Severe Combined Immunodeficiency (SCID) and Transplant

Severe combined immunodeficiency (SCID) is the name for a group of inherited immune system disorders. SCID disorders are the most severe of the inherited immune system disorders. Babies are born with these disorders, which can become life-threatening within the first year of life. SCID is rare. About 1 in 200,000 babies are born with SCID.

Causes of SCID

Inherited immune disorders are also called primary immune deficiency disorders. They are caused by a mutation (mistake) in a gene that affects the immune system. Genes carry an inherited code of instructions that tells the body how to make every cell and protein in the body.

Some types of SCID are caused by a mutation of a gene on the X chromosome, which comes from the mother. Disorders inherited on the X chromosome appear only in males. A female with the mutated gene will not have the disease but will be a carrier. This means she may pass the mutated gene on to her children.

Other types of SCID appear when a gene mutation is inherited from both parents. (In other words, the child has two copies of the same gene mutation.) These disorders occur in both males and females.

In most cases, no one knows what causes the mutation to appear the first time. Once a mutation appears, it can be passed from parent to child through many generations.

SCID and the immune system

The immune system is made up of organs and cells that work together to protect the body from infection and disease. The immune system uses white blood cells to fight infections. The white blood cells identify and attack cells that they do not recognize as belonging in the body.

There are several types of white blood cells, each with its own role. In children with SCID, the immune system does not work well because of problems with certain types of white blood cells known as lymphocytes. There are three types of lymphocytes:

• B cells make antibodies. Antibodies are proteins that attach to foreign cells and mark them to be attacked and destroyed.
• T cells direct B cells to make antibodies against foreign cells. T cells also direct the rest of the immune system when to attack or stop attacking foreign cells. They also help in the attack.
• Natural killer cells (NK cells) destroy infected cells and cancer cells.

The three types of lymphocytes work together, and all three types are needed for the immune system to function normally. In children with SCID, T cells are missing, defective, or at very low levels. B cells in SCID children, if they are present at all, cannot produce antibodies because of the defective or absent T cells. Sometimes, the natural killer (NK) cells are affected as well.

Symptoms and diagnosis of SCID

Children with SCID are at risk for life-threatening infections. From their first months of life, they have infections that may be frequent, severe, long-lasting or hard to treat. Infections may occur in the lungs (pneumonia), around the brain and spinal cord (meningitis) or in the blood stream. Many babies also get diarrhea that does not go away. Babies with SCID do not gain weight or grow at a healthy rate (fail to thrive). A baby diagnosed with SCID needs immediate treatment. Without effective treatment, most children with SCID die of infection with failure to thrive within the first year of life.

Diagnosis

If a baby shows signs of a possible immune disorder, a doctor can do a blood test to count the number of lymphocytes (the white blood cells affected in SCID) and test their function. Babies with SCID will generally have very low numbers of lymphocytes.

Families affected by SCID may want to talk with a genetic counselor about family planning and the chances of having children with the disorder. Early diagnosis can enable early treatment and significantly improve a child's chances of a good outcome.

Types of SCID

There are several types of SCID. Two of the more common are:

• Classical X-linked SCID — Almost half of patients with SCID have classical X-linked SCID (sometimes called "boy in the bubble" disease). It is inherited on the X chromosome and appears only in boys.
• ADA deficiency SCID — About 15% of patients with SCID have adenosine deaminase (ADA) deficiency. These patients have low levels of the enzyme ADA. Lack of ADA leads to low numbers of T cells and B cells. This type of SCID can appear in either girls or boys.

Treatment for SCID

Preventing infections

For children with SCID, the first concern is to prevent infections. Children with SCID need to be protected from germs. This includes keeping them away from crowds and sick people. They are treated with antibiotics to prevent infections such as Candida albicans (a type of yeast) and Pneumocystis pneumonia (PCP) infections.

