Incidence

The exact incidence of Severe Combined Immunodeficiency (SCID) is unknown, except that it is recognized as rare in most population groups. It is believed that its incidence is in the neighborhood of 1 in 1,000,000. SCID is actually a group of disorders. These diseases are either X-linked or autosomal recessive in inheritance.

Disease Description

Severe Combined Immunodeficiency represents a severe defect in T- and B- lymphocyte development resulting in marked susceptibility to severe and complicated infections. (White blood cells are necessary for normal immunity.) The onset of infection usually occurs in the first six months of life. Severe Combined Immunodeficiency is considered to be the most serious of the primary immune disorders.

This set of disorders arises because of the inheritance of abnormal genes from one or both parents. The most common form is found in males, and is transmitted via an abnormal X chromosome, provided by the mother. The second most common defect is transmitted to the infant because both parents have contributed an abnormal gene governing the production of a cell enzyme (adenosine deaminase or nucleoside phosphorylase) needed for the development of immunity. (This type of inheritance is called autosomal recessive inheritance.) There are additional forms of SCID which have been recognized in the past few years; in a number of cases, the defective genes have been identified.

There are three main features of Severe Combined Immunodeficiency:

• T-helper cells (a kind of white blood cell) function poorly or are absent.
• The thymus gland may be small and functions poorly or is absent.
• Bone marrow stem cells, from which mature T- and B-lymphocytes arise, are absent, or defective.

Little or no antibody production occurs. If the T-helper cells are absent or function poorly, normal functioning of T- and B-lymphocytes are impaired. If the thymus gland is absent or functioning poorly, this impacts negatively on the normal maturation process for T-helper and T-suppressor cells. In the absence of fully developed T-lymphocytes, the immune system can never function normally. If stem cells (or precursor cells for T- and B-cells) in the bone marrow are defective or absent, this eliminates or damages the original source of T- and B-lymphocytes.

It is not known exactly why these defects occur. However, it is believed that the defect or error occurs during fetal development. As further research is carried out, different kinds of immune defects are being identified as the cause of the SCID phenotype.

In cases of specific enzyme deficiency, immunodeficiency occurs because of a build up of metabolic poisons in the lymphocytes. These children may present at slightly older age than other infants with SCID perhaps because it takes time for the metabolic poisons to accumulate. This form of Severe Combined Immunodeficiency is also inherited through an autosomal recessive pattern, (two abnormal genes, one from each parent, are required).

Clinical Signs and Symptoms

Infants with SCID have an unusual number of bacterial, viral, fungal, or protozoal infections that are much more life threatening, serious, and less responsive to treatment than would normally be expected. These include, but are not limited to: pneumonia, meningitis, and/or blood system infection.

Symptoms suggestive of graft-versus-host disease (a reaction of the engrafted tissue against the recipient) may appear in neonates (an infant up to six weeks in age) since maternal cells can not be destroyed by the neonate's immune system.

Exposure to the chicken pox virus, either through live vaccination or in the environment, can be life threatening causing infection of the lungs and brain. The relatively common and harmless cytomegalovirus (a common type of herpes virus) found in the salivary glands of many people can cause fatal pneumonia in children with Severe Combined Immunodeficiency. Even the herpes simplex virus (which causes the common cold sore) and the measles (rubeola) virus can be dangerous to these children.

Pulmonary symptoms are common and may present as overwhelming pneumonia with common bacteria (staphylococci, pneumococcus or hemophilus); or Pneumocystis carinii , cytomegalovirus (a common type of herpes virus); or the measles virus. These latter agents should be suspected when a patient with this syndrome presents with interstitial (spaces within an organ or a tissue) or alveolar (within the air cells of the lungs) pneumonia bilaterally; a nonproductive cough and low blood oxygen levels. These patients may also present with symptoms of chronic inflammation around the bronchial tubes which may be asymptomatic or associated with prominent bronchospasm (involuntary muscle contraction involving the bronchus).

Fungal infections such as mouth thrush (Candida albicans) or a yeast infection in the diaper area may be less resistant to treatment that would be effective for an infant with a normal immune system.

Persistent diarrhea is common in these patients, and may lead to severe weight loss and malnutrition. Another gastrointestinal manifestation includes chronic hepatitis secondary to cytomegalovirus or unknown agents. If the liver is affected by this disorder, liver damage may focus on the bile ducts (small passage that carries bile from the liver). Skin problems may persist, including chronic bacterial and fungal infections.

Abnormalities of the blood cells include neutropenia (abnormally low in a type of white blood cells called neutrophils); red cell aplasia (bone marrow does not produce red blood cell); or megaloblastic anemia (anemia with abnormal, large red blood cells) resistant to vitamin B12 or folic acid (a type of vitamin B treatment). Eosinophilia (abnormal number of granular type of a white blood cell called eosdinophils) and monocytosis (excessive number of white blood cells called monocytes) may signal an unusual infection such as Pneumocystis carinii pneumonia.

