people. This fungus may also cause esophagitis, a type of diaper rash, or a blood infection. Cryptococcus can cause meningitis, an inflammation of the membranes surrounding the brain and spinal cord. Aspergillus, an ordinarily harmless mold, can cause severe infections in those with PI, especially infections of the lung.

One possibility might be to replace a mutated gene through gene therapy. Another way might be to supply the missing protein as a medicine.

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Signs And Symptoms

The most common problem in PI disease is an increased susceptibility to infection. For people with PI, infections may be common, severe, lasting, or hard to cure.

Even healthy youngsters may get frequent colds, coughs, and earaches. For example, many infants and young children with normal immunity have one to three ear infections per year. Children with PI, however, can get one infection after another. Or they get two or three infections at a time. Weakened by infection, the child may fail to gain weight or fall behind in growth and development.

Despite the usual antibiotics, the infections of PI often drag on and on, or they keep coming back—that is, they become chronic. One common problem is chronic sinusitis (infection and inflammation of the sinuses, air passages in bones of the cheeks, forehead, and jaw). Another common problem is chronic bronchitis (infection and inflammation of the airways leading to the lungs).

DNA, Genes, And Chromosomes

All our traits—height, eye color, foot size—are determined by the genes that we inherit from our parents. A gene is a working subunit of DNA. DNA is like a huge database, made up of millions of chemical building blocks. DNA resides in the core of every cell, and it carries a complete set of instructions, or blueprint, for making everything the cell will ever need.

The DNA in each human cell contains about 100,000 genes. Each gene encodes the instructions that allow the cell to make one specific product—for example, a protein such as an enzyme. (Proteins are major components of all cells. Enzymes are proteins which help carry out chemical reactions.)

When genes are working properly, our bodies develop correctly and work well. But small changes, or mutations, in just one gene sometimes can have huge effects, leading to birth defects and other diseases.

DNA is packaged in structures known as chromosomes. Chromosomes come in pairs, and a normal human cell contains 46 chromosomes. These consist of 22 pairs of "autosomes" and two "sex chromosomes," X and Y. A female has two X chromosomes while a male has one X and one Y.

We inherit one chromosome of each pair from our mother and the other from our father. Since genes are lined up on the chromosomes, we thus inherit two copies of most genes, one from each of our parents.

If one copy of a gene is not working properly, its partner from the other parent can often compensate. However, this is not possible if both copies of the gene are defective or, in the case of an X chromosome gene defect in a boy, where there is only one X chromosome.

Serious infections, especially bacterial infections, may cause a youngster to be hospitalized repeatedly. Pneumonia is an infection of the smallest airways and airsacs in the lungs, which prevents oxygen from reaching the blood and makes breathing hard. Meningitis, an infection of the membranes that surround the brain and spinal cord, causes fever and severe headache, and can lead to seizures, coma, and even death. Osteomyelitis is an infection that invades and destroys bones. Cellulitis is a serious infection of connective tissues just beneath the skin.

Some people with PI develop blood poisoning, an infection that flourishes in the bloodstream and spreads rapidly through the body. Some people may develop deep abscesses, pockets of pus that form around infections in the skin or in body organs.

Some children with PI are infected with germs that a healthy immune system would hold in check. These are known as "opportunistic" infections because the germs take advantage of the opportunity afforded by a weakened immune system. Such an unusual infection may be the tip-off to an immunodeficiency.

For example, Pneumocystis carinii is a microscopic parasite that infects many healthy people without making them sick. But when the immune system is compromised, Pneumocystis can produce a severe form of pneumonia.

Toxoplasma is another widespread parasite that usually produces no disease. In persons with a weakened immune system, it causes toxoplasmosis, which can be a life-threatening infection of the brain that can cause confusion, headaches, fever, paralysis, seizures, and coma.

Patterns Of Inheritance

Scientists studying inherited diseases group them according to the way in which the disease-causing gene is passed on. In general, "recessive" diseases occur when there is no normal copy of a gene to compensate for a defective one, while "dominant" diseases are manifest even with one normal and one abnormal gene copy. Diseases caused by defects in a single gene fall into one of the following categories:

  • X-linked recessive diseases are caused by genes located on the X chromosome. Although we have two copies of most genes, men have only one X chromosome and only one copy of genes on that X chromosome. If a man inherits a disease-causing gene mutation that is on the X chromosome, he has no backup normal X gene, and he will likely develop the disease.

A woman will not usually develop an X-linked recessive disease because she has two X chromosomes, but she can be a "carrier." She remains healthy because the normal gene on one X chromosome continues to function, even though she carries the mutated gene, and can pass it on to her children. With each and every pregnancy, there is an equal chance that the baby will be a boy with the disease, a healthy girl who is a carrier, a healthy boy, or a healthy girl who is not a carrier.

For some X-linked recessive immunodeficiency diseases, carriers can be identified by laboratory tests. With others, a woman is discovered to be a carrier only after she gives birth to a child with the disease.

  • Autosomal recessive diseases occur when a person inherits two faulty recessive genes located on autosomes (non-sex chromosomes), one from each parent; both parents are healthy carriers. These diseases are as likely to affect girls as boys. With every pregnancy, there is one chance in four that the baby will have the disease, two chances in four that the baby will be healthy but a carrier, and one chance in four that the child will be healthy and not carry a defective copy of the gene.
  • Autosomal dominant disorders are caused by a single dominant gene. One of the parents is not just a carrier, but has the disease. Each child in the family has a 50-50 chance of inheriting the defective gene and the disorder.
  • New mutations may cause diseases. In some cases, neither parent has the disease-causing mutation. This may occur because the mutation in the gene occurred in the parents' germ cells (sperm or egg) but not other cells of their body. New mutations account for a substantial proportion (up to one-third) of X-linked immunodeficiency diseases.

Although many PI diseases can be traced to a single gene, others cannot. No family pattern is evident, and they are said to occur "sporadically."

A sporadic disorder might be the result of several disabled genes interacting, interactions between particular forms of genes, and environmental influences. It might develop from gene changes that occur during a person's lifetime. Or it might be due to new mutations in germ cells or an inheritance pattern that has not been recognized yet.

Some PIs are X-linked, others autosomal recessive. At least one is autosomal dominant. Some PIs have more than one pattern of inheritance. For example, a group of diseases known as Common Variable Immunodeficiency (CVID) can be inherited as autosomal recessive, autosomal dominant, or X-linked. Most cases of CVID, however, are sporadic.

Besides all the infections, some immunodeficiency diseases produce other immune system problems, including autoimmune disorders. Autoimmune disorders develop when the immune system gets out of control and mistakenly attacks the body's own organs and tissues.

In some autoimmune disorders, the faulty immune system targets a single type of cell or tissue. For example, an immune attack on blood cells can lead to anemia (a debilitating loss of red blood cells). An attack on islet cells of the pancreas can lead to diabetes (a disorder caused by insufficient amounts of insulin, a pancreatic hormone that helps the body convert digested food into energy).

In other situations, the immune system strikes multiple cells and tissues, producing diseases such as rheumatoid arthritis or systemic lupus erythematosus (SLE). Rheumatoid arthritis targets primarily the joints, but it can also damage nerves, lungs, and skin. Lupus strikes skin, muscles, joints, kidneys, and other organs, causing rashes, joint pain, fatigue, and fever, among other things.

Finally, an immunodeficiency can be just one part of a complex syndrome, with a telltale combination of signs and symptoms. For example, children with DiGeorge Anomaly not only have an underdeveloped thymus gland (and a corresponding lack of T cells), they typically have congenital heart disease, malfunctioning, or underdeveloped parathyroid glands, and characteristic facial features. Young boys with Wiskott-Aldrich Syndrome, in addition to being prone to infections, develop bleeding problems and a skin rash.

