Lung Transplantation for Children With CF May Do More Harm Than Good

Key Point

In the most extensive study of its kind to date, lung transplantation in children with cystic fibrosis appeared to have no benefit.

NEW ORLEANS—Lung transplantation—the therapy almost every patient with cystic fibrosis (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 concluded in the most extensive study of the issue to date.

Their findings argue strongly for a comprehensive look at determining which children with CF are the best candidates for lung transplants, said principal study investigator Theodore G. Liou, MD, from the Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine at the University of Utah School of Medicine in Salt Lake City.

Published in the November 22, 2007, 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 US lung transplantation waiting list from 1992 to 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—as high as 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 Dr. Liou, who is 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 Dr. Liou and colleagues—including Sir David R. Cox, PhD, 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. Dr. Cox, Professor of Statistics at Oxford University in the United Kingdom, aided the University of Utah investigators in using the proportional hazards model for their study.

THREE PRIMARY FACTORS

In estimating the mortality risk in children who undergo transplantation, the researchers looked at 26 statistical variables. The researchers eventually identified three primary factors that affect posttransplantation survival: age at transplantation (older age increased mortality risk), the presence of Staphylococcus aureus infection (children with the bacteria at or after transplantation faced a significantly higher mortality risk), and presence of diabetes before transplantation (recipients who had the disease before transplantation fared better than those who did not). A fourth factor, infection with Burkholderia cepacia, produced equally deleterious consequences whether or not a patient received new lungs.

Although the reason is not clear, 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 Dr. Liou.

After 18, however, age seems to have little bearing on survival in lung recipients, but the reason why is also unknown, according to study coauthor Frederick R. Adler, PhD, from the University of Utah Department of Mathematics. “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.”

Although it hurt survival rates after transplantation, S aureus infection actually helped increase survival in children before the procedure. “The protective effect of S aureus infection is most likely due to active competition between S aureus and more harmful Pseudomonas aeruginosa organisms in the airways of patients with CF,” the investigators noted.

Diabetes develops in most patients who receive new lungs, according to Dr. 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 before transplantation 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.

IDENTIFY CHILDREN LIKELY TO BENEFIT

To make the most efficient use of available lungs, it is critical to develop a way to identify the sickest children who would benefit from transplantation, said Drs. Liou and Adler. Another key aspect of transplantation—its effect on quality of life—also needs to be studied.
In the current study, the researchers found mixed indicators of how transplantation affected quality of life: Some children spent fewer days than others in the hospital in the first two years following transplantation; some children spent more. Many recipients also faced more medical complications, while others did not. “We couldn’t really answer the quality-of-life question,” Dr. 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, Dr. Liou said.

“We can’t allocate lungs rationally right now,” Dr. Adler said, “because we don’t have all the data, particularly on quality of life.” The study authors call for a prospective trial to “fully address potential biases, search for additional selection criteria, thoroughly evaluate the effect of transplantation on quality of life, and show the effect of the procedure on survival.”

''STARTLING" FINDINGS

In an accompanying editorial, Julian Allen, MD, who holds the Robert Gerard Morse Endowed Chair in Pediatric Pulmonary Medicine at the Children’s Hospital of Philadelphia, and Gary Visner, DO, a transplant surgeon at Children’s Hospital Boston, called the study results “startling.”

“The study’s results make it clear that physicians must be more judicious than ever in referring children with cystic fibrosis for lung transplantation, with careful consideration of the severity of the child’s illness,” said Dr. Allen. He said that cystic fibrosis centers must provide appropriate social and psychological support to help families make the best choice for their children.

Dr. Allen added that it is possible that a lung transplant may improve a patient’s quality of life, as the current study had only limited information on that question. He urged that future studies of lung transplantation in CF patients ought to carefully measure quality of life as well as measuring how closely patients adhere to posttransplant medical treatments.

One fact that may change future results, said Dr. Allen, is that the new organ allocation system initiated in 2005 takes into account the severity of a patient’s illness, in addition to other factors such as the length of time a patient remains on the waiting list for a donated organ. The system in place when the study was performed allocated lungs based only on the duration of the patient’s wait.           

Suggested Reading
Allen J, Visner G. Lung transplantation in cystic fibrosis—primum non nocere? N Engl J Med. 2007;357(21):2186-2188.
Liou TG, Adler FR, Cox DR, Cahill BC. Lung transplantation and survival in children with cystic fibrosis. N Engl J Med. 2007;357(21):2143-2152.

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