Penn researcher-led study aims to improve long-term outcomes of lung transplants

Lung transplantation can be a life-extending option, but severe postoperative complications- including reduced lung function caused by organ rejection- often affect a recipients' quality of life and limit long-term survival. Now, as part of an effort to improve long-term outcomes, a national team led by a researcher at Penn Medicine has launched a study to better understand clinical and biological processes that occur after transplant and lead to the development of these complications. Funded by a seven-year, $9.8 million grant from the National Institutes of Health (NIH), the multi-center study will collect data from more than 4,000 lung transplant recipients to identify the underlying biologic mechanisms that determine the effectiveness and long-term viability of the transplant.

Researchers will also measure the functional status and health-related quality of life among recipients to better understand which patients seem to benefit most from lung transplants.

"Lung transplant is still a relatively new field, and there are considerable gaps in our understanding of the mechanisms that impact lung function and long-term outcomes post-transplant," said the study's principal investigator Jason D. Christie, MD, MS, chief of the division of Pulmonary, Allergy and Critical Care Medicine and the Robert M. Kotloff/Nancy P. Blumenthal Professor for Advanced Lung Disease at Penn. "With such a large and diverse population of transplant recipients, this study presents an unparalleled opportunity to examine long-term outcomes of lung transplant recipients and advance our knowledge of the mechanisms that lead to post-transplant complications, organ rejection and functional outcomes."

About 2,300 adults undergo lung transplants each year in the United States, including more than 100 via the Penn Lung Transplant program. Although patient outcomes have improved significantly since the 1990s, more than 40 percent of recipients die within five years of transplant. Many patients experience a form of chronic lung allograft dysfunction (CLAD), the leading cause of mortality among lung transplant recipients that manifests as decreasing lung function.

Little is known about what causes CLAD, or who is at risk for specific CLAD phenotypes, such as bronchiolitis obliterans syndrome (BOS), the most common form of CLAD and a condition characterized by progressive airflow obstruction and small airways fibrosis. Additionally, questions remain about the biologic mechanisms that drive CLAD, including the link with primary graft dysfunction (PGD)-;a severe, life-threatening form of acute lung injury that develops within the first days of the transplant-;and other early transplant events

In this study, researchers will use data collected for routine clinical visits, and will collect additional biosamples to perform long-term phenotyping on more than 4,200 patients to identify the development of CLAD and the risk factors associated with its different forms. Investigators will also conduct exams at six-month intervals to measure lung function, frailty status and health-related quality of life to understand which patients seem to benefit most from lung transplants.

The study serves as an extension of research done by the Lung Transplant Outcomes Group (LTOG), an 11-center cohort founded by Christie in 2007 to investigate lung transplant complications. Originally, the LTOG –which has enrolled more than 3,400 participants in the last 11 years – focused on the clinical risks and biomarkers of PGD. Since then, investigators in the LTOG have helped to define PGD's underlying mechanisms and identified people with a heightened risk of developing the condition.

Ongoing LTOG research aims to further understand the mechanisms so investigators can identify new treatment approaches, safely expand the donor pool and establish target populations for clinical research trials that test treatments to prevent PGD.

In order to develop targeted approaches to prevent and treat conditions like BOS, we first need to address these fundamental questions about risk and mechanisms. We hope our work will lead to improved clinical care and management of patients with advanced lung diseases as we comprehensively define the long-term benefit of lung transplantation and generate new knowledge on CLAD mechanisms that may change treatment paradigms."

Jason D. Christie, study's principal investigator