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Diagnosing PI

The 10 Warning Signs Of Primary Immunodeficiency*

*Courtesy of The Jeffrey Modell Foundation and the American Red Cross.

  1. Eight or more new ear infections within a year.
  2. Two or more serious sinus infections within a year.
  3. Two or more months on antibiotics with little effect.
  4. Two or more pneumonias within a year.
  5. Failure of an infant to gain weight or grow normally.
  6. Recurrent deep abscesses in the skin or organs.
  7. Persistent thrush in mouth or on skin, after age one.
  8. Need for intravenous antibiotics to clear infections.
  9. Two or more deep-seated infections such as meningitis, osteomyelitis, cellulitis, or sepsis.
  10. A family history of primary immunodeficiency.

Sometimes the signs and symptoms of a PI are so severe, or so characteristic, that the diagnosis is obvious. In most cases, it is not clear if a long string of illnesses are just "ordinary" infections, or if they are the result of an immunodeficiency.

Many conditions can produce an immunodeficiency, at least temporarily, and most children who seem to have "too many" infections are not, in fact, suffering from an immunodeficiency. Experts estimate that half of the children who see a doctor for frequent infections are normal. Another 30 percent may have allergies, and 10 percent have some other type of serious disorder. Just 10 percent turn out to have a primary or secondary immunodeficiency.

The Basics

When a pattern of frequent infections suggests an immunodeficiency, the doctor begins by exploring the patient's "history" and the family's history, and then conducts a physical examination.

  • The patient's history. What infections has the patient had in the past, or has now? Have they been unusually frequent, or severe, or long-lasting? Have they failed to respond to standard treatments? When a child who is immunologically normal develops a string of infections, they are usually mild and short-lived, and between infections the child recovers completely.

What, besides a PI, might explain the high rate of infections? Normal immune responses can be suppressed by many factors, including malnutrition, injuries such as burns, and certain types of drugs (corticosteroids, for instance). Immune responses can also be muted by some diseases, such as leukemia, and some infections, including: infectious mononucleosis (mono), measles, chicken pox, and AIDS. In fact, almost every serious illness impairs the immune responses.

  • Physical examination: Is the child well-nourished and growing well? A severely immunodeficient child is likely to look sickly and pale. Very often the child is underweight and lags behind in growth and development.

The child may be shy or quiet. An active, robust, healthy-looking child is less likely to have a serious immune deficiency.

The doctor will listen for changes in the lungs and look for rashes, sores, thrush in the mouth, an enlarged spleen or liver, and swollen joints. Some immunodeficient children may lack palpable tonsils or lymph nodes in the neck.

  • Family history. Have any family members or relatives ever been diagnosed with PI or shown an unusual susceptibility to infections? Have there been any infant deaths from infections? Were only boys affected?

Evaluating Immune Responses

To find out if illness can be traced to an immunodeficiency, laboratory tests are necessary. These tests, most of which can be performed on a sample of blood, probe the soundness of the various parts of the immune system. Are all the right immune cells present, in adequate numbers, and are they working properly? Are there normal amounts and types of antibodies?

Screening starts out with a few relatively simple and inexpensive routine tests. In fact, just two routine tests—complete blood count and quantitative immunoglobulins—will detect most, but not all, immunodeficiencies.

If antibodies are normal—or if the patient's infections seem to be caused by viruses or fungi—the T cells should be checked. If the T cells are present in normal numbers and function normally, phagocyte function should be evaluated.

The most common screening tests include:

  • Blood count. A complete blood count (CBC) shows levels of red blood cells and white blood cells as well as platelets. A "differential count" itemizes the different types of white blood cells, including lymphocytes and neutrophils.
  • Quantitative immunoglobulins. This standard laboratory test measures various immunoglobulin levels in the blood. In addition to total immunoglobulins, it shows levels of the different immunoglobulin types (IgG, IgM, and IgA).
  • Antibody responses. Are immunoglobulins working properly? A blood test can show if the blood contains antibodies to the usual childhood immunizations, i.e., tetanus, measles, pertussis, or diphtheria. Sometimes a person may be given a booster shot, or a specific immunization such as a tetanus shot, to see if she or he responds by producing antibodies.
  • Complement. A laboratory test using a sample of blood indicates how effectively the complement system is working.
  • Skin tests. These tests, which are similar to TB skin tests, show how well T cells are functioning. Tiny amounts of several standard reaction-provoking antigens (including mumps and Candida) are injected into the skin. A person with a healthy immune system usually develops local swelling within 24 to 48 hours. However, these tests are not as accurate in very young infants.

When screening tests indicate an immunodeficiency—or when they fail to explain a stubborn infection—additional tests will likely be needed. There are dozens of sophisticated tests that allow doctors to identify and count subsets of B cells and T cells, and to assess subtle abnormalities in antibodies, immune cells, and immune tissues. Tests can also probe the characteristics of infectious germs.

Evaluating Infections

If an infection proves resistant to standard treatments, the doctor will want to find out exactly what germs are involved. Samples of mucus, sputum, or stool, or sometimes a small sample of the infected tissue itself, removed surgically, can be "cultured" in the laboratory. This allows germs to grow until they are plentiful enough to study in detail. Once the germ is identified, it becomes possible to select the most effective treatment.

The infection itself often provides a good clue to the nature of an immune defect. Common bacteria typically elicit antibodies, while viruses and fungi stimulate T cells. Thus, sinus infections and respiratory infections, which are most often due to bacteria, suggest an antibody deficiency. Infections caused by a variety of viruses and fungi, or by Pneumocystis, point to a T cell defect. Recurrent infections involving the skin or soft tissues can often be traced to problems with phagocytes. Blood-borne infections caused by encapsulated bacteria, including meningitis, may be linked to complement deficiencies.

An experienced physician will also find clues in particular combinations of details, such as age and sex, along with the physical findings. For example, a young infant suffering from diarrhea, pneumonia, and thrush, and exhibiting "failure to thrive," may well have SCID. A 4-year-old with swollen lymph glands, skin problems, pneumonia, and bone infections may have Chronic Granulomatous Disease (CGD). A 10-year old with sinus and respiratory infections, an enlarged spleen, and signs of autoimmune problems is apt to have Common Variable Immunodeficiency.

Prenatal Diagnosis

Some PIs can be detected even before birth. Prenatal testing may be sought by families that have already had a child with a PI.

Cells for prenatal diagnosis can be obtained in several ways. In amniocentesis at about 14 weeks of pregnancy or later, a small amount of amniotic fluid containing cells shed by the fetus is removed from the uterus. In chorionic villus sampling, cells are taken from the chorion, the tissue that becomes the placenta, as early as 9-10 weeks of pregnancy. After about the 18th week of pregnancy, it is possible to obtain a sample of blood from the fetus.

Prenatal tests make it possible to identify abnormalities in cells or, in the case of some deficiencies, of enzymes. In disorders where a gene mutation has been identified, DNA from fetal cells can be checked for the gene defect.

In some cases, test results make it possible to be ready to treat the baby with a bone marrow transplant soon after birth. Intrauterine bone marrow transplantation of the fetus is also being studied.

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Treatments For PI

Treating PI involves not only curing infections but also correcting the underlying immunodeficiency. In addition, any associated conditions, such as autoimmune disorders or cancer, need special attention.