Diagnosis

A diagnosis of Severe Combined Immunodeficiency is usually suspected in infants less than one year of age who present with excessive and/or serious infections; fungal infections resistant to treatment; persistent diarrhea and weight loss; and chronic skin infections. These patients can have a large liver and/or spleen, or enlarged lymph nodes.

A series of tests must be performed to confirm the diagnosis. Among these tests are:

• Lymphocyte (a kind of white blood cell) count from a blood smear. There are usually more than 1,500 lymphocytes per cubic millimeter in normal blood. Infants with Severe Combined Immunodeficiency usually have significantly decreased numbers.
• Lymphocytes can be differentiated into the various subgroups and each population counted. This will determine the total number of B-, T-, helper T- and killer or suppressor T-cells.
• Lymphocyte function can be tested by its reaction to specific stimulation with plant extracts called mitogens.
• Levels of immunoglobulin IgA, IgA, and IgM, which can be quite low in these patients, can be measured. Antibody formation is virtually absent.

All tests should be repeated several times to ensure tests results are not skewed by ongoing infections.

Treatment

The treatment of choice for these children is bone marrow or stem cell transplantation. The ideal donor is a tissue matched relative. Matching is determined by testing the blood cells for surface proteins HLA-A, HLA-B, and HLA-D, with HLA-D being the most important match to insure significant survival. Prior to transplantation, the patient may undergo irradiation ( form of radiation therapy) or immunosuppressive chemotherapy (a group of chemicals that reduce the chances of rejection) to insure survival of the donated bone marrow or stem cell.

This measure is taken to prevent graft-versus-host disease (a reaction of the engrafted tissue against the recipient) and to insure that all new B- and T-cells arise from the donor's normal bone marrow stem cells. In the absence of a tissue matched sibling, patients can be given a T-cell depleted bone marrow transplant from a relative or other partially matched donor. However, graft-versus-host disease (reaction of the engrafted tissue against the recipient) or incomplete reconstitution can occur if no identical normal donor is available. Other sources of donor stem cells can come from the blood of the donor, if procedures are used to boost the number of stem cells that are present. An additional source of stem cells which can be used in the reconstitution of an infant with SCID is the cord blood of unrelated normal infants. In several research studies, it has been shown that saving cord blood samples from normal infants can provide additional resource; as for bone marrow or other stem cell transplants, one attempts to match the donated stem cells to the infant.

Restoration of normal cellular immunity occurs three to six months following a successful transplantation, while normal antibody production may take one to three years. During this period, gammaglobulin therapy may be used to provide protection against recurrent pyogenic (pus producing) infections.

When successful, this treatment corrects the patient's immune system defect. Recent success rates for this procedure approach 80% for tissue matched bone marrow or stem cell donors.

Other approaches to overcoming the patient's immune defect have been reported, but with varying success. One method, for infants or children with adenosine deaminase deficiency, has been to infuse normal red cells which are a source of this enzyme, or treat with a drug called PEG-ADA.

Pending correction of the immune defect, children with this serious chronic disease should be isolated from children outside the family, and even their own brothers and sisters if the latter are exposed to a virus (especially chicken pox), bacteria, or fungi. School officials should be asked to notify the family if chicken pox occurs in a sibling's school. If a sibling has had a close contact with chicken pox, the affected child should move to another house during the incubation period.

Accidental exposure to chicken pox should be followed with varicella immune globulin within 72 hours. Acyclovir should be used if lesions appear. Siblings should be vaccinated with only killed virus because they might excrete live virus, which could be dangerous to the immune compromised patient. These patients should never receive live virus vaccinations.

Prior to transplantation, infants with Severe Combined Immunodeficiency should generally not be taken to such public places as day care nurseries, church nurseries, shopping centers, or other places where they may be exposed to infection. Their contact with relatives, especially small children, should be limited.

Other precautions include hand washing, good nutrition (which may include intravenous feeding), and prophylactic doses of trimethoprim/sulfamethoxazole (brand name: Bactrim/Septra) to prevent infection with Pneumocystis carinii pneumonia.

Although it does not replace B-cell (antibody producing cells) deficiency, gammaglobulin therapy should be instituted to restore antibody levels in the blood until the B-cell system is restored by transplantation.

Finally, these infants need a great deal of family support because of repeated hospitalizations and painful procedures associated with hospitalization. In some geographical areas, support groups and other resources are available for these families to assist parents in dealing with the affected child, in maintaining spousal relationship and in providing love and support to other children in the family.

Prognosis

Without a bone marrow transplant, a child with Severe Combined Immunodeficiency is at risk for severe or fatal infection and may be best kept in a sterile isolation. Without treatment, survival beyond one year of age is unusual.

Prevention

Tests which identify carriers can provide prenatal diagnosis in some families in which the X-linked form of Severe Combined Immunodeficiency has been previously identified. However, as with all X-linked disorders, more than half of affected males represent the first manifestation of a new mutation in their families. Carrier detection and prenatal diagnosis is also available for adenosine deaminase deficient and some of the more recently identified forms of SCID.

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