IDF PATIENT/FAMILY HANDBOOK | CHAPTER V
Severe Combined Immunodeficiency
Severe combined immunodeficiency is a rare primary immunodeficiency disease in which there is combined absence of T-lymphocyte and B-lymphocyte function. It is caused by a number of different genetic defects. These defects lead to extreme susceptibility to infection. This condition is generally considered to be the most serious of the primary immunodeficiencies.
DEFINITION: Severe combined immunodeficiency (SCID, pronounced “skid”) is a rare syndrome of diverse genetic causes in which there is combined absence of Tlymphocyte and B-lymphocyte function. In many cases, there is also absence of natural killer, or NK, lymphocyte function. There are at least five currently known genetic types of SCID:
Deficiency of the common gamma chain of T-lymphocyte receptors for growth factors:
This is the most common form of SCID, affecting nearly 45% of all cases. It is due to mutations in a gene on the X chromosome that encodes a component (or chain) shared by receptors for growth factors on the surface of T-lymphocytes and NK-lymphocytes. This component (referred to as ?c for common gamma chain) is necessary for normal growth and function of T-lymphocytes. This form of SCID is inherited as an X-linked recessive trait (see chapter on Inheritance). Thus, only males have this type of SCID. Mutations in this gene result in very low T-lymphocyte and NK-lymphocyte counts, but the B-lymphocyte count is normal. Despite the normal number of B-lymphocytes, there is poor B-lymphocyte function.
Deficiency of Janus kinase 3:
This type of SCID is caused by a mutation in a gene on chromosome 19 that encodes an enzyme called Janus kinase 3 (Jak3). This enzyme is necessary for function of the above-mentioned common gamma chain, ?c. Infants with this form of SCID have the same kinds of T, B and NK-lymphocyte counts as those with X-linked SCID. However, this form of SCID is inherited as an autosomal recessive trait (see chapter on Inheritance). Thus, both boys and girls can be affected. Jak3 deficiency accounts for less than 10% of all cases of SCID.
Deficiency of the alpha chain of the IL-7 receptor:
This form of SCID is due to mutations in a gene on chromosome 5 that encodes a component of another T-lymphocyte growth factor receptor, the alpha chain of the IL-7 receptor (IL-7R?). Infants with this type of SCID have B- and NK-lymphocytes but no T-lymphocytes; the B-lymphocytes don’t work because of the lack of T-lymphocytes. This form of SCID is inherited as an autosomal recessive trait (see chapter on Inheritance). IL-7R? deficiency is seen in less than 5% of SCID cases.
Deficiency of Adenosine Deaminase:
This type of SCID is caused by mutations in a gene on chromosome 20 that encodes an enzyme called adenosine deaminase (ADA) that is essential for the metabolic function of a variety of body cells, but especially T-lymphocytes. The absence of this enzyme leads to an accumulation of toxic metabolic by-products within lymphocytes that cause them to die. ADA deficiency accounts for approximately 15% of cases of SCID. Babies with this type of SCID have the lowest total lymphocyte counts of all, with T, B and NK-lymphocyte counts all being very low. This form of SCID is inherited as an autosomal recessive trait (see chapter on Inheritance).
Deficiency of Recombinase
Activating Genes:
This type of SCID is due to mutations in genes on chromosome 11 that encode enzymes necessary for the development of the antigen recognition receptors on T and B-lymphocytes. These genes are called recombinase activating genes 1 and 2 (RAG1 and RAG2). Infants with this type of SCID lack T- and B-lymphocytes but have NK-lymphocytes. This form of SCID is inherited as an autosomal recessive trait (see chapter on Inheritance). Finally, there are other types of SCID for which the molecular defects have not yet been identified.
CLINICAL PRESENTATION: The most common symptom in infants with SCID is an excessive number of infections. The onset of infections usually occurs in the first few months of life. However, the infections are not usually the same types of infections that normal children have, e.g., frequent colds. The infections in patients with SCID can be much more serious and even life-threatening. These may include pneumonia, meningitis or bloodstream infections.