Treating Infections

The first goal of treatment is to clear up any current infection. Doctors can prescribe a wide range of infection-fighting antimicrobials. Some are broad-spectrum antibiotics that combat a range of germs. Others zero in on specific germs.

When an infection fails to respond to standard medications, the patient may need to be hospitalized to be treated with antibiotics and other drugs intravenously.

For chronic infections, a variety of medicines can help relieve symptoms and prevent complications. These may include drugs like aspirin or ibuprofen to ease fever and general body aches, decongestants to shrink swollen membranes in the nose, sinuses, or throat, and expectorants to thin mucus secretions in the airways.

People who have chronic respiratory infections may be made more comfortable with a technique known as postural drainage (or bronchial drainage). Developed for persons with cystic fibrosis, postural drainage uses gravity, along with light blows to the chest wall, to help clear secretions from the lungs.

Bone Marrow Transplantation (BMT)

In bone marrow transplantation (BMT), bone marrow is taken from a healthy person and transferred to the patient. Because bone marrow is the source of all blood cells, including infection-fighting white blood cells, a successful bone marrow transplant amounts to getting a new, working immune system.

BMT usually takes place in the hospital. The donor is put to sleep with a light general anesthesia, and bone marrow is removed through a large needle inserted into the pelvic bone in the lower back. A small amount of marrow is removed from each of several sites.

The bone marrow may be treated to remove mature T cells which could attack the recipient's tissues. It is then given to the patient like an ordinary blood transfusion. Marrow cells travel to the patient's own marrow spaces, inside the bones. There they begin making a complete assortment of healthy blood cells.

Preventing Infections

When the immune defenses are weak, it is essential to avoid germs. Precautions range from common sense practices like good hygiene (using mild soaps to keep the skin clean and brushing teeth twice a day) and good nutrition to elaborate measures to prevent all contact with infectious agents.

Anyone with an immunodeficiency needs to avoid unnecessary exposure to infectious agents. This means staying away from people with colds or other infections, and avoiding large crowds. (On the other hand, it is important not to become overly cautious. Children are encouraged to attend school, to play in small groups, and to participate in sports.)

Antibiotics are important for preventing or controlling infections. If infections threaten to become chronic, the doctor may prescribe continuous long-term low-dose antibiotics. Such preventive, or "prophylactic," therapy may help prevent hearing loss or permanent breathing problems.

When Pneumocystis pneumonia is a danger—for instance, in children with a profound T cell deficiency—an appropriate prophylactic treatment may consist of a combination of two drugs, trimethoprim and sulfamethoxazole.

Correcting Immunodeficiencies

Not long ago, little could be done to actually cure an immunodeficiency. Today, researchers have developed several possibilities for replenishing the immune defenses. No single approach works for all immunodeficiencies or in all cases but, taken together, these new treatments have transformed a dismal prognosis into one of hope and promise.

For several life-threatening immunodeficiencies, bone marrow transplantation (BMT) offers the chance of a dramatic, complete, and permanent cure. Since the first BMT was performed in 1968, nearly 1,000 children with PI, including SCID, Wiskott-Aldrich Syndrome, Leukocyte Adhesion Defect, and other disorders, have shown a remarkable recovery. They recover from infections, gain weight, and move on to essentially normal lives.

Unfortunately, bone marrow transplants don't work for everyone. To be successful, the transplant needs to come from a donor whose body tissues are a close biological "match." That is, the donor's tissues and the recipient's tissues should have identical, or nearly identical, sets of marker molecules (known as HLA antigens) that serve as unique tissue ID tags.

Without a good match, a reaction known as graft-versus-host disease (GVHD) may occur, in which cells in the donor marrow see the recipient's tissues as foreign and react against them.

Because tissue marker molecules come in many varieties, finding a good match is not easy. With new techniques and the availability of large donor banks, however, finding a suitable match is easier. The best matches are likely to be with close relatives, especially brothers or sisters.

Another option is marrow from a close relative—typically a parent—who shares half of the patient's major HLA antigens (and many of the minor antigens as well.) Cleansed of mature T cells that could trigger a GVHD, such half-matched transplants have saved the lives of many children.

BMT works especially well for SCID, because children with SCID lack T cells that could attack the bone marrow graft and cause rejection. Anyone with T cells may need to be treated, prior to transplantation, with radiation or drugs. Although this eliminates the recipient's T cells, it also temporarily wipes out other immune defenses, further increasing the patient's risk of infection.

Even with a good match, BMT does not always succeed. Results are best when the child is young, in fairly good health, and free of serious infection at the time of the transplantation.

Another treatment option, for children with a specific form of SCID who don't have a suitable bone marrow donor, is enzyme replacement therapy. About 15 percent of all cases of SCID are due to lack of the enzyme known as adenosine deaminase (ADA). This type of SCID can be partially treated with regular injections of the missing enzyme. For treatment, ADA is linked to a chemical, polyethylene glycol (PEG), which protects ADA from being quickly eliminated from the bloodstream.

For many people with antibody deficiencies, antibody replacement therapy can be a lifesaver. The patient receives regular infusions or injections of immunoglobulins, or antibodies, that have been removed from the blood of healthy donors and purified. Immunoglobulins from thousands of donors are pooled so that each batch contains antibodies to many different types of germs. Because purification removes most IgM and IgA, the product consists almost entirely of IgG. It is known as gammaglobulin, immunoglobulin, or immune serum globulin.

Taken regularly and in large doses, gammaglobulins can boost serum immunoglobulins to near normal levels and eliminate most infections. If treatment begins early enough, it can prevent lung damage from pneumonia.

Immunoglobulin is administered either intramuscularly or intravenously. Intravenous immunoglobulin (IVIG) is usually preferred because it can be given in large doses, it is fast-acting, and it avoids the pain associated with large intramuscular injections. Infusions of IVIG take two to four hours and are administered every three or four weeks, either at home or in an outpatient clinic.

Injections of cytokines, which are natural chemicals produced by immune cells, are another new way to treat immune deficiencies. For example, the symptoms of Chronic Granulomatous Disease can be traced to faulty phagocytes; phagocytes can be activated with injections of a natural or synthetic product of immune cells called gamma interferon.

In some immune deficiencies, the numbers of neutrophils may be reduced either because they are under attack or are not produced in normal numbers. In certain cases, this problem can be offset by the injection of growth factors. These growth factors increase the production of neutrophils. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a natural chemical that boosts the development of blood cells, including the white blood cells known as granulocytes and macrophages. Another granulocyte colony-stimulating factor (G-CSF), is also helpful in raising levels of granulocytes.

Transplanting Cells From Umbilical Cord Blood

Transplanting cord blood stem cells is even newer than transplanting bone marrow, and easier. Stem cells are long-lived parent cells that continually give rise to fresh blood cells. Ordinarily, they live in the bone marrow. Some stem cells circulate in the blood, but they are scarce and difficult to extract. However, stem cells are plentiful in blood in the umbilical cord of healthy infants at the time of birth.

To obtain cord blood stem cells, blood is drained from the umbilical cord and placenta as soon as a healthy baby is born and the cord clamped and cut. The cord blood is typed, frozen and stored. Later it can be transplanted into a matched recipient with an immunodeficiency.

Doctors have used stem cells from cord blood to treat a variety of blood diseases in children. The cord blood has usually come from cord blood banks.

Research suggests that cord blood stem cells may not need to be matched as closely as bone marrow.

