Chronic lung allograft dysfunction is nothing new. It even has an established acronym, CLAD. But emerging data show a pathophysiology that is more complex than many clinicians or researchers realize. CLAD comes in multiple phenotypes and at least two distinct flavors.

“We have gotten very good over the past 20 years or so at selecting patients for transplant and getting them through the postoperative phase,” says Allan R. Glanville, MBBS, MD, past president of the International Society for Heart and Lung Transplantation and conjoint professor of medicine at the University of New South Wales in Sydney, Australia. “The short-term results have improved dramatically. But the longer-term results, when you look at conditional survival after the first year, haven’t improved terribly much.” 

Dr. Glanville will co-chair Wednesday’s session. He will share the platform with Elizabeth Anne Belloli, MD, assistant professor of medicine, and Vibha N. Lama, MD, MS, professor of pulmonary/critical care medicine, both from the University of Michigan. 

As the number of lung transplants grows, so does the number of patients with CLAD. About 4,000 lung transplants are reported annually to ISHLT registry. Most are conducted in North America. More than 36,000 lung transplants have been conducted between January 1988 and February 2018 in the U.S. alone, according to the Organ Procurement and Transplantation Network. 

Allan R. Glanville, MBBS, MD

The growing recognition of different phenotypes of CLAD dawned as researchers began to realize that the traditional focus on bronchiolitis obliterans syndrome could not fully explain the varieties of allograft dysfunction that were being seen in clinical practice. There are at least two mechanisms at work: one destructive of the small airways, the other a restrictive fibrosis that involves the parenchyma of the lung. 

Both mechanisms lead to CLAD, but the biomolecular pathways and risk factors have yet to be identified. A working group drawn from the ISHLT, the ATS, and other organizations is looking at how best to define CLAD and how to define the different phenotypes that have been observed.

Neither the destructive nor the restrictive mechanisms have been fully characterized, Dr. Glanville notes. Both appear to be largely the result of rejection, a mix of early cellular rejection and later-stage antibody-mediated rejection. Antibody-mediated rejection in turn may be HLA-dominant or dominated by antibodies produced to cryptic antigens exposed in the graft following infection or some other insult.

“If the immune system isn’t properly controlled following a viral infection or something similar, you can develop antibodies that go on to cause fibrotic damage,” Dr. Glanville says. “That is what we think probably happens with grafts that end up fibrosing with CLAD.”

One of the key issues dealing with CLAD is the lack of assays and other diagnostics. There is currently no way to stratify patients by their risk of developing CLAD and no clear strategies to reduce risk of either the destructive or the restrictive forms of chronic allograft dysfunction.

“If we can focus attention on the causes, the mechanisms, and the pathophysiology of the different forms of CLAD, we might be able to develop some solutions and more effective management strategies,” Dr. Glanville says. “Recognizing that CLAD comes in different forms should be a game changer. We don’t have the solutions, but this symposium takes you through real cases to help you think about CLAD more broadly, to think about the evidence, and to use the consensus guidelines to best manage your patients.”