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Ann Thorac Surg 2004;78:1142-1151
© 2004 The Society of Thoracic Surgeons
a Department of Surgery, Duke University Medical Center, Durham, NC, USA,
b Department of Medicine, Duke University Medical Center, Durham, NC, USA;
c Duke Clinical Research Institute, Durham, North Carolina, USA
Accepted for publication April 12, 2004.
* Address reprint requests to Dr Davis, Department of Surgery, Duke University Medical Center, Box 3864, Durham, NC 27710, USA
davis053{at}mc.duke.edu
Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.
Abstract
BACKGROUND: Chronic allograft dysfunction limits the long-term success of lung transplantation. Increasing evidence suggests nonimmune mediated injury such as due to reflux contributes to the development of bronchiolitis obliterans syndrome. We have previously demonstrated that fundoplication can reverse bronchiolitis obliterans syndrome in some lung transplant recipients with reflux. We hypothesized that treatment of reflux with early fundoplication would prevent bronchiolitis obliterans syndrome and improve survival.
METHODS: A retrospective analysis of 457 patients who underwent lung transplantation from April 1992 through July 2003 was conducted. Patients were stratified into four groups: no history of reflux, history of reflux, history of reflux and early (< 90 days) fundoplication and history of reflux and late fundoplication.
RESULTS: Incidence of postoperative reflux was 76% (127 of 167 patients) in pH confirmed subgroups. In 14 patients with early fundoplication, actuarial survival was 100% at 1 and 3 years when compared with those with reflux and no intervention (92% ± 3.3, 76% ± 5.8; p < 0.02). Further, those who underwent early fundoplication had improved freedom from bronchiolitis obliterans syndrome at 1 and 3 years (100%, 100%) when compared with no fundoplication in patients with reflux (96% ± 2.5, 60% ± 7.5; p < 0.01).
CONCLUSIONS: Reflux is a frequent medical complication after lung transplantation. Although the number of patients undergoing early fundoplication is small, our results suggest early aggressive surgical treatment of reflux results in improved rates of bronchiolitis obliterans syndrome and survival. Further research into the mechanisms and treatment of nonalloimmune mediated lung allograft injury is needed to reduce rates of chronic lung failure.
Since its first description by Hardy in 1963 [1], clinical lung transplantation has evolved from an experimental approach into an effective treatment for patients with end-stage lung disease. Improvements in postoperative care, immunosuppression regimen, and in surgical technique have prolonged 1-year survival to greater than 70%, with some centers reporting greater than 80% survival at 1 year [2]. Long-term success of lung transplantation is limited by chronic allograft dysfunction; thought primarily due to chronic allograft rejection. This injury has been characterized by scar formation and fibrosis of the small airways, and defined as bronchiolitis obliterans (BO) [3]. The diagnosis of BO requires a histopathologic specimen that includes the small- to medium-sized airways. However, transbronchial biopsies are insensitive for the diagnosis of BO because mostly alveolar tissues are obtained and bronchioles are infrequently sampled. The International Society for Heart and Lung Transplantation (ISHLT) developed a reproducible and reliable surrogate marker for BO that utilizes declining FEV1, the bronchiolitis obliterans syndrome (BOS) [4]. The system has been widely adopted and validated as a useful surrogate for histologic BO.
Bronchiolitis obliterans syndrome is the most common cause of morbidity and mortality following lung transplantation. At 5 years, 50% of transplanted patients have developed BOS and of the survivors, more than 33% continue to carry this diagnosis. Quality of life is significantly reduced once BOS develops, and the risk for death due to infection may also be increased [5–8]. The lung seems to be particularly sensitive to chronic allograft injury compared with other organs, and overall survival post lung transplant at 5 years remains a modest 42% [9].
