WASHINGTON -- They lived short lives in sterile rooms. Children with a disorder known as "bubble boy" disease were born without an immune system, and they inevitably died from common infections. Their fate was dramatized by a documentary film of a young Texas patient who lived and died in a germ-free plastic sphere.
Now, researchers at Duke University Medical Center are reporting that the disease, known as severe combined immune deficiency (SCID), can be cured in many cases if diagnosed and treated early enough.
A 15-year study by Duke physicians shows that more than 90 percent of babies born with the disorder can be given a healthy immune system if they receive a bone marrow transplant within three months of birth. They also have learned that these children need not have a perfectly matched donor, but can use a parent's "half-matched" marrow. Furthermore, the babies do not need toxic pre-transplant chemotherapy, as is often thought and currently practiced.
The results of the study of 79 children were prepared for presentation May 3 at the joint American Pediatrics Society/Society for Pediatric Research annual conference. Duke is one of only a few hospitals in the country that specializes in treating children with SCID.
"This once-fatal disease should be now seen as a pediatric emergency, a condition that needs immediate diagnosis and treatment," said Dr. Rebecca Buckley, chief of Duke's division of pediatric allergy and immunology.
Buckley said early diagnosis of SCID is rare because doctors do not routinely perform a test in newborns to count white blood cells. Such a blood test could pick up children with SCID as well as those with other serious immune deficiencies that would not be apparent until the child developed an infection. "A simple blood test could allow us to treat, and most likely cure, SCID in a child for as little as $25,000," Buckley said. "If found later, less effective treatment can run into the millions."
Babies born with SCID suffer from a variety of genetic defects, all leading to a lack of T or B immune cell function, which is essential for protection against infection. The defect is said to occur once in every 500,000 to 1 million births, but it could be more common, researchers say, because babies who die of a simple infection often are not given an autopsy.
"Without an immune system, a patient is completely vulnerable to infection. A pathogen that would be harmless to a person with normal immunity would destroy a SCID patient. Until 1982, SCID was invariably fatal unless the patient had a brother or sister who was an exact match to donate bone marrow," Buckley explained. "What we see now is that a sibling match isn't necessary; haploidentical parental marrow will work, too." A haploid match is a half match.
But the key is timing, according to Buckley. The transplant needs to be done before the onset of opportunistic infection, she explained, and in the first few weeks of the baby's life, when the donor marrow takes hold quickest. Waiting until after the first four weeks of life increases the risk of infection, as well as slowing the development of immunity from the donor transplant.
Buckley also found that transplants can be done without exposing the infant to toxic chemotherapy, which can have life-long repercussions.
Many doctors give chemotherapy to all bone marrow transplant patients because they are following standard cancer treatment protocol, Buckley said. But chemotherapy is not necessary in children with SCID because they have no T-cells to attack and destroy the foreign donor marrow, as is the case with cancer patients.
"Patients with SCID have no immune systems to reject the transplants. Our approach avoids toxic agents and their possible complications," she said.
Moreover, Buckley has found a way to reduce a potentially fatal complication of transplants called graft-versus-host disease (GVHD). By removing the donor's T-cells before the transplant, the donor's marrow cannot rise up and attack the patient's vital organs -- a common complication with bone marrow transplants.
And, by removing these cells before the transplant, the infant avoids the toxic drugs normally given to suppress the donor's T-cells.
Results from the study of 79 SCID patients who received bone marrow transplants at Duke between May 1982 and January 1997 indicate that parents, as well as siblings of SCID-affected babies, can be successful marrow donors. None of the patients received pre-transplant chemotherapy. Overall, 78 percent of the patients have survived -- some are now teenagers -- including all 12 recipients who received identical marrow transplants. Seventy-four percent of the 67 haploidentical (or parent donor) marrow recipients survive.
Within the total group of 79 patients receiving marrow transplants, 18 babies were diagnosed with SCID in utero or at birth because of a family history. Thirteen of those early-diagnosed babies received marrow transplants from eight to 24 days after birth. Twelve of 13 -- 92 percent -- survive; one is now 15. The other six received a transplant within three months and all survived. The Duke researchers found no difference in eventual outcome between identical or half-match stem-cell transplants, leading them to support early diagnosis and neonatal transplant as key to curing SCID patients.
Newborn screenings can detect the genetic defect in SCID babies. With the mother available as a marrow donor, the life-saving transplant can be done in the first few days of a baby's life. The patient can receive treatment as an outpatient or with "observation admission" (23 hours in the hospital).
"This makes the treatment both easier on the mother and baby and cost-effective" said Buckley. "What we're saying is that essentially every baby with SCID could be cured if diagnosed early enough. SCID should be considered a pediatric emergency."
Buckley characterized the Duke researchers' approach as conservative when compared with recent attempts to treat SCID in utero. Neonatal treatment bypasses the instrumentation risks associated with pre-term treatment, she said.