Researchers in the United Kingdom have demonstrated that high levels of pepsin, a digestive enzyme that is a marker for gastric aspiration, are associated with acute rejection of a lung transplant. This research provides further evidence that lung rejection may be caused by factors other than alloimmunity, the attack the body mounts to protect itself against “foreign” cells.
“We think gastric aspiration [the taking of stomach fluids into the lung] may contribute to an overall injury to the transplanted lung,” said Chris Ward, Ph.D., lead author of the study. “This pattern of injury may be similar to rejection or increase the risk for further rejection.”
Dr. Ward, of Newcastle University, and the other researchers reported their findings in the June 15, 2007, issue of American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.
The study included 36 lung transplant recipients, 17 subjects with normal lung function but unexplained cough who served as “disease controls” for the study, and 4 normal, nonsmoking control subjects. The researchers determined pepsin levels in all the subjects using bronchoalveolar lavage (BAL)
“Our primary finding was that, compared with control subjects,” wrote the researchers, “BAL pepsin levels were elevated in stable lung transplant recipients, subjects with acute rejection, and subjects with bronciolitis obliterans [a common manifestation of lung transplant rejecton]. Our secondary finding was that the highest levels of pepsin appeared in the transplant recipients with clinically significant acute rejection (grade A2 or greater).”
These findings support the growing recognition that gastroesophageal reflux (GER) is a potential cause for post-transplant lung injury and other airway and lung diseases. Although none of the transplant patients were formally evaluated for GER, nearly all were treated with acid suppression medications, which is standard therapy after lung transplantation.
Despite those medications, known as proton pump inhibitors, the researchers found evidence of gastric aspiration. “It is important to recognize that proton pump inhibitors do not prevent reflux per se, but rather act to cut down on acidic reflux,” the researchers noted. They also noted, that in addition to the damage that might be done to the new lung by acid reflux, pepsin is not targeted by these drugs and may be a separate cause of lung injury.
The researchers reported that the “disease control” group—those with normal lung function, but unexplained cough—did not have pepsin in their lungs, even when 10 of 17 were diagnosed during the study as having gastroesophageal reflux disease (GERD). “A diagnosis of GERD does not mean that patients are refluxing out of the esophagus and hence aspirating,” they explained. “Even if the refluxate reaches the upper airway, it is almost certainly cleared by a hyperactive cough reflex.”
In their article, the researchers note ongoing studies being done at Duke University that appear to show lung transplant patients who undergo fundoplication, a surgical procedure that strengthens the valve between the stomach and the esophagus, before the transplant have longer survival rates and delayed onset of bronchiolitis obliterans syndrome than those who do not.
If fundoplication is confirmed as a useful prophylaxis in preventing lung rejection, they write, “markers of aspiration may contribute to identifying patients who might derive clinical benefit.”
This study was supported by fellowships from Newcastle-upon-Tyne Hospitals Special Trustees a European Society Fellowship, and the Medical Research Council of the United Kingdom, as well as a grant-in-aid from GlaxoSmithKline.
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