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Important Precautions

Children with PI diseases, especially those with defective T cells, X-linked agammaglobulinemia, and ataxia telangiectasia should not receive live virus vaccines, such as the oral polio, measles, and chicken pox (varicella) vaccines. It is not even safe to give live virus vaccines to children suspected of immunodeficiency until a definitive diagnosis is rendered. There is a risk that such vaccines could cause serious illness or even death. Moreover, blood transfusions should not only be free of infectious viruses (e.g., hepatitis or cytomegalovirus), but also—for T cell deficient children—irradiated to incapacitate mature donor T cells that might attack the tissues of the recipient and result in GVHD.

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Primary Immunodeficiency Diseases: Some Examples

Primary immunodeficiencies are complex diseases. Since each one can be traced to the failure of one or more parts of the immune system, one of the more convenient ways to group them is according to the part of the immune system that is faulty:

  • B cell (antibody) deficiencies
  • combined T cell and B cell (antibody) deficiencies
  • T cell deficiencies
  • defective phagocytes
  • complement deficiencies
  • deficiencies/cause unknown

B Cell (Antibody) Deficiencies

More than half of all PIs are caused by a lack of infection-fighting antibodies (immunoglobulins). The person has either too few antibody-producing B cells or B cells that don't work properly.

In some disorders, the B cells make almost no antibodies, leaving the person susceptible to a wide range of infections. In others, the B cells make some antibodies, but not enough to give strong protection. In yet other conditions, the B cells fail to make special subsets of antibodies, creating a risk for just certain kinds of infections.

  • X-Linked Agammaglobulinemia (XLA) youngsters make no antibodies at all ( a = without, gammaglobulin = antibodies, emia = in the bloodstream). These patients have few or no mature B cells or antibody-secreting plasma cells.

It is called X-linked because the mutated gene responsible for the disease is located on the X chromosome. (This gene encodes an enzyme necessary for B cell development.) As an X-linked disease, XLA affects only males. (See section on Genetics)

For their first few months, baby boys who have inherited XLA are healthy, protected by IgG they received from their mothers via the placenta before birth and in the breast milk after birth. As the mother's IgG fades, however, the baby develops a steady stream of infections.

They get infections caused by bacteria that would normally be controlled by antibodies—ear infections, sinus infections, eye infections, skin infections, and pneumonia. They can also develop encephalitis, meningitis, or blood poisoning. Antibiotics clear up one infection, only to have another start up soon.

Boys with XLA are also susceptible to viruses that are normally neutralized by antibodies during their spread in the bloodstream. These include common viruses that cause diarrhea as well as viruses that cause liver disease (hepatitis) and polio. (An XLA child who receives oral polio vaccine risks paralysis.)

Laboratory tests show extremely low levels of B cells, especially the mature B cells capable of secreting immunoglobulins. Overall immunoglobulin levels in the blood are low, and specific antibodies—for instance, to any vaccines the child has received—are missing. Tissues rich in B cells such as tonsils and lymph nodes may be undersized or scanty.

Although XLA cannot be cured, it can be controlled with immunoglobulin therapy. Large doses of immune globulins, taken regularly for life, will prevent most infections. For the most part, these children will be able to live relatively normal and active lives.

  • Common Variable Immunodeficiency (CVID) is the name given to a group of disorders characterized by low levels of gammaglobulins and too few IgA antibodies. People with CVID may have normal numbers of B cells, but their B cells don't function properly. Their T cells also show a variety of defects.

This disease—also known as hypogammaglobulinemia ( hypo = low, gammaglobulin = antibodies, emia = in the blood)—can occur in children, but it is more common in people in their twenties or thirties. It affects both men and women. Most patients have no family history of CVID, but they may have relatives with Selective IgA Deficiency.

Like most antibody deficiencies, CVID causes frequent bacterial infections, typically involving the ears, sinuses, and airways. Many CVID patients experience several bouts of pneumonia and some develop infections in joints, bones, and skin.

About a quarter of the people with CVID develop immune system illnesses, including anemia and rheumatoid arthritis. They also have an increased risk of cancer.

Disorders of the digestive tract are common. In addition to diarrhea caused by Giardia parasites, people with CVID are prone to inflammatory bowel diseases such as ulcerative colitis, or even colon cancer. Many have an enlarged spleen and swollen lymph glands, and some develop lymph system cancer (lymphoma).

Tests helpful in diagnosing CVID include measures of IgG and IgA levels in the blood and measures of antibody responses to immunizations.

Although antibiotics will help to control infections, the cornerstone of treatment is gammaglobulin therapy. Gammaglobulins will raise antibody levels and fend off infections, allowing many persons with CVID to enjoy a normal lifestyle.

  • Hyper-IgM Syndrome youngsters often have high levels of IgM, the early-response antibody. However, they have no IgA, the class of antibody found in body fluids such as saliva, mucus, and tears, and they have very low levels of IgG, the common immunoglobulin in the blood. They also may have very low levels of the infection-fighting white blood cells called neutrophils.

The underlying problem in one form of Hyper-IgM involves T cells. In the X-linked form of Hyper-IgM Syndrome, the faulty gene fails to encode a molecule that normally permits T cells to communicate with B cells. B cells making IgM fail to get a signal from T cells, telling them to switch to making IgA and IgG.

Sometime before their first birthday, children with Hyper-IgM Syndrome begin to contract bacterial infections—ear infections, sinus infections, pneumonia, and tonsillitis. Many develop sores inside their mouths. In addition, they are susceptible to opportunistic infections, especially Pneumocystis pneumonia.

Another aspect of Hyper-IgM Syndrome is autoimmune disease. Autoimmune attacks on red blood cells lead to anemia, while autoimmune destruction of infection-fighting neutrophils further increases the risk of infection.

Many youngsters with Hyper-IgM Syndrome respond well to treatment, become symptom-free and resume normal growth. The cornerstone of treatment is regular IVIG, which not only supplies missing IgG antibodies, but also prompts a drop in IgM antibodies.

  • Selective IgA Deficiency is characterized by a deficiency of immunoglobulins in body secretions and the mucous membranes lining the airways and digestive tract. IgA normally stands guard at the body entrances, intercepting bacteria, viruses, toxins, and certain food components.

IgA Deficiency is the most common of the PIs. Studies of blood samples from blood bank donors show that IgA Deficiency occurs in as many as 1 of every 333 Americans with a Caucasian background.

Although this makes IgA Deficiency more common than all other immunodeficiencies combined, most people never know they have it. They remain healthy, with no more than the usual number of infections. Others suffer through more than their share of infections without ever knowing why.

When IgA Deficiency is diagnosed, it is usually because of an increase in the number of ear, sinus, and lung infections that are slow to respond to standard antibiotics. Treatment consists mainly of antibiotics, for specific infections and to prevent infections from becoming chronic.

IVIG isn't effective because there is no way to deliver IgA to mucous membranes. Moreover, some people with IgA Deficiency have anti-IgA antibodies, which can trigger a severe reaction to any blood products, including IVIG, that contain IgA.

The cause of IgA Deficiency is not known, and it may differ from one person to the next. B cells appear normal, but they seem unable to mature into cells capable of secreting IgA antibodies. Although no T cell defect has been found, some researchers suspect a problem with T cell regulation.

IgA Deficiency sometimes seems to run in families. It is more common among the relatives of people with CVID. In some cases, IgA Deficiency may progress to CVID.

IgA Deficiency itself seldom causes serious trouble. However, people with IgA Deficiency are very likely to have any of a variety of other problems. They are especially prone to allergies, including asthma; autoimmune diseases, including rheumatoid arthritis and diabetes; diseases of the gastrointestinal tract, and neurologic diseases. Thus anyone diagnosed with IgA Deficiency should have periodic checkups to look for such possibilities.

