Ann Thorac Surg 2005;80:1260-1261
© 2005 The Society of Thoracic Surgeons
Original article: General thoracic
Invited commentary
R. Duane Davis, MD
Surgery/Division of Cardiothoracic Surgery, Duke University Medical Center, Box 3864, Trent Dr, Duke South, Rm 3543, Blue Zone, Durham, NC 27710
(Email: davis053{at}mc.duke.edu).
Gastroesophageal reflux disease (GERD) has been demonstrated to be highly prevalent in patients with a variety of lung diseases, particularly patients with asthma, cystic fibrosis, and pulmonary fibrosis [1–3]. In a retrospective analysis of 458 patients undergoing lung transplantation at Duke, 74 patients had a 24-hour ambulatory pH probe study that was obtained pre-transplant of which 42 had abnormal studies (56.8%) and 158 patients had pH probe assessment post-transplant with 119 (74.9%) abnormal studies [4]. Of 37 recipients who had testing pre-transplant and post-transplant, 48.6% had abnormal pH studies pre-transplant, whereas 74.3% demonstrated abnormal pH studies post-transplant (paired t test; p = 0.005; odds ratio = 2.24). In addition, delayed gastric emptying was seen in 13.8% of patients pre-transplant and 38.2% post-transplant. Esophageal motility studies were abnormal in 28.6% of pre-transplant patients and 26.7% post-transplant. The findings of D'Ovidio and colleagues [5] that patients with end-stage lung disease being evaluated for lung transplantation had an incidence of 38% of an abnormal pH study, 32% of an abnormal DeMeester score, 72% of a hypotensive lower esophageal sphincter, and 44% prolonged gastric emptying is comparable with the previous data. The differences in incidence probably reflect different definitions of an abnormal value between laboratories and differing percentages of patients with pulmonary fibrosis, cystic fibrosis, and scleroderma (ie, all diseases associated with the highest incidence of GERD).
The importance of these data demonstrating a high incidence of GERD in patients with end-stage lung disease and after lung transplantation is the association between GERD and lung allograft injury. Gastroesophageal reflux disease has been associated with the development of bronchiolitis obliterans with organizing pneumonia [6]. At least one early report suggested that two forms of bronchiolitis obliterans syndrome (BOS) exist after lung or heart-lung transplant. In a small autopsy series of heart-lung transplant recipients [7], 4 of 7 patients who had early onset BOS characterized by a more focal and cellular histology, also had evidence of aspiration with foreign material upon examination of the lungs at autopsy. In addition, repetitive aspiration can contribute to bronchiolitis outside the context of transplant, a series of reports from Japan [8] have proposed an entity known as diffuse aspiration bronchiolitis in elderly patients with altered mental status (dementia) and chronic aspiration. Further studies involving greater numbers of patients have demonstrated that patients with post-transplant GERD have increased rates of acute rejection and BOS [9]. In addition, it has been shown that early post-transplant surgical treatment of reflux with fundoplication can be performed safely and compared with medical therapy with proton pump inhibitors, patients treated with a fundoplication have reduced acute rejection episodes and an apparent dramatic reduction in the development of BOS and improved survival [9–11].
An important concept regarding these observations is that measurement of gastroesophageal reflux using a pH probe is a surrogate marker for aspiration risk. Although ambulatory 24-hour esophageal pH probe testing is a standard assessment for esophageal reflux, it is unlikely that it is acid reflux that is responsible for the lung injury observed after lung transplantation, given the lack of benefit achieved using acid suppression therapy. D'Ovidio and colleagues previously have demonstrated an association between the concentration of bile acid in bronchoalveolar lavage fluid from lung transplant recipients and the development of BOS [12]. The abnormalities in foregut mechanics put patients at risk for aspiration of both gastric and duodenal contents. From this perspective, measurement of acid reflux will be at best indirect and perhaps misleading. Our laboratory has developed a rodent model of recurrent micro aspiration: repetitive aspiration injury in a nontransplant model is associated with a pro-inflammatory cellular response, an elevated TH-1 cytokines, and the pro-fibrotic cytokine TGF-beta, as well as with histology demonstrating a significant increase in peri-bronchiole fibrosis. Lesions were present that were comparable with those of acute and chronic rejection. In association with transplantation, repetitive aspiration caused accelerated graft loss in an allo-dependent manner. The histologic phenotype was that of marked peri-vascular and peri-bronchiole mononuclear infiltrate and fibrosis. Again, a pro-fibrotic and pro-inflammatory TH-1 cytokine milieu was present. In addition, an augmented T cellular immunity against the donor was induced. Importantly, severe lung injury occurred only in an allo-dependent manner. These data are consistent with the hypothesis that repetitive aspiration that could occur from gastroesophageal reflux could greatly accelerate lung failure and augment an anti-donor immune response. Better assessment of aspiration events such as directly measuring gastroduodenal contents in the lung is needed to enable a better understanding of the mechanisms responsible for lung injury and to develop appropriate treatment strategies to prevent this injury.
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