They will also be given intravenous immune globulin (IVIG). Immune globulin is also called immunoglobulin or gammaglobulin. It contains antibodies that would normally be made by healthy B cells to help the body fight infection. Immune globulin is usually infused into a vein. Patients with SCID usually require IVIG infusions once every 3-4 weeks. Each infusion may take from one to five hours. Treatments may be given in a doctor's office, hospital outpatient unit or at home. Many people have no side effects from IVIG infusion, but some people may have side effects such as chills, headaches, fever, nausea and chest tightness. These can usually be controlled with medicine or adjustments to the rate of infusion.

Enzyme therapy for ADA deficiency SCID

The standard treatment for ADA deficiency SCID is treatment with a form of the ADA enzyme called PEG-ADA. Treatment with PEG-ADA is effective in about 90% of children. [1] However, despite PEG-ADA therapy, some children continue to require IVIG treatments.

Gene therapy

A treatment option being studied in clinical trials is gene therapy. Gene therapy has shown promising results for some patients with ADA deficiency SCID. At first, gene therapy also appeared to be a promising treatment for X-linked SCID, but some children treated with gene therapy developed leukemia. New trials of gene therapy are in progress. But despite some promising results, gene therapy remains an experimental treatment for SCID.

Transplant

The only known cure for SCID is a bone marrow or cord blood transplant (also called a BMT).

Transplant for SCID

A bone marrow or cord blood transplant replaces the child's abnormal blood-forming cells and immune system with healthy blood-forming cells from a family member or unrelated donor or cord blood unit.

The donor must closely match the patient's tissue type. The best donor is usually a matched sibling. Each sibling has a 25% chance of being a suitable match, but since SCID is inherited, many children with SCID do not have a healthy matched sibling.

Doctors may also use one of the child's parents or another partly matched family member as a donor. Each parent's tissue type matches half of the child's tissue type (a haploidentical match). Haploidentical transplants have had disappointing outcomes for many other diseases treated with transplant. However, for SCID, survival rates have been high enough to make them a good option for patients who do not have a matched sibling donor.

For children without a suitable family donor, doctors may search the Be The Match^SM Registry for an unrelated adult donor or cord blood unit.

Unlike transplants for most other diseases, a transplant for SCID may not include a preparative regimen of high-dose chemotherapy. The preparative regimen destroys cells in the bone marrow to make room for the donated cells. It also destroys immune cells so they cannot attack the donated cells. Some children with SCID do not need a preparative regimen because they have so few immune cells.

Factors that affect SCID transplant outcomes

Patient, disease and transplant factors can affect a child's chances of survival and his or her quality of life after transplant. In general, a child has a higher likelihood for a good outcome when:

• A transplant is done early, within the first few months of life, if possible.
• The child has not had severe infections or shown a failure to thrive.
• The child has a type of SCID with normal B cell function.
• The donor is a close match. A matched sibling offers the highest likelihood of success, but a partly matched (haploidentical) family member or an unrelated donor or cord blood unit can also provide a good outcome.

Whether or not a preparative regimen is used can affect some of the risks of a transplant. Without a preparative regimen, a child avoids risks of serious side effects from the high-dose chemotherapy. However, other risks are increased. The risk that the transplant will not engraft (make new blood cells for the body) is slightly higher. The risk that the child will not develop the B cell function needed for a normal immune system may also be higher. A child who does not develop normal B cell function will need ongoing treatment with IVIG after transplantation to help his or her immune system fight infection.

Whether a child with SCID receives a preparative regimen may depend on the form of SCID, the donor used and the transplant center. A preparative regimen is used for most transplants from unrelated donors, but may be omitted for transplants from related donors. If you are planning a transplant for your child, you can ask your child's doctor about whether a preparative regimen will be used.

Whether or not the donor's cells are filtered to remove T cells (T-cell depleted) can also affect the outcome. T cells play an important role in the immune system, but they are also involved in a transplant complication called graft-versus-host disease (GVHD). GVHD can range from mild to life-threatening. Whether or not the transplant is T-cell depleted depends on the donor used and the transplant center.