  • IgG Subclass Deficiency is another PI caused by the lack of certain antibodies. In this case, the person is missing one or two of the four subclasses of IgG (IgG1, IgG2, IgG3, and IgG4).

Each IgG subclass plays a slightly different role. IgG1 and IgG3 antibodies are formed in response to certain proteins, including toxins produced by some bacteria and the proteins of some viruses. IgG2 antibodies target the capsules that shield certain bacteria. Antibodies of some IgG subclasses cooperate with the complement system; others do not. As a result of such differences, each type of subclass deficiency leaves a person vulnerable to specific types of infections.

Overall IgG levels may be near normal, so it is necessary to measure each of the IgG subclasses. Patients may be immunized with a vaccine against encapsulated bacteria (such as Streptococcus pneumoniae or Haemophilus influenzae) to see if they respond with the appropriate antibodies.

Patients with IgG Subclass Deficiency have infections that are not as severe as those seen with broader immunoglobulin deficiencies such as XLA or CVID.

The usual treatment in IgG Subclass Deficiency consists of antibiotics to control and prevent infections. IVIG is usually reserved for children who are seriously ill and who are not responding to antibiotic therapy.

Combined T Cell And B Cell (Antibody) Deficiencies

Some cases of PI are the result of a combined deficiency. Both of the immune system's major weapons—antibodies and T cells—are disabled. In some, the deficiency is almost total, and nearly any infection is a threat to life. In many combined immunodeficiencies, the pattern of signs and symptoms creates a distinctive syndrome.

  • Severe Combined Immunodeficiency (SCID) is what most people think of when they hear about PI disease. It is the disease of "the boy in the bubble," who spent his life in an isolation chamber to protect himself from germs.

SCID is rare; chances of a child being born with SCID are about one in 500,000 births. Until recent years, it was always fatal.

There are several major causes of SCID. Each is caused by a different genetic defect, and each develops along a different pathway. In X-linked SCID, the most common type, a genetic flaw damages molecules that allow T cells and B cells to receive signals from crucial growth factors. Another type of SCID is ADA Deficiency. This condition results from the lack of an enzyme that helps cells—especially immune cells—get rid of toxic byproducts. Without ADA, poisons build up and kill the lymphocytes. Purine nucleoside phosphorylase (PNP) Deficiency results from a similar enzyme problem, but B cells are less affected and the immunodeficiency is less severe, although affected patients may have other problems (neurologic).

Yet another variation is known as MHC Class II Deficiency or Bare Lymphocyte Syndrome. MHC molecules are specialized proteins found on the surface of body cells and play an important role in bone marrow transplantation. Class II MHC molecules, which appear on many immune cells, allow B cells and other immune cells to recognize, interact with, and activate T cells. Without this B cell/T cell communication, the immune defenses are compromised.

Whatever the underlying problem that causes SCID, the consequences are nearly always the same. The child lacks almost all immune defenses, develops life-threatening infections, and needs major treatment to survive beyond infancy. Although the specifics vary from case to case, these children are vulnerable to serious infections caused by bacteria, as is typical with a B cell deficiency, and also by viruses and opportunistic germs, as is the case with a T cell deficiency.

Usually by the time a baby is three months old, he or she (because many cases of SCID are X-linked, SCID is more common in boys than in girls) is likely to have persistent thrush or extensive diaper rash. Weakened by chronic diarrhea, the baby may stop growing and gaining weight. Some children develop a sharp, persistent cough with Pneumocystis pneumonia, blood disorders, or chronic hepatitis. Meningitis and blood poisoning pose a constant threat.

Viruses that are not harmful in children with normal immunity can pose a serious danger. For example, the virus that causes chicken pox (varicella) can trigger a severe infection in the lungs and the brain of SCID patients. Other threats come from the viruses that cause cold sores (herpes simplex) and measles (rubeola).

Laboratory tests confirm multiple problems. There may be extremely low levels of lymphocytes. B cells may be normal in number, but they don't function normally; immunoglobulin levels are low. There are few T cells, and those few are unresponsive. A chest x-ray may show that the thymus gland has failed to develop.

A diagnosis of SCID constitutes a medical emergency. The immediate concern is to bring any current infections under control, and to strengthen the baby's weakened condition with adequate nutrition. IVIG may help to bolster the immune responses.

A lasting remedy, however, requires a more drastic approach. A bone marrow transplant from a matched donor or parent is arranged as quickly as possible.

Children whose SCID is due to ADA Deficiency have another alternative. Injections of PEG-ADA will protect them against recurrent infections, allow them to control ordinary childhood infections such as chicken pox, and make it feasible for them to lead nearly normal lives.

  • Partial Combined Immunodeficiencies are characterized by both the antibody and cell-based defenses being impaired, but not totally shut down. Problems are limited to certain functions of B cells and certain T cells. In these conditions, the immunodeficiency is part of a complex clinical picture. Other body systems are involved, too. The result is a distinctive set of symptoms, or a syndrome.
  • Wiskott-Aldrich Syndrome (WAS) is characterized by a tendency to bleed easily and development of an intensely itchy, scaling skin rash (eczema). This is in addition to the severe recurrent infections seen in young boys who develop this X-linked syndrome. Many have brothers or uncles with the same disease.

The infections are the result of abnormal B cells and certain T cell functions. Because of B cell defects, these boys cannot make antibodies against some types of bacteria. This leaves them susceptible to ear infections, pneumonias, blood infections, and meningitis. Because of the T cell defects, they are vulnerable to infections with opportunistic germs, including Candida, Pneumocystis, and the herpes viruses.

Patients with WAS also have defective blood platelets. Platelets are essential for blood clotting as well as certain immune responses. The platelets of youngsters with WAS are too few and too small. (The size of the platelets confirms the diagnosis.)

The lack of platelets causes bleeding, often for no obvious reason. These patients develop bruises, bleeding gums, prolonged nose bleeds, and bloody bowel movements. They also risk deadly bleeding into the brain.

Eczema in WAS can range from mild to severe. It can cause children to itch and scratch themselves until they bleed. This is aggravated by dry skin. Thus, it is important to identify food allergies that cause the skin to itch. Bath oil, moisturizing and steroid creams, and antibiotics on the skin may help relieve the eczema, but keeping the skin clean is also important.

The leading treatment option for WAS is bone marrow transplantation. When marrow is available from a brother or sister who is an identical match, the cure rate exceeds 85 percent.

To correct severe bleeding, a life-saving alternative may be surgery to remove the spleen. In WAS, the spleen wrongly filters platelets out of the blood. Removing the spleen (a relatively simple operation) allows platelets to remain in the bloodstream and prevents dangerous bleeding. However, removing the spleen makes the patient more susceptible to certain infections (e.g., blood poisoning). Consequently, surgery is rarely used. Conservative measures such as antibiotics, IVIG, and avoidance of allergic foods should be tried before spleen removal or BMT.

At one time, a boy with WAS was unlikely to live past the age of 10. Today, thanks to BMT or surgery to remove the spleen coupled with daily antibiotics or regular IVIG to prevent infections, these youngsters may live relatively normal lives for many years. Freed from the risk of easy bleeding and constant infections, they can ride bikes, play contact sports, and mix freely with other children. Many young men with WAS are now living productive lives in their twenties and thirties.

  • Ataxia-Telangiectasia (AT) is a PI syndrome that affects several body systems, and the symptoms grow worse with time. Children with AT have nervous system problems that cause them to walk unsteadily and clumsily (ataxia), as well as dilated blood vessels (telangiectasia) in the eyes and skin. They also develop frequent sinus and respiratory infections such as bronchitis and pneumonia.