Current understanding of chronic lung rejection is at best incomplete. Competing hypotheses of alloantigen-dependent and -independent processes have been suggested [3]. Although alloantigenic processes have been implicated, intensification or alternation of immunosuppressive regimens has had little impact on the progression of BO/BOS [10–15]. Many groups have sought predictive factors for the development of BO/BOS. Among numerous studies the following have been identified as risk factors: the number, timing of onset (first 6 months vs later) and severity of acute rejection episodes, human leukocyte antigen (HLA) mismatches and antibody stimulation to HLA class I antigens [16–18]. Increasing evidence suggests nonimmune mediated injury such as due CMV infection and particularly, cytomegalovirus pneumonitis, and gastroesophageal reflux may contribute to the development of BO/BOS [19–21]. We have also recently demonstrated that type of transplant operation is a significant risk factor for BOS, with significantly increased rates of BOS in single lung transplant recipients. It is unclear if this represents an artifact of the nomenclature system, an immunologic difference with one versus two allografts, or nonimmune mediated effect related to the presence of the native lung.
Population-based studies have demonstrated that 11% of Americans experience typical symptoms of reflux daily and 33% experience symptoms during a 72-hour period [22]. Increasing evidence has suggested that gastroesophageal reflux may contribute to the pathophysiology of many pulmonary diseases, particularly with respect to repetitive injury as seen in asthma [23]. Further, reflux is common in patients with advanced lung disease who typically present for transplantation such as cystic fibrosis [24] and idiopathic pulmonary fibrosis [25]. Additionally, evidence suggests pneumonectomy itself results in esophageal and upper gastrointestinal dysmotility [26]. This evidence taken together with the loss of local defense mechanisms, consequent to denervation and reduction of mucociliary clearance [27], may help identify why the allograft is more vulnerable to aspirated particles and inhaled pollutants.
Previous experiments have demonstrated that fundoplication is able to reverse BOS in some lung transplant recipients with gastroesophageal reflux, presumably before irreversible fibrosis has occurred [28]. In this study, we hypothesized that prevention of gastroesophageal reflux with early fundoplication (< 90 days) would prevent BOS and improve survival to a greater extent.
Patients and Methods
A retrospective analysis of 457 patients who underwent lung transplantation at Duke from April 1992 through July 2003 was conducted. Institutional Review Board approval was obtained before beginning the study. Standard operative techniques were used. Demographic data were collected on all patients. The immunosuppressive regimen has evolved but has consisted of a cyclophilin, antimetabolite, and steroid. Before October 2000 this consisted of cyclosporine A, azathioprine, and methylprednisolone, after which tacrolimus replaced cyclosporine. A small number of patients received mycophenolate mofetil as an alternative to azathioprine, as part of a prior randomized study [29]. Induction therapy was used on a subset of patients with either rabbit antithymocyte globulin (RATG) alone or monoclonal interleukin-2 receptor antibody (daclizumab or baliximab). Episodes of acute allograft rejection were treated with methylprednisolone, 500 mg/d for 3 days, followed by a 2-week oral prednisone taper. Further description of immunosuppressive regimens and antimicrobial prophylaxis has been provided elsewhere [30].
Surveillance FEV1 measurements were obtained at each clinic visit or at any suggestion of clinical deterioration. The best postoperative FEV1 measurement was used as baseline for all further comparisons. ISHLT criteria [31] for BOS was used for diagnosis of chronic rejection. ISHLT criteria stipulate that a 20% or greater decrease in FEV1 must be present in the absence of other explanatory causes, including anastomotic stricture, infection, or acute rejection. Recipients were eligible for analysis only if they survived at least 3 months. The 3-month threshold was used to exclude the early hazard of the lung transplant operation, to have stable spirometry measurements, and to compare groups in a time within which fundoplication was performed in the early group. BOS was treated as a binary variable (present or not) therefore no distinction was made regarding severity of BOS. Fundoplication was performed according to standard laparoscopic or open practice.
pH studies
Reflux studies were first obtained in May 1997 and only obtained in symptomatic patients. From March 1998 until July 2000, patients were studied prospectively under an institutional review board protocol. Since that time, pH studies have been performed in all transplant candidates as part of their routine pretransplant and posttransplant evaluation.
