Overview
Sometimes a transplanted lung that has been working well suddenly works less well. Breathing tests drop over days or weeks. This is called acute lung allograft dysfunction, or ALAD.
What happens next varies. Some people recover completely. Some stay at the lower level. Some continue to decline toward permanent damage. From the outside, at the moment it happens, these three situations can look identical, which makes it hard to know how aggressively to treat.
Until recently there was a more basic problem: different transplant centers did not agree on what counted as an episode at all. Without a shared definition, studies could not be compared and trials in these patients were nearly impossible to run. Our laboratory led the international effort to fix that, and then went looking for the biological differences that separate episodes that resolve from those that do not.
Defining the syndrome
John Greenland led the International Society for Heart and Lung Transplantation effort that established an international definition of acute lung allograft dysfunction, and led a multicenter validation of it using 87,000 spirometry measurements from 2,877 participants in the Lung Transplant Outcomes Group. Spirometry is the standard breathing test that measures how much air a person can blow out and how quickly. In that validation, recipients meeting the ALAD definition were roughly five times as likely to go on to graft failure.
What separates episodes that progress
Episodes that look the same on a breathing test are not the same underneath. By measuring which genes are active in small airway samples, both across whole samples and cell by cell, we found that persistent and progressive ALAD carry distinct cellular and molecular patterns rather than representing one biological state. A related study found that a mismatch between the activity of macrophages, a scavenging immune cell, and CD8 T cells, a killing immune cell, was associated with progression.
From biology to trial
That work fed directly into a therapeutic study. TIGER-Lung is a randomized, placebo-controlled trial, meaning participants are assigned by chance to receive either the drug or an inactive comparison. It is evaluating a drug called emapalumab, which blocks a specific inflammatory signal called interferon gamma, in recipients whose ALAD shows a high level of that signal. The trial is testing whether identifying the responsible pathway first and then treating it changes the course of the injury.