Infections in infants with SCID may be caused by organisms that cause infections in normal children, or they may be caused by organisms that are usually not harmful to children with normal immunity. Among the most dangerous is an organism called Pneumocystis carinii that can cause a rapidly fatal pneumonia (PCP) if not diagnosed and treated promptly. Another very dangerous organism is the chickenpox virus (varicella). Although chickenpox is annoying and causes much discomfort in healthy children, it is usually limited to the skin and mucous membranes and resolves in a matter of days. In infants with SCID, it may be fatal because it does not resolve and can then infect internal organs such as the lung, liver and often the brain. Cytomegalovirus (CMV), another common virus, may cause fatal pneumonia in infants with SCID. Other dangerous viruses for infants with SCID are the infectious mononucleosis virus (Ebstein-Barr Virus), respiratory syntitial virus (RSV), parainfluenzae virus, cold sore virus (Herpes simplex), polioviruses, the measles virus (rubeola), adenovirus and rotavirus.
Because infants receive live virus vaccines for chickenpox, polio, and measles, infants with SCID can contract chronic infections from the viruses present in these vaccines.
Fungal (yeast) infections may also occur in infants with SCID and can be very difficult to treat. As an example, thrush (candida infection of the mouth) is common in most babies but usually disappears spontaneously or with simple oral medication. In contrast, for the child with SCID, thrush persists despite this medication. The skin and diaper area may become chronically infected with the same fungus (candida) that infects the mouth and causes thrush. Occasionally, candida pneumonia, esophageal infection or even meningitis may develop in SCID infants.
Persistent diarrhea is also a very common problem in children with SCID. It may lead to severe weight loss and malnutrition. The diarrhea may be caused by the same bacteria, viruses or parasites that affect normal children. However, in the case of SCID, the organisms are very difficult to get rid of once they become established.
Finally, some infants with SCID may have a complication caused by the mother’s T-lymphocytes that entered the baby’s circulation through the placenta before birth. This reaction, called graft (the mother’s T-lymphocytes) - versus — host (the baby with SCID) disease (GVHD) takes a variety of forms but most commonly causes a rash that may be mistaken for eczema.
DIAGNOSIS: The diagnosis is usually first suspected in children with the above symptoms. However, in some instances there has been a previous child with SCID in the family and this positive family history may prompt a diagnosis in a new infant before he/she develops any symptoms. An easy way to find a clue to the presence of SCID is to count the number of lymphocytes in the blood. There are usually more than 4,000 lymphocytes (per microliter) in a normal infant’s blood during the first year of life. SCID infants usually have many fewer lymphocytes than this; the average for all types of SCID is 1,700 lymphocytes (per microliter) and many are below 1,000.
More complicated tests are usually necessary to confirm the diagnosis. The different types of lymphocytes can be identified with special stains and counted. In this way, the number of total T-lymphocytes, helper T-lymphocytes, killer Tlymphocytes, B-lymphocytes and NK-lymphocytes can be counted. However, since there are other conditions that can produce lower than normal numbers of the different types of lymphocytes, the most important tests are those that examine T-lymphocyte function. The most definitive test involves incubating the infant’s blood lymphocytes in culture tubes and treating them with various stimulants for several days. Normal T-lymphocytes react to the stimulants by undergoing cell division. In contrast, lymphocytes from patients with SCID usually do not react to the stimulus. Immunoglobulin levels are usually very low in SCID. Most commonly (but not always), all immunoglobulin classes are depressed (i.e. IgG, IgA, IgM and IgE).
The specific molecular defect responsible for SCID can be identified in many cases by analyzing the different genes responsible for the defects. These tests are usually only available in specialized research labs. Every effort should be made to make a specific molecular and genetic diagnosis since knowing the exact genetic defect will provide valuable insight into the way in which the disorder is inherited, or passed on in the family, the risks for having another affected child and who else in the family may be at risk for having an affected infant.
