Lung transplantation, the therapy almost every cystic fibrosis patient (CF) considers at some point to prolong survival, rarely helps children with the disease live longer and, in fact, often increases their risk of dying, University of Utah researchers conclude in the most extensive study of the issue to date.
The findings argue strongly for a comprehensive look at determining which children with CF are the best candidates for lung transplants, said Theodore G. Liou, M.D., the study's principal investigator and associate professor of internal medicine at the University of Utah School of Medicine.
Published in the Nov. 22 issue of The New England Journal of Medicine, the study analyzed the largest data set ever constructed of children with CF—514 patients, 18 and younger, on the U.S. lung transplantation list from 1992-2002. Of the 248 children who actually received new lungs in that 11-year period, only one patient showed a clear benefit from transplantation, while 162 (nearly two-thirds), were at a higher risk of dying after the procedure—up to sevenfold in some cases. The researchers were unable to determine the harm or benefit of transplantation in the remaining 85 children who received new lungs.
“The implication is that most children with CF are going to be harmed by lung transplantation,” said Liou, also with the University's Intermountain Cystic Fibrosis Center. “We shouldn't expect lung transplantation to prolong their lives.”
The study underscores the need for CF patients to follow a consistent regimen of conventional therapy and medical care to maximize their survival, according to Liou and co-authors Frederick R. Adler, Ph.D., professor of biology and mathematics, Barbara C. Cahill, M.D., associate professor of internal medicine and medical director of University Health Care's Lung Transplant Program (both from the University of Utah); and Sir David R. Cox, Ph.D., who in the 1970s developed proportional hazards modeling, a statistical technique that revolutionized the study of survival expectations related to events such as organ transplants. Cox, professor of statistics at the Oxford University, United Kingdom, aided the U of U investigators in using the proportional hazards model for their study.
Cystic fibrosis is a hereditary disease that attacks multiple systems in the body, most dramatically affecting the lungs and gastrointestinal tract. CF causes excess sticky mucus in the lungs, turning them into a breeding ground for bacteria. People with the disease often have a cough that produces phlegm and experience shortness of breath. Difficulty digesting food often leads to malnutrition. Although treatments can slow the disease, there is no cure yet. The median age at death for people with CF is 25 today, compared with median survival of less than one year a few decades ago. Advances in therapy now allow some CF patients to live into their 40s, 50s, and beyond.
In using the proportional hazards model to estimate the risk of death in children who undergo transplantation, the researchers looked at 26 statistical variables that potentially could predict health hazards related to the procedure. The researchers eventually identified three primary factors affecting post-transplantation survival: age at transplantation—the older a child gets, the more likely the procedure will cause harm; the presence of S. aureus staph infection—children with the bacteria at or after transplantation faced a significantly higher risk of death; and whether a patient had diabetes before transplantation (recipients who had the disease before transplantation fared better than those who didn't) A fourth factor, infection with B. cepacia—bacteria that cause pneumonia in CF patients—produced equally deleterious consequences whether or not a patient received new lungs.
Although the reason is not clear, the risk of death after lung transplantation increases steadily as children with CF get older, and is influenced markedly by whether a recipient was infected with S. aureus before or at the time of the transplantation. By age 17, children with S. Aureus had almost a sevenfold increased chance of dying after transplantation. The reason possibly stems from the compromised immune systems of transplant patients, making them more susceptible to harm from the bacteria, according to Liou.
Although it hurt survival rates after transplantation, S. Aureus infection actually helped increase survival in children before the procedure. That's most likely explained by competition between S. aureus and Pseudomonas aeruginosa, a harmful organism that lodges in the airways of CF patients. This competition may help mitigate some of the damage from Pseudomonas aeruginosa.
“S. aureus is good before a transplant,” Liou said. “Afterward, it becomes a killer.” But even lung recipients who didn't have S. aureus were more likely to die as they got older: Recipients with neither the staph infection nor diabetes had a threefold greater risk of dying by age 18.
After 18, however, age seems to have little bearing on survival, but the reason why is also unknown, according to Adler. “Something fundamental seems to change as they reach adulthood,” he said. “But we don't know what that is. We hope further studies on adults with CF will help us understand the reason.”
Diabetes didn't harm a child's chances of survival after receiving new lungs—as long as the patient already had the disease at the time of transplantation. Diabetes develops in most patients who receive new lungs, according to Liou, and the physical toll the disease takes may account for a large proportion of the harm to patients after transplantation. Children who have diabetes when they're transplanted have, in effect, already paid the physical costs of the disease before receiving new lungs and don't bear that added burden on their chances of survival.
Although lung transplants, as currently allocated, don't help most children with CF, it doesn't mean transplantation can't benefit children, Liou and Adler say. But to make the most efficient use of lungs available, it's critical to develop a way to identify the sickest children who would benefit from transplants. Another key aspect of transplantation, its effect on quality of life, also needs to be studied.
In the current study, the U of U researchers found mixed indicators of how transplantation affected quality of life: some children spent fewer days in the hospital in the first two years following transplantation; others spent more. Many recipients also faced more medical complications, while others did not. “We couldn't really answer the quality-of-life question,” Liou said, “but it can no longer be assumed that lung transplantation has a beneficial effect on quality of life or survival.”
Identifying children who will benefit from receiving new lungs is something the entire CF transplant community, including patients, physicians, families, and researchers needs to decide, Liou said. Currently, transplant candidates are selected because of low lung function, worsening symptoms of the disease, and other factors than may indicate a poor prognosis. Those criteria aren't working, the researchers write in the NEJM .
“… The finding that only 1 of 248 children with CF transplanted during 1992-2002 had clearly improved survival suggests that factors actually used to select transplant candidates could not identify patients likely to have survival benefits,” they conclude.
With their study, the U of U researchers hope to start a discussion in the CF community to figure out how to determine the best candidates for transplantation. “We can't allocate lungs rationally right now,” Adler said, “because we don't have all the data, particularly on quality of life.”