Duke Physicians Predict Risks of Deadly Infections After Cord Blood Transplants
DURHAM, N.C. -- Transplant physicians at the Duke Comprehensive Cancer Center have identified several risk factors that make certain children more likely than others to die of viral infections after receiving umbilical cord blood transplants to cure their deadly cancers, immune diseases and rare metabolic disorders.
The Duke team has already applied their findings in the laboratory toward strengthening cord blood's ability to wage an immune response. Doctors ultimately plan to infuse these bolstered immune cells into transplant patients to more effectively fend off opportunistic infections, said Paul Szabolcs, M.D., assistant professor of pediatrics and immunology at the Duke Pediatric Bone Marrow and Stem Cell Transplant Program.
Children are at highest risk of infection during the first 100 days after transplant, when their new immune system struggles to take hold or "engraft." Even after engraftment occurs, cord blood lymphocytes may remain relatively immature and "naïve" to viral infections because they have never been exposed to nor vaccinated against viruses.
As a result, almost half of all deaths after cord blood transplantation are caused by infections, and among those, viruses are by far the most common. The children who live, however, are typically cured of their deadly cancers, immune disorders and rare metabolic diseases. Which patients will succumb to infection and which will survive has been a mystery.
In an effort to predict a child's risk of infection, Szabolcs studied the immune status of 102 children at the Duke Pediatric Bone Marrow and Stem Cell program. He looked for immune system differences that could explain why some children succumb to infections and die while others do not.
"Our goal was to predict which children would be at greatest risk for infection so that, in the near future, we can reinforce a child's immune response immediately following their transplant," said Szabolcs. "Until now, we haven't understood what factors predict for opportunistic infections that claim the lives of certain patients."
Szabolcs will present findings of his study at the International Bone Marrow Transplantation Research meeting Feb. 12 - 17, 2004, in Orlando.
In his study, Szabolcs recorded each patient's age, size, gender and various levels of immune factors on the 50th day following their transplants. He then followed patients for up to three years and compared their initial demographic information and immune markers to their eventual outcomes.
First, he found that younger children and children who weighed less had a lower risk of infection than did older and larger children. Presumably, younger and smaller children received higher numbers of immune cells called "T lymphocytes" in proportion to their weight. The greater the army of immune cells, the more powerfully they can wage war against infections, said Szabolcs.
The researchers supported that theory by showing that children with the highest number of T lymphocytes present in their blood by day 50 were at lower risk of infection. Of all the T lymphocytes, the most powerful for infection control appeared to be the "helper" or CD4+ T lymphocytes. Children with higher levels of these cells -- median of 137 -- developed no infections, while children with lower levels -- median of 44 -- had the most infections, the study found.
Third, Szabolcs found that low numbers of certain type of immune cells called "lymphoid" dendritic cells correlated with higher risk of infections. Dendritic cells are among the front-line soldiers in the immune system's army, alerting the troops to the presence of invaders. They do so by activating other lymphocytes to react against the invading virus.
Surprisingly, the number of stem cells the children received had no impact on their risk of infection in the first 100 days following transplant, although stem cells play a vital role in long-term immunity, said Szabolcs. While stem cells are critical for repopulating the blood-forming and immune systems and correcting metabolic defects in children, it presumably takes at least 100 days or longer before certain stem cells develop into new T cells, he said.
Fourth, Szabolcs found that children who received a relatively closer cord blood match were at lower risk for infection. A close match is measured by how many of the donor's "human leukocyte antigens" (HLAs) match those of the patient. Children who shared five out of six of the major HLA molecules with their donor suffered fewer life-threatening infections than children with three or four matching HLAs.
Szabolcs speculates that increased mismatch of HLA molecules between the patient and donor can interfere with immune cell messages that must connect in order for the body to recognize an infection and wage war against it.
Finally, the study showed that children who suffered from a severe form of "graft-versus-host disease," or GVHD, an incompatibility reaction in which the donor cells attack the patient, were at higher risk of infection because the condition is treated with high doses of immune-suppressing drugs.
Based on his current data, Szabolcs has already begun testing young patients within the 30 days following transplant -- even before official "engraftment" occurs -- to determine which factors truly predict a patient's immune recovery and which merely reflect ongoing infections.
Simultaneously, Szabolcs is using his new data to manipulate T lymphocytes in the laboratory. His team has developed methods to selectively remove the specific T lymphocytes that could recognize the host and cause dangerous GVHD.
Furthermore, his team is bolstering T-cells in the laboratory by exposing them to small bits of viral material before they are infused into the patient. Their goal is to generate an immune "memory" against a range of viruses, so that when T cells encounter a virus in patients, they will be primed to target and destroy it. Szabolcs' team hopes to begin administering the immunized T cells that are devoid of GVHD potential to patients within the next one to two years.