Proton pump inhibitors were discontinued for at least 5 days before the pH studies. Histamine (H-2) blockers and promotility agents were stopped at least 24 hours before the studies. The esophageal pH laboratory at Duke University Medical Center uses standard techniques [32]. A distal esophageal probe was inserted in a standardized manner by one technician in all patients. The probe was removed after approximately 24 hours. Patients were instructed to proceed with their daily activities as usual. A small number of nonselected patients also had a proximal pH probe placed in the esophagus. The correlation between the distal and the proximal probe measurements was excellent, and therefore there was no need for a proximal probe in all patients. Abnormal acidity in the esophagus was recorded every time the pH decreased to less than 4. The results were reported as the percentage of abnormal acid contact time in the distal esophagus. Normal values for acid contact times were as follows: total less than 5%, upright less than 8%, and supine less than 3%. The laboratory does not report the DeMeester score.
Fundoplication
Initially, pH studies and decision to perform fundoplication was based on unexplained decrease in FEV1 in patients with very abnormal pH studies (total acid contact time > 10%). With the demonstration of safety and efficacy, our practice has evolved such that those with substantially positive studies regardless of symptoms or patients who have met criteria for BOS with any positive study are referred for fundoplication. It is our practice to perform laparoscopic Nissen fundoplications in all patients who do not have a contraindication. Manometry is performed on all patients before ambulatory 24-hour pH testing. Patients with borderline esophageal clearance underwent a Toupet. In patients with very poor esophageal motility the management algorithm was much more complicated. Typically these patients receive a Nissen with both a gastrostomy and jejunostomy tube. Alimentation and medication delivery is achieved through this access. Oral intake is established only after demonstration of recovery of esophageal motility which in our experience has occurred over a few weeks. Patients were not systematically restudied after fundoplication; however, previous studies by our group have demonstrated significant reduction in acid contact time as compare to individuals with normal pH studies. Fundoplication was performed according to standard practice.
Statistical Analysis
Descriptive statistics were used for demographic data. ANOVA was used for comparison of means with the Student-Newman-Keuls multiple range post test. Overall survival was determined by using Kaplan-Meier actuarial analysis. Differences in actuarial survival or freedom from BOS between groups were determined with the log-rank test. Data analysis was performed using SAS software version 8.0 (Cary, NC, USA). Values were reported as mean ± SD except where noted.
Results
From its inception in April 1992 to July 2003, the Duke Lung Transplant Program has performed 457 lung transplantations. With respect to pH studies, the program has evolved over three eras (no pH studies, pH studies for symptomatic patients, and routine pH studies). Over that time period, 202 patients have been evaluated for reflux postoperatively by pH probe and 76 patients ultimately underwent posttransplant fundoplication. For analysis, four groups were designated based on ICD-9 diagnosis and surgical status. International classification of diseases (ICD-9) was determined based of a comprehensive chart review. If the patient carried the diagnosis of gastroesophageal reflux the patient was labeled as having reflux regardless of the presence or absence of adjunctive studies. Patients with reflux were then stratified based on surgical status (ie, early vs late fundoplication) (Fig 1A). Utilizing the same patients, an alternative algorithim was used based on pH status and time to surgery. Further evaluation was performed on a subgroup of pH confirmed patients (Fig 1B). Patient characteristics can be found in Tables 1 and 2.
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Fundoplication
Eighty-five antireflux operations were performed in this cohort (9 preoperatively in the remote past). Seventy-one (84%) were laparoscopic Nissens, 5 (6%) were open Nissens, 4 (5%) were laparoscopic Toupets, 3 (4%) were Belsey-Mark IVs, 1 (1%) was a Toupet, and 1 (1%) a Nissen, both of unknown type done at an outside hospital. There was no in-hospital or 30-day mortality after the fundoplication operations. On average patients in the early surgery group underwent fundoplication at 43 ± 32 days (median 36, range 0 to 87 days) while those in the late surgery group underwent fundoplication at 684 ± 637 days (median 447, range 106 to 2999 days). Patient demographics were similar between groups with few exceptions (Tables 1 and 2). In general, the early fundoplication group were younger CF patients who did not smoke but had a higher incidence of hiatal hernia and diabetes. Additionally, there were no differences between groups for risk factor for chronic rejection (Tables 1 and 2).
