C O N T E N T S

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

I N T R O D U C T I O N

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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W H A T   I S  P R I M A R Y   I M M U N O D E F I C I E N C Y ?

API 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.

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.

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T H E   I M M U N E   D E F E N S E S

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.

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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G E N E S   A N D   P I

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.

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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S I G N S   A N D   S Y M P T O M S

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).

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.

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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D I A G N O S I N G   P I

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.

T H E   B A S I C S

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