The diagnosis of SCID can also be made in utero (before the baby is born) (see chapter on Inheritance) in some situations. For example, if there has been a previously affected infant in the family and the genetic (molecular) defect has been identified, a diagnosis can be made by molecular testing of cells from the placenta (chorionic villous sampling or CVS) or from an amniocentesis, where a small amount of fluid (which contains fetal cells) is removed from the uterine cavity. Even if the genetic (molecular) abnormality had not been fully characterized in the family, there are tests that can rule out some specific defects. For example, adenosine deaminase deficiency can be ruled in or out by enzyme analyses on the CVS or amnion cells. If the form of SCID is the X-linked form, one can determine the sex of the unborn child, and if the fetus is a female she would not be affected. If the family chooses to wait until the baby is born before testing, the diagnosis can be made by examining the lymphocytes in the cord blood of the baby (see above).
INHERITANCE: All types of SCID are due to genetic defects. These defects can be inherited from the parents or can be due to new mutations that arise in the affected infant. As already noted, the defect can be inherited either as an Xlinked (sex-linked) defect, where the gene is inherited from the mother, or as one of a number of types of autosomal recessive defects (see above section on what causes SCID) where both parents carry a defective gene (see chapter on Inheritance). The reader should read the chapter on Inheritance in order to understand more fully how autosomal recessive and sex-linked recessive diseases are inherited, the risks for having other children with the disease and how these patterns of inheritance affect other family members. Parents should seek genetic counseling so that they are aware of the risks of future pregnancies.
It should be emphasized that there is no right or wrong decision about having more children. The decision to have children should be made in light of the special factors involved in the family, the basic philosophy of the parents, their religious beliefs and background, their concept of the impact of the illness upon their lives and the lives of the members of the family. All of these factors will be different for each family.
GENERAL TREATMENT: The infant with SCID needs to be isolated from children outside the family, especially from young children. If there are siblings who attend daycare, Sunday school, kindergarten or grade school, the possibility of bringing chickenpox into the home represents the greatest danger. Fortunately, this threat is being diminished by the widespread use of the chickenpox vaccine (Varivax). Nevertheless, parents need to alert the school authorities to this danger, so that the parents can be notified when chickenpox is in the school. If the siblings have been vaccinated or have had chickenpox, there is no danger. If the siblings have not been vaccinated and they have not had chickenpox, and if they have had a high level of exposure to a child with chickenpox, they should live in another house during the incubation period (11 to 21 days). A high level of exposure is said to occur when there is close contact of the sibling (same reading table, eating together, playing together) with a child who breaks out in the “pox” anytime within 72 hours of that exposure. If the sibling breaks out with “pox” at home and exposes the infant with SCID, the infant with SCID should receive varicella immunoglobulin (VZIG) immediately. If the SCID infant breaks out with “pox” in spite of receiving VZIG, he or she should receive acyclovir, a medication active against chickenpox. The SCID infant should not receive the chickenpox vaccine (Varivax), since it is a live virus vaccine and no live virus vaccine should be used in children with SCID (see below).
Children who have been vaccinated with live polio vaccine may excrete live poliovirus that could be dangerous to the SCID infant. Therefore, children who come in contact with the infant with SCID (e.g. siblings) should receive the killed polio vaccine and not the live (oral) vaccine. Fortunately, the use of live polio vaccine in the United States has been discontinued and infants are now routinely immunized with the killed polio vaccine. Thus, the chance that an infant with SCID will be inadvertently exposed to the live polio vaccine has markedly diminished.
Usually the infant with SCID should not be taken to public places (day care nurseries, church nurseries, doctors’ offices, etc.) where there are likely to be other young children who could be harboring infectious agents. Contact with relatives should also be limited, especially those with young children. However, neither elaborate isolation procedures nor the wearing of masks or gowns by the parents is necessary at home. Handwashing by everyone who comes in contact with the infant with SCID is essential, however.
Although no special diets will cure SCID, nutrition is very important. In some instances, the child with SCID cannot absorb his or her food normally, which in turn can lead to poor nutrition. As a result, some children may need continuous intravenous feedings to maintain normal nutrition. Sick children generally have poor appetites, so maintaining good nutrition may not be possible in the usual fashion. (See chapter on General Care- Nutrition.)