The infections in AT can be traced to defects in both B cells and T cells. B cell responses are substandard, and levels of IgA and IgG may be low. T cells are few and weak; the thymus gland is immature.

Usually AT is first suspected when a child is learning to walk, and has trouble with balance and coordination. A history of infection may or may not be present. The dilated blood vessels typically don't develop before the age of 3 or 4.

The diagnosis can be confirmed by a blood test showing "fetal proteins." These are substances normally produced during the development of a fetus. When levels remain high after birth, it is usually a sign of certain disorders, including AT.

NEW TREATMENTS HAVE TRANSFORMED A DISMAL PROGNOSIS INTO ONE OF HOPE AND PROMISE.

Children with AT gradually lose more and more control of their muscles, and they may develop writhing and jerking movements. By the time they are in their teens, many are confined to a wheel chair. Their infections multiply, too. In addition, they are liable to develop cancers, especially cancers related to immune system cells and organs.

However, the symptoms and severity of AT differ greatly from one child to another, and the disease develops at a different rate for each one. Some have lived well into adulthood, attending college and living independently.

Medical researchers have tried a number of new approaches, including transplants of thymus tissue and BMT. To date, however, nothing has succeeded in halting the disease's advance.

Treatment is geared to helping the children maintain as normal a lifestyle as possible. They are encouraged to attend school and participate in a wide variety of activities. Physical therapy helps the children remain mobile and active.

Infections, of course, need to be treated promptly. AT in children with an IgG deficiency may benefit from IVIG.

T Cell Deficiencies

  • DiGeorge Anomaly is the result of a birth defect. In the growing fetus, a group of cells that give rise to various parts of the head and neck develops abnormally. Developmental changes can affect the face, parts of the brain, and the heart, as well as the thymus, where T cells mature.

The symptoms of DiGeorge Anomaly may be different for each child, depending on which organs are abnormally affected. The abnormalities can range from mild to severe.

Some children with DiGeorge Anomaly have a distinctive look, with an underdeveloped chin, eyes that slant downward, and misshapen ear lobes. Some children also have underdeveloped parathyroid glands. The parathyroids, located in the neck next to the thyroid gland, produce a hormone that helps to control levels of calcium in the blood; when calcium levels are not balanced, the child can develop convulsions. Children with DiGeorge Anomaly may also have a variety of heart defects, which causes symptoms ranging from a heart murmur to heart failure.

Many children with DiGeorge Anomaly have a very small thymus that is normal. In others, the thymus is missing altogether. With too few T cells, or T cells that are not functioning properly (which means B cells dependent on T cells aren't functioning, either), the child falls prey to infection.

Because of the unusual mixture of characteristic features, DiGeorge Anomaly is usually diagnosed soon after birth. Laboratory analysis of the chromosomal defects in the child's blood cells can be used to confirm the diagnosis.

Treatments are geared to correcting the various defects. The heart malformation, which is usually the most serious problem, requires drugs and often surgery. The child may be given IVIG to prevent infections and drugs to defend against Pneumocystis pneumonia. Other treatments include calcium supplements and parathyroid hormone.

ABOUT A FIFTH OF ALL CASES OF PI ARE THE RESULT OF A COMBINED DEFICIENCY.

For many children with DiGeorge Anomaly, a tiny thymus will eventually grow big enough to produce enough T cells to stave off infection. About a quarter of all children, though, will require some sort of treatment, and researchers are working to find what works best.

An experimental approach is an identically matched BMT which contains T cells that are mature and thus work independently of a thymus. Another experimental technique being used is the transplantation of fetal thymus tissue.

  • Cartilage Hair Hypoplasia is an immune system abnormality linked to dwarfism. The child has abnormally short limbs and thin, sparse hair. The skin forms extra folds around the neck, hands, and feet, and the joints are loose.

Youngsters with Cartilage Hair Hypoplasia can get frequent infections of the skin and mouth, the result of too few T cells. Their biggest danger is chicken pox which can be deadly.

The prognosis is considerably better than most T cell immunodeficiencies, because the susceptibility to infection is less. Although some children succumb to overwhelming infections in infancy, most get relatively few infections and some live normal lives. Some children have been successfully treated with BMT.

Defective Phagocytes

  • Chronic Granulomatous Disease (CGD) is the name given to a group of inherited immunodeficiency diseases caused by faulty phagocytes. Normally, these large white blood cells engulf germs and destroy them. In CGD, phagocytes are unable to produce the oxygen-transporting compounds that they need in order to kill certain types of germs.

There are four types of CGD, each caused by a different gene defect. Each of these genes encodes one of four proteins that act together to allow phagocytes to kill germs. One gene is on the X chromosome while the other three are recessive genes on autosomes. (About two-thirds of the cases occur in boys.)

By their second birthday, most children with CGD will have infections that are unusually frequent or severe. The infections often respond poorly to standard antibiotics, and in some instances the child may need to be hospitalized for prolonged intravenous antibiotic treatment.

A commonplace bacterium such as Staphylococcus aureus or a usually harmless fungus such as Aspergillus may cause skin infections and rashes, liver abscesses, fever and persistent cough. Almost all the youngsters develop lung disease, including pneumonia. CGD can also cause chronic inflammatory conditions, including gum disease, inflammatory bowel disease, and enlarged lymph glands.

In addition, CGD causes tumor-like masses called granulomas. Granulomas are made up of clusters of white blood cells that continue to collect in infected areas even after the infection is gone. If large and in critical locations, granulomas can obstruct the passage of food through the digestive tract or the flow of urine.

The key to managing CGD is a prompt diagnosis (special blood tests that show how well phagocytes utilize oxygen and how efficiently they kill bacteria) and quick treatment with powerful antibiotics.

Once current infections and granulomas have been brought under control, attention turns to forestalling future infections. Children treated with routine preventive antibiotics can go three or four years between serious infections. The outlook is better yet when they receive regular injections of gamma interferon. This promising new treatment results in many fewer serious infections and shorter hospital stays.

Patients with CGD are encouraged to have frequent checkups, and to see their doctors for even minor infections. It is also important to keep the skin clean because many germs gain entry through the skin.

Thanks to preventive treatments and to prompt and aggressive therapy when infections do occur, the outlook for patients with CGD is good. Although they must guard against serious infections, they can look forward to long periods of good health and long, productive lives.

  • Leukocyte Adhesion Defect (LAD) causes recurrent, life-threatening infections because phagocytes are unable to migrate to the scene of an infection. These phagocytes lack a molecule that allows them to attach to blood vessel walls, a first step in leaving the circulation to enter tissues. Other white cells also lack adhesion molecules, preventing them from attaching to target cells and surfaces.

LAD typically manifests itself in infancy. One of the first signs may be a problem with the baby's umbilical cord; it fails to drop off, in the normal way, within a few weeks. The baby has a very high white blood cell count. Children with LAD are prey to severe infections caused by bacteria and fungi, especially infections of the soft tissues. They get tissue-eroding infections of the skin without forming pus, severe infections of the gums—leading to tooth loss—and infections of the intestinal tract. Wounds heal poorly and may leave scars.

Treatment of LAD begins with early and aggressive therapy of infections with antibiotics. Most recently, LAD has joined the ranks of the other PIs treated successfully with BMT.

  • Chediak-Higashi Syndrome (CHS) is a rare and potentially severe disorder caused by a flaw in three distinct types of cells: phagocytes, platelets, and melanocytes.

