PHILADELPHIA — A multi-institution study led by researchers at the Perelman School of Medicine at the University of Pennsylvania has identified several important risk factors, including a donor’s smoking history and recipient obesity, linked to severe primary graft dysfunction (PGD), the major cause of serious illness and death after lung transplantation. PGD is a common complication that affects up to 25 percent of lung transplant patients shortly after surgery. The study also found that some previously identified risk factors, including donor sex, race, age, and means of death, were not associated with PGD.
The study published in the March issue of the American Journal of Respiratory and Critical Care Medicine, is the first prospective, multicenter cohort study of risk factors for severe PGD after lung transplantation. It included 1,255 lung transplant recipients at ten U.S. lung transplant centers over an eight-year period. The researchers evaluated potential risk factors for severe PGD previously identified in the literature or with hypothetical clinical or biologic plausibility to be associated with PGD.
A key finding is that lung recipients from donors who were smokers have an absolute five percent higher risk of developing PGD than those who received lungs from nonsmokers. Researchers previously found that donor smoking increased the rate of death for lung recipients; the current study found that the cause of this is an increased rate of serious – or Grade 3 – PGD.
“Even though donor smoking is tied to higher death rates and incidence of Grade 3 PGD, this doesn’t mean we should prohibit smokers from donating lungs,” said lead study author Joshua Diamond, MD, MSCE, instructor of medicine in the Division of Pulmonary, Allergy, and Critical Care at Penn. “Although PGD was higher after receiving a lung from a smoking donor compared with a non-smoking donor, other studies show that overall survival is significantly better than remaining on waiting lists for lung transplantation when donors with a smoking history are part of the donor pool. Given the limited pool of available lung donors, it’s simply not feasible to exclude patients who were previous smokers as potential lung donors.”
Another key finding is that overweight recipients had an absolute seven percent higher risk for PGD compared with normal weight, and obese recipients had an 11 percent higher risk of PGD. Active research is underway on the immune mechanisms behind this finding. Because of the known association between weight and PGD, lung transplantation centers generally restrict transplant candidates to those with a body/mass index of 30 or 35.
Grade 3 PGD usually occurs within the first three days after lung transplantation. Diamond and his colleagues found that patients with PGD had a 23 percent risk of dying within 90 days of surgery, compared to a five percent risk of those not diagnosed with PGD. After one year, the death rate for those with PGD was 34 percent, compared to a death rate of 11 percent for those not diagnosed with PGD. Therefore efforts aimed at improved understanding, better predicting, and preventing PGD would dramatically improve transplant outcomes.
Jason Christie, MD, MS, senior study author and associate professor of Medicine and Epidemiology, said that further study was needed on determining donor smoking history. “Our study relied on a straightforward question of family members: ‘Had the donor ever been a smoker?’ We are currently researching better ways to quantify smoke exposure, including passive smoking, using molecular markers. We are also asking why lungs from a smoker would be more prone to lung injury, so that we can give preventative treatments before the transplant.”
The study also identified several other risk factors for PGD, including certain types of lung disease and several surgical procedures often used to help sicker patients survive the surgery. In these latter cases it is not clear if the fact that patients were sicker and needed the procedures explained the higher PGD rates or if the procedures themselves resulted in greater rates of PGD.
Other authors from Penn include James C. Lee, MD, Steven M. Kawut, MD, Rupal J. Shah, MD, A. Russell Localio, PhD, Scarlett L. Bellamy, ScD, Edward Cantu, MD, Benjamin A. Kohl, MD, and Ejigayehu Demissie.
The study was supported by grants from the National Institutes of Health (R01 HL087115, R01 HL081619, and R01 HL096845).
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.9 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $409 million awarded in the 2014 fiscal year.
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