Death from infection with Pneumocystis carinii, an organism which causes pneumonia in SCID patients, used to be a common occurrence in this primary immunodeficiency disease. However, pneumonia from this organism can be prevented by prophylactic (preventive) treatment with trimethoprim-sulfamethoxazole. Therefore, all infants with SCID should receive this preventive treatment until the defect in their immune systems has been corrected.
LIVE VIRUS VACCINES AND NONIRRADIATED BLOOD OR PLATELET TRANSFUSIONS ARE DANGEROUS. If you or your doctor suspects that your child has a serious immunodeficiency (or if there is a family history of an immunodeficiency), you should not allow rotavirus, chickenpox, mumps, measles, live virus polio or BCG vaccinations until his or her immune status has been evaluated. As mentioned above, the patient’s siblings should not receive live poliovirus vaccine. Viruses in the other live virus vaccines, if given to the patient’s siblings, are not likely to be shed or transmitted from the sibling to the patient.
If an infant with SCID needs to have a blood or platelet transfusion, he/she should get irradiated and Cytomegalovirus-negative blood or platelets. This precaution is necessary to prevent fatal Graft — Versus — Host Disease (GVHD) from T-lymphocytes in blood products and to prevent his/her contracting an infection with Cytomegalovirus.
Importantly, infants with SCID need all the support and love that parents can provide. They may have to tolerate repeated hospitalizations that may be associated with many painful procedures. Parents need to develop internal and external sources of support to cope with the anxiety and stress of this devastating problem. Support groups are helpful to many parents. Although the demands on the time and energies of the parents are overwhelming, parents need to remember the child’s siblings continue to need their love and attention, and information about the patient’s condition. The parents also need to maintain their own relationship with each other.
SPECIFIC THERAPY: Intravenous immunoglobulin (IVIG) replacement therapy should be given to SCID infants. Although IVIG will not restore the function of the deficient T-lymphocytes, it does replace the missing antibodies resulting from the B-lymphocyte defect and is beneficial.
For patients with SCID due to ADA deficiency, replacement therapy with a modified form of the enzyme (called PEGADA) has been used with success. However, the immune reconstitution affected by PEG-ADA is not a permanent cure and requires subcutaneous injections for the rest of the child’s life.
The most successful therapy for SCID is immune reconstitution by bone marrow or cord blood transplantation. Bone marrow and cord blood stem cell transplantation for SCID is best performed at medical centers that have had experience with SCID and its optimal treatment. In a bone marrow transplant for SCID, bone marrow or cord blood stem cells from a normal donor are given to the immunodeficient patient to replace the defective cells of the SCID patient’s immune system with the normal cells of the donor’s immune system. The ideal donor for a SCID infant is a matched normal brother or sister. Lacking that, techniques have been developed over the past 2 decades that permit good success with halfmatched related donors (such as a mother or a father). Several hundred marrow transplants have been performed in SCID infants over the past 3 decades, with an overall survival rate of 60-70%. However, the outcomes are better if 1) the donor is a matched sibling (>85% success rate), 2) if the transplants are performed without pre-transplant chemotherapy (>80% success rate) even if half-matched related (parental) donors are used, or 3) if the transplant can be performed soon after birth, or when the infant is less than 3.5 months of age (>95% survival even if only half-matched).
Finally, another type of treatment that has been explored over the past decade is gene therapy, and it has provided much hope for the future. The first type of SCID for which gene therapy was performed was SCID due to ADA deficiency. In the initial trials, the normal ADA gene was inserted into the T-lymphocytes of the ADA deficient children and those Tcells survived and expressed the normal gene. The results from those initial trials were so encouraging, that recently gene therapy has been tried as a treatment for the X-linked recessive form of SCID due to deficiency of the common gamma chain of T-lymphocyte receptors. In these trials, the normal gene has been inserted into their stem cells and the children have done very well in the first years after this form of gene therapy.
EXPECTATIONS: Severe combined immunodeficiency syndrome is generally considered to be the most serious of the primary immune deficiencies. Without successful therapy, the patient is at constant risk for a severe or fatal infection. With successful therapy, such as a bone marrow transplant, normal T-lymphocyte function is restored. For example, the first bone marrow transplantation for SCID was performed in 1968. That patient is alive and well today!