Because of the flawed phagocytes, the child has little resistance to frequent and severe infections. In addition to repeated sinus infections and pneumonia, the individual develops infections that infiltrate beneath the skin (cellulitis).

The defective platelets, for their part, result in a mild bleeding disorder.

Melanocytes are cells containing melanin, a pigment that provides color to the skin, hair, and eyes. The skin and hair of a youngster with CHS lack color (partial albinism), while lack of pigment in the eyes makes the person overly sensitive to light.

The infections of CHS are treated aggressively with antibiotics. Ultimately, however, CHS will enter an accelerated phase. The patient develops a lymphoma-like illness, with fever and jaundice; lymphoid organs such as the spleen fill with T cells that behave like cancer. Despite treatment with steroids and anticancer drugs, the condition is usually fatal within months.

Fortunately, the immunodeficiency of CHS is one more condition that can be cured with BMT. A recent study found a majority of children to be alive and well up to 13 years after BMT treatment.

Complement Deficiencies

For the complement system to function, all of its 20-plus components must work closely together. Yet each of the components can be thrown out of step by a different genetic mutation.

Immunodeficiencies involving the complement system are not common. Often they don't cause disease until adulthood.

Symptoms vary from one type to another. Some complement deficiencies foster the same kinds of bacterial infections seen with antibody deficiencies, as well as immune system disorders such as SLE. Other complement deficiencies lead to an increase of blood-borne infections such as meningitis.

Cure is not possible, and there is no specific therapy for complement deficiencies. However, proper management can usually prevent serious consequences. Sometimes immunization against encapsulated bacteria helps to keep infections in check. Recent investigations are exploring the use of complement concentrates to replace the deficient complement components.

Deficiencies/Cause Unknown

  • Hyper-IgE Syndrome is a relatively rare condition characterized by extremely high (hyper) levels of IgE in the blood. From infancy, children with Hyper-IgE are plagued by severe, recurrent abscesses, especially of the skin and lungs.

Most of the infections in Hyper-IgE are caused by Staphylococcus aureus. However, they can be produced by other germs, and they can involve the joints, eyes, ears, nose, sinuses, and blood.

Skin infections typically appear as abscesses on the scalp, face, and neck. They often need to be lanced and drained.

CLINICAL SCIENTISTS ARE DEVELOPING NEW TREATMENTS TO ALLEVIATE SYMPTOMS AND PREVENT COMPLICATIONS.

Children with Hyper-IgE Syndrome may have recurrent pneumonias, lung abscesses and often have coarse features, an itchy rash, and skeletal abnormalities, including thin bones prone to repeated fractures. Their growth rate may also be slow.

Because the primary defect is unknown, there is no specific therapy for Hyper-IgE Syndrome. Treatment consists of lifelong antibiotics to combat staphylococcus infections. Other drugs, such as antifungal agents, are given for specific infections. Persons with antibody deficiency may benefit from IVIG.

  • Chronic Mucocutaneous Candidiasis is associated with other immunodeficiencies. The patients are unable to defend themselves against the Candida fungus. As a result, they develop rashes and sores on the skin, nails, and the mucous membranes.

Within the first few months of life, infants develop persistent thrush, a Candida infection of the mucous membranes of the mouth, and Candida diaper rash. Candida infections on the hands and feet can destroy fingernails and toenails.

Patients with chronic mucocutaneous candidiasis can also get other types of infections. Both bacteria and viruses can infect the skin and the respiratory tracts. In addition, they risk autoimmune blood disorders such as anemia. Many have problems with endocrine glands such as the parathyroid, thyroid, and adrenal glands.

Treatment has two goals: to clear up infections and to cure the underlying immune defect. A variety of antifungal drugs are effective against Candida, and it may be necessary to try several—of increasing strength—to find one that works. Sometimes intravenous drugs are necessary.

Unfortunately, the effects of drug treatment don't last. Infections will usually flare up again a few weeks or months after the antifungal drugs are stopped.

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Research In Progress

Research on PIs is under way on many fronts. Geneticists, immunologists, molecular biologists, microbiologists, and biochemists are working to understand fundamental defects and to devise remedies. New genes are being identified, and scientists are making rapid progress in untangling the intricate connections and pathways that govern immune responses. Clinical scientists are developing new treatments to alleviate symptoms and prevent complications.

Gene Therapy

Gene therapy is one of the most publicized forms of treatment for PI. This revolutionary approach was first used to treat two young girls with SCID due to ADA deficiency.

TREATMENT IS GEARED TO HELPING THE CHILDREN MAINTAIN AS NORMAL A LIFESTYLE AS POSSIBLE.

Gene therapy attempts to cure disease by inserting a healthy version of a missing or malfunctioning gene into a cell to restore normal function. If successful, the newly inserted gene directs the cell to produce the missing protein.

In the pioneering 1990 experiment, some of the girls' T cells were removed, treated to make them more active, and a gene for ADA was introduced. These T cells carrying the new gene were then reinjected into the girls. Meanwhile, these girls still continued to receive their PEG-ADA treatment.

Today, the girls are healthy and free of severe infections. Both of them are attending school and living relatively normal lives.

One of the two girls has had an especially good response. She has some T cells that carry the new gene and produce the ADA enzyme. However, since both girls have always received PEG-ADA, it is not clear how much of the credit for their good health can be attributed to the new genes.

Still more recently, doctors have tried gene therapy using stem cells, which are much longer-lived than T cells. In three different cases, babies were diagnosed with ADA deficiency before they were born. Their own umbilical cord blood was collected, and stem cells taken from the cord blood had new genes inserted. Each of the babies was then given a transfusion of his/her own genetically-engineered stem cells.

These children did well initially. But like the girls given T cell gene therapy, they continue to require other treatments.

Currently, gene therapy remains strictly experimental, and not yet used routinely for therapy.

Basic Research Efforts

The National Institute of Child Health and Human Development (NICHD), part of the National Institutes of Health (NIH), in collaboration with the Jeffrey Modell Foundation (JMF), supports a 5-year basic research initiative on developmental and genetic defects of immunity. The research is exploring the genes and molecular mechanisms that play a role in the development of the immune system in the fetus, newborn, infant, and child. Insights emerging from this basic research will lead to new and better strategies for the diagnosis, treatment, and prevention of PIs. In addition, the NICHD and the National Institute of Allergy and Infectious Diseases (NIAID) sponsor a basic research program on PIs. The objectives are to identify and characterize the genes, and to elucidate the molecular and genetic mechanisms that cause PIs. Moreover, the NIAID and the JMF support basic research studies to develop gene transfer methods for correcting the genetic defects of PIs.

Registries

The NIAID, working with the Immune Deficiency Foundation, has established a registry of patients with CGD. The Registry will allow researchers to gather data on hundreds of patients being enrolled. Early indications from the Registry show that CGD may be four times more common than previously thought.

A similar registry supported by the NIAID has been established at the Immune Deficiency Foundation for patients with eight different types of PIs.

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Future Research Challenges

Since there are many different types of PIs, they present a formidable research challenge to the scientific community. However, thanks to the timely and extraordinary advances of genetics, molecular biology, and molecular medicine, the challenge can be met and conquered. Already these exciting new scientific tools have unraveled many of the mysteries behind the PIs, and have significantly increased our insight and basic understanding of them. Moreover, they have contributed to the development of new and improved approaches and strategies to diagnose, treat, and prevent PIs.

A major challenge is to identify the genes that cause PIs and characterize the nature of each genetic defect and its associated immunodeficiency disease. More than 70 PI genes have already been identified and characterized. With more advances in genetic technology and rapid molecular analytical methods, progress on defective gene identification and characterization should accelerate.