SCID transplant outcomes

When looking at SCID outcomes data, it is important to keep the factors that can affect transplant outcomes (described above) in mind. Another factor to think about is the quality of life for long-term survivors. Sometimes a transplant for SCID provides normal T cell function, but not B cell function, so the immune system still cannot fight infection normally.

A child can survive for the long term without normal B cell function, but will need ongoing treatment with IV immune globulin (IVIG) to help his or her immune system fight infection. The need for ongoing monthly treatments can affect a child's quality of life and the treatment is expensive. However, IVIG treatment usually has few side effects.

Related donor transplant outcomes

Use of closely matched donors tends to lead to better transplant outcomes. For most children who receive transplants from a matched related donor (usually a sibling), the likelihood of success is 90% or higher, especially when transplants are performed early in life before a serious infection develops. [1] Unfortunately, few children with SCID have a suitable matched sibling.

For babies with SCID, a transplant can also have good results using a parent or other family member who is at least half-matched (haploidentical) to the patient.

In a study of 89 children with SCID who received transplants at Duke University Medical Center in North Carolina between 1982 and 1998, only 12 had a matched related donor. [3] The others had a partly-matched related donor. The children in this study did not receive a preparative regimen before transplant. At the time of the report, between 3 months and 16 years after transplant:

• All 12 children with a matched related donor were alive.
• Of the 77 children with a partly matched donor, 60 (78%) were alive.
• All but four of the survivors had normal T cell function, but 45 children did not have normal B cell function and were being treated with IVIG.

In a European multi-center study of 475 children with SCID who received a transplant between 1968 and 1999, 153 had a matched related donor. [4] Eleven had an unrelated donor and 294 had a partly matched related donor. Use of a preparative regimen and T-cell depletion of the transplant varied.

• For children with a matched donor — either related or unrelated — the 3-year survival rate was 77%.
• For children who had a partly matched related donor, the 3-year survival rate was 54%.
• Rates of normal T cell and B cell function were not reported.
• This study spanned more than 30 years. The results for all types of transplants improved over time.

In a two-center study of 94 children with SCID, the outcomes for children who underwent matched unrelated donor transplants was significantly better than those who received transplants from mismatched related donors such as half-matched parents (haploidentical donors). [5]

Unrelated donor and cord blood transplant outcomes

Transplants using unrelated donors can be a life-saving option for children with SCID who do not have a suitable related donor. Of the 35 children with SCID who received an unrelated donor transplant facilitated by the NMDP between 1998 and 2006, the estimated survival rate was 75% (Figure 1).

Figure 1.
Severe Combined Immunodeficiency: Survival of pediatric (age <18 years) marrow recipients with all preparative regimens, unrelated donor transplant facilitated by NMDP, 1998-2006. (NMDP data)

View Larger Version    How to read this figure

Because a child with SCID needs a transplant quickly, a cord blood transplant may be an important option. A suitable cord blood unit may be easier to find and more quickly available than an unrelated adult donor. Although cord blood units have fewer cells than a typical collection from an adult donor, this is not an issue because the transplant recipeints are infants. Cord blood recipients also generally get less GVHD, so this makes cord blood an attractive option for infants with SCID.

The NMDP facilitated cord blood transplants for 104 children who had disorders that were not malignant (not leukemia, lymphoma or another cancer) (Figure 2). Twenty-four of these children had SCID or another inherited immune system disorder. Figure 2 shows only NMDP-facilitated transplants and does not reflect worldwide experience. The use of cord blood for transplants is growing.

