Highly effective treatments can successfully protect patients against the threat of the acute form of rejection that occurs immediately after transplant surgery. Yet even the best medical therapies are powerless against the tide of chronic rejection, which slowly and steadily undermines the health of over half of lung transplant patients during the first three to five years after transplantation. Since chronic rejection may lead to the demise of transplanted lungs in five to ten years, and is the leading cause of death among lung transplant recipients, it is "the major Achilles heel in lung transplantation," according to Joshua R. Sonett, MD, Surgical Director of the Lung Transplant program.
Frank D'Ovidio, MD, PhD, Assistant Professor of Surgery in the Section of Thoracic Surgery and the Lung Transplant program, has shed light on the role of gastro-esophageal reflux (GER) as one of the causes of chronic lung transplant dysfunction, and/or chronic rejection.
Many people think of "reflux" as an annoying condition that can be treated with anti-acid medications. But for patients who undergo lung transplantation, reflux may be a far more serious problem because it can expedite the body's rejection of the transplanted lung. It has been recognized since the 1990's that GER contributes to the deterioration of lung tissue among lung transplant recipients. Until recently, however, no studies defined the way in which GER might actually lead to chronic lung rejection, or established which patients would truly benefit from anti-reflux surgery (known as gastric fundoplication).
Among those patients who experience GER (the passage of fluid from the stomach upward into the esophagus), some also aspirate the refluxed fluid into the lungs. Although not all lung transplant patients with GER aspirate, those who do usually remain unaware of this danger because it occurs in small quantities and causes no unique symptoms. Chronic micro-aspiration of gastric content as bile acid is toxic to lung tissue, creating an inflammatory process and possibly disrupting the innate immune system (which normally responds to the presence of infectious agents, dusts, and allergens in the environment). "The ongoing inflammatory state induced by chronic micro-aspiration is likely to cause an earlier development of chronic rejection," says Dr. D'Ovidio.
By testing samples of patients' broncho-alveolar lavage fluid collected during bronchoscopies after transplantation, Dr. D'Ovidio is the first researcher to confirm an association between the presence of bile acid in the airways as a marker of and toxic agent in GER, and clinical outcomes among lung transplant patients. He found micro-aspiration of bile acid to be a predictor of early chronic lung transplant dysfunction. Also known as bronchiolitis obliterans syndrome, chronic lung dysfunction has been considered a clinical indicator of chronic rejection.
"The documentation of the relationship between aspirated bile acid and bronchiolitis obliterans syndrome validated previous observations that GER could contribute to chronic lung rejection. In fact it provides evidence that GER is truly a problem for some lung transplant recipients," explains Dr. D'Ovidio.
Moreover, Dr. D'Ovidio's research has provided a potentially far more useful diagnostic test in the lung transplant context than has been available to date. Until now, tests to detect reflux have relied on pH-testing methods. These detect stomach acid reflux, but miss the non-acid type of reflux that can occur with bile acid.Most importantly, pH testing misses the most dangerous aspect of reflux for lung transplant recipients the aspiration." Not all patients with reflux end up aspirating," says Dr. D'Ovidio.
Various lung transplant centers have been performing Nissen fundoplication, a relatively safe, laparoscopic anti-reflux surgical procedure, in the majority of their lung transplant patients with GER. This treatment has likely helped to curtail chronic rejection in some patients, says Dr. D'Ovidio, but "not every lung transplant patient with GER needs to have surgery." The lung transplant program is now developing protocols to routinely test patients for aspiration about three months post-transplant. Testing is done via broncho-alveolar lavage during routine bronchoscopy, so that patients need not come in for extra appointments. Those found positive for aspiration of bile acid are then considered for treatment by Nissen fundoplication.
"With early testing now available, we may be able to block or prevent this relentless inflammatory agent in patients with proven reflux," says Dr. Sonett.
In addition to providing key evidence about aspiration and a new diagnostic tool to detect it, Dr. D'Ovidio's work has opened the door to understanding how the lung's specific innate immune system may influence chronic lung rejection. As he studied the way in which bile acid disrupted his patients' lung innate immunity and in particular the lung surfactant system, Dr. D'Ovidio discovered that genetic variations of certain proteins, called surfactant proteins, were associated with earlier dysfunction of the transplanted lung. This suggests that the ability of some transplanted lungs to be more or less able to withstand injury, infection, and other assaults, may be determined at a genetic level. "Further study in this area may help explain why certain lungs, despite our best selection criteria, fare worse than others after transplantation." In time, he suggests, genetic tests might be used to better modulate medical therapy or even match organs with recipients. For this outstanding contribution, Dr. D'Ovidio was awarded the 2005 Philip K. Caves Award by the International Society for Heart and Lung Transplantation. More about this genetic work will be published in scientific journals later in 2006.
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