Although gammaglobulin therapy, bone marrow transplantation, gamma interferon, and PEG-ADA have been effective for treating specific forms of PI, new and emerging opportunities for improving these therapies show great promise. In addition, research into using gene therapy will continue to improve the prognosis of patients with PIs. Finally, an important research challenge is to develop new and innovative treatments that are more effiacious, easier to administer, less costly, and that allow the patient to lead a normal lifestyle.

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Resources

Information on basic and clinical research on PI diseases is available from the NIH institutes listed below. For information on the diagnosis, treatment, and clinical care of patients with PI, consult your pediatrician or family physician. Additional information may be obtained from the two PI organizations listed below. They are valuable resources for information on research, referral centers, physician and patient education, patient support, and public awareness of PIs.

National Institutes Of Health

National Institute of Child Health and Human Development, NIH

Public Information and Communications Branch
31 Center Drive, Room 2A32
Bethesda, MD 20892-2425
301-496-5133
Internet: http://nichd.nih.gov

National Human Genome Research Institute, NIH

Information Office
31 Center Drive, Room 4B09
Bethesda, MD 20892-2152
301-402-0911

National Institute of Allergy and Infectious Diseases, NIH

Office of Communications
31 Center Drive, Room 7A50
Bethesda, MD 20892-2520
301-496-5717

National Heart, Lung, and Blood Institute Information Center, NIH

Post Office Box 30105
Bethesda, MD 20824-0105
301-251-1222

Other Organizations

Expert information and advice are available from two national organizations that focus specifically on PIs.

The Jeffrey Modell Foundation is a nonprofit research foundation devoted to PI. It sponsors symposia and workshops; supports research and training; and provides diagnostic, clinical, and education services. Its 24-hour-a-day national hotline, which offers information and referrals to immunologists at major medical centers around the country, can be reached at 1-800-JEFF-844. Its Internet Home Page can be accessed at http://www.jmfworld.com External Web Site Policy. Its E-mail address is info@jmfworld.com.

The Immune Deficiency Foundation, a non-profit foundation, has chapters nationwide to serve patients, families and medical professionals dealing with the PI diseases. It supports scientific research and training and fosters public education. Its publications include a Patient Handbook and a National Newsletter. The number for its Patient Support Line is 1-800-296-4433. Its Internet Home Page can be accessed at http://www.primaryimmune.org External Web Site Policy. Its E-mail address is idf@clark.net.

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Glossary

Acquired immune deficiency

: immune deficiency disorder acquired during one's lifetime; may be due to infection, drugs, radiation, etc.

Adenosine deaminase (ADA)

: an enzyme essential for normal development of the immune system.

Agammaglobulinemia

: absence of immunoglobulins in the blood.

Acquired immune deficiency syndrome (AIDS)

: a disease caused by HIV virus infection.

Anemia

: an abnormal condition when the hemoglobin or red blood cells are below normal.

Antibody

: a protein in the blood that is produced by certain white blood cells; develops primarily in response to foreign antigens; important for immunity against certain germs.

Antigen

: a substance recognized as foreign by the body; stimulates antibody production and a T cell response.

Autoimmune

: describes a condition characterized by a specific immune response against the body's own tissues.

Autoantibody

: an antibody that reacts against the body's own tissue.

B lymphocyte (B cell)

: a small white blood cell from bone marrow responsible for producing antibody and serving as a precursor for plasma cells.

Bone marrow transplantation (BMT)

: a method that takes bone marrow from a suitable donor and transfers it into a recipient.

Bone marrow

: soft tissue containing stem cells, young blood cells and platelets; the source of various blood cells; found in hollow center of bones.

Chronic granulomatous disease (CGD)

: an inherited genetic disorder characterized by a failure of phagocytes to kill certain microorganisms; treated with gamma interferon.

Chromosome

: a linear DNA- containing body within the cell nucleus that is responsible for transmitting genetic and hereditary characteristics.

Combined immunodeficiency

: a condition when both T cells and B cells are inadequate or lacking.

Complement

: one of at least 20 serum proteins important in immunity and inflammation.

Cytokine

: small proteins produced by cells that affect the physiology and function of other cells.

Deoxyribonucleic acid (DNA)

: constitutes the genetic material in the chromosomes.

Eczema

: skin inflammation with redness, itching, encrustations, and scaling.

Enzyme

: protein that helps chemical reactions.

Gammaglobulin

: immunoglobulins, predominantly IgG, used primarily for treating hypogammaglobinemia.

Gamma interferon

: a cytokine primarily produced by T cells; important in immunoregulation and protection from viral infection; improves bacterial killing by phagocytes; treatment for CGD.

Gene

: a biological unit of heredity composed of DNA that has a specific function.

Gene therapy

: a new treatment for replacing defective or missing genes to restore normal function.

Graft-versus-host-disease (GVHD)

: a condition after transplantation when the donor's tissue reacts against the recipients tissue.

Granulocyte colony-stimulating factor (G-CSF)

: a cytokine that stimulates proliferation, development, and function of white blood cells called granulocytes.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)

: a cytokine that stimulates proliferation, development, and function of red and white blood cells, including granulocytes and macrophages.

Human immunodeficiency virus (HIV)

: infects and destroys immune cells and causes AIDS.

Hypogammaglobulinemia

: a condition where all classes of immunoglobulins in the blood are abnormally low.

Hypoplasia

: underdevelopment or incomplete development of an organ or tissue.

Immunodeficiency

: a condition where the immune response is deficient or subnormal.

Immunoglobulin (Ig)

: any of 5 classes (IgM, IgG, IgA, IgE, IgD) of antibody.

Intravenous immunoglobulin (IVIG)

: a treatment to deliver immunoglobulins directly into the blood of the patient.

Lymphocyte

: a small, mononuclear, non-phagocytic white blood cell found in the blood, lymph, or lymphoid tissue; major cell of the immune system that is essential for immunity.

Monocyte

: a mononuclear phagocytic white blood cell that acts as a scavenger.

Neutrophil

: a polymorphonuclear phagocytic white blood cell containing characteristic granules.

Opportunistic infection

: an infection by germs that do not usually cause disease, but occurs only under certain conditions, such as in immunodeficient or immunosuppressed patients.

Polyethylene glycol-adenosine deaminase (PEG-ADA)

: a replacement enzyme for normalizing some functions of the immune system.

Phagocyte

: a cell (e.g., neutrophil, monocyte or macrophage) capable of engulfing material or other cells and digesting them.

Plasma cell

: a cell that produces antibody and is descended from B cells.

Platelet

: a structure in blood that functions in blood coagulation.

Primary immunodeficiency (PI)

: immunodeficiency due primarily to inheritance of altered or mutated genes that can be passed from parent to child or can arise as genes are copied.

Protein

: a substance composed of amino acids found in living matter and essential for growth, repair, and structure; also function in chemical reactions (enzymes).

Secondary immunodeficiency

: immunodeficiency that is acquired and not inherited.

Sepsis

: germs or their toxins in the blood or tissues.

Stem cell

: a progenitor cell that can develop into different blood cell types.

T lymphocyte (T cell)

: thymus-dependent lymphocyte that matures in the thymus; important in cell-mediated immunity and helping B cells.

Thrush

: a fungal disease characterized by white plaques on mucous membranes; caused by Candida albicans infection.

Thymus

: a lymphoid organ in front of the heart that is important for immunity and development of T cells.

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Primary Immunodeficiency cover

Last Updated Date: 04/07/2008
Last Reviewed Date: 04/07/2008
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