Figure 2.
Non-Malignant Diseases: Survival of pediatric (age < 18 years) cord blood recipients with myeloablative preparative regimens, unrelated cord blood transplants facilitated by NMDP, 1998 - 2006. (NMDP data)

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Effect of age on transplant outcomes

A study at Duke University Medical Center, North Carolina, focused on the effect of age on outcomes. For transplants between 1982 and 1998, survival rates were higher for babies who received a transplant within the first month of life than for those who received a transplant later. [2] Babies who were treated early in life were diagnosed at or before birth because of a family history of the disease. However, without a known family history of disease, most children are not diagnosed until 6 months of age or older. At the time of the report, 8 months to 19 years after transplant:

• Of 21 babies who received a transplant within 28 days after birth, 20 (95%) were alive.
• Of the 96 babies who received a transplant later in life, 71 (74%) were alive. These children received a transplant 45 to 516 days after birth. The median (middle) age at the time of transplant was 190 days.

All these transplants were done without a preparative regimen. Most were T-cell depleted and used a haploidentical related donor. All surviving children developed normal T cell function after transplant, but many did not develop normal B cell function. They continued to be treated with IVIG.

Making treatment decisions

If your child has SCID, it is important to see a doctor who is an expert in these disorders. If your doctor has not treated other patients with SCID, ask him or her to refer you to an expert for consultation.

A doctor who is an expert in SCID can talk with you about the best treatment for your child and explain the possible risks and benefits. For children with ADA deficiency, enzyme therapy is a good first option.

However, if a child with ADA-SCID has a matched sibling donor, transplant may be an alternative option because it provides a potential for cure and helps avoid the need for lifelong enzyme therapy. For other types of SCID, a transplant is usually recommended. A transplant has serious risks and is not an option for all children, but it provides a chance for a cure of their disease.

Transplant timing and limitations

In general, it is best to have a transplant as soon as possible. Children with SCID are at risk for dying of infection before they can receive a transplant. Children who have had severe infections or show failure to thrive may be too weak to tolerate a transplant.

Even after a successful transplant, some immune system problems may persist. Children who do not receive a preparative regimen will often continue to require IVIG treatments. Additional problems noted in transplant recipients include autoimmune problems often involving red blood cells.

Selecting a donor or cord blood unit

If a child with SCID does not have a family member who is a suitable donor, doctors may start a search for an unrelated adult donor or cord blood unit. If your child needs a transplant, your doctor can discuss the choice of a donor and the possible risks and benefits with you.

More information on severe combined immunodeficiency

You can get more information about SCID from disease-specific organizations, such as:

• National Primary Immunodeficiency Resource Center
  http://www.info4pi.org/aboutPI/index.cfm?section=aboutPI&CFID=12977514&CFTOKEN=62075299
• Immune Deficiency Foundation
  http://www.primaryimmune.org/about_pi/about_pi.htm
• SCID.net: Missing Body Defense Systems http://www.scid.net/about.htm

For other organizations that offer information and resources, see Organizations That Can Help: A Searchable Directory.

References

1. Fischer A. Severe combined immunodeficiencies (SCID). Clin Exp Immunol. 2000; 122:143-149.
   http://dx.doi.org/10.1046/j.1365-2249.2000.01359.x
2. Myers LA, Patel DD, Puck JM, Buckley RH. Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood. 2002; 99(3):872-878.
   http://www.bloodjournal.org/cgi/content/full/99/3/872
3. Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 1999; 340(7):508-516.
   http://content.nejm.org/cgi/content/full/340/7/508
4. Antoine C, Müller S, Cant A, et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99. Lancet. 2003; 361(9357):553-560.
   http://dx.doi.org/doi:10.1016/S0140-6736(03)12513-5
5. Grunebaum E, Mazzolari E, Porta F, et al. Bone marrow transplantation for severe combined immune deficiency. JAMA. 2006; 295(5):508-518.
   http://jama.ama-assn.org/cgi/content/full/295/5/508

Contributing editors

Naynesh Kamani, M.D., Children's National Medical Center, Washington, D.C.
Neena Kapoor, M.D., Childrens Hospital Los Angeles, Los Angeles, Calif.
Charles Peters, M.D.