Continuing Pharmacy Education
What you need to know about…
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.
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 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).
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.
- 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.