BOS
Freedom from BOS, as determined by Kaplan-Meier method based on ICD-9 diagnosis of gastroesophageal reflux without regard to pH studies, was significantly different between groups (p = 0.01, Fig 2). At 1 year, the reflux patients with early surgery (100%) demonstrated greater freedom from BOS than those with no reflux history (91%), reflux and no surgery (92%), and reflux and late surgery (90%). By 3 years, freedom from BOS was significantly higher for patients in the early surgery group (100%) than those with no reflux history (62%), reflux and no surgery (60%), and reflux and late surgery (47%).
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Gastroesophageal reflux is a common problem experienced by as much as 11% of all Americans when defined by daily feelings of heartburn [22], though this is likely an underestimate due to individuals who are asymptomatic or present with atypical symptoms. Nonetheless, the prevalence of reflux in patients with end-stage lung disease is higher than in the general population, particularly with respect to patients with CF and pulmonary fibrosis [24, 25]. In lung transplant recipients at our center, the prevalence increases after transplantation to 76%. This increase is likely consequent to many factors.
It has previously been reported that perturbations in gastrointestinal function occur commonly after lung transplantation [33–36]. Lubetkin and colleagues [35] reported a 51% prevalence of gastrointestinal complications in a cohort of lung transplant patients they followed for 3 years at their institution. Included in the list of complications were gastroesophageal reflux; however, specifics of diagnosis and effects on pulmonary function were not described, though survival was decreased. Other investigators have demonstrated that delayed gastric emptying is also common [26, 34, 36].
Reid and colleagues [33] were the first to demonstrate the association between BO and chronic aspiration. In a series of 11 heart-lung transplant patients, antireflux therapy, the specifics of which was not defined, resulted in improvement in pulmonary function, though to an unspecified degree. This association was further recognized by Berkowitz and colleagues [36] in their series of 38 lung and heart-lung transplant patients in whom 2 of 4 patients with OB were found to have food particles in their BAL samples.
The consequence of a denervated graft with impaired mucociliary clearance of foreign material [27, 37–39] and a markedly prolonged contact time due to loss of the cough reflex [40] has been the object of our investigation. Early in our experience, we reported that fundoplication could improve pulmonary function in a subset of patients with BOS [28, 41]. However, in patients with more advanced stages of BOS there was less of an improvement presumably due to irreversible scar formation within the graft. Subsequently, in patients with documented gastroesophageal reflux in the pretransplant evaluation, we have performed fundoplication within 3 months of the transplant. For patients undergoing fundoplication after transplantation, either early or late, there has been no in-hospital or 30 day mortality [41]. This report is a summary of our experience thus far.
With respect to BOS, we have demonstrated a significant improvement in the subset of patients with early fundoplication when compared with all other groups. Whether this is a consequence of decreasing direct lung parenchymal injury from reflux (alloantigen independent) or decreasing alloantigen-dependent injury is still unclear. Previous experiments in animal models have demonstrated that if an allogeneic organ or airway graft, which has begun to demonstrate signs of chronic rejection, is removed after a critical timepoint and transplanted back into a syngeneic host, injury will continue to progress in the absence of continuing alloimmune injury [42–44]. Further, in a sygneic heterotopic transplant model of tracheal grafts, al-Dossari and colleagues [45] were able to create obliterative airway lesions by use of platelet-derived growth factor or basic fibroblast growth factor suggesting that, in the absence of alloimmune stimuli, these factors can induce fibroproliferation. Though alloimmune injury continues in our patients, perhaps the removal of nonalloimmune injury decreases the nonspecific inflammatory response, which typically results in augmented cytokine, growth factor, and major histocompatibility complex class I and II expression.
Although we did not seek to define the immunologic events leading to BOS, we sought to define the relationship between alloimmune and nonalloimmune injury, by examining the rate and severity of acute rejection in this cohort. There were no significant differences with respect to total number, severity, and timing of rejection between groups; though there was a trend to decreased early and late rejection episodes in the pH confirmed normal pH study group. This was not surprising because the mean time to fundoplication in early and late groups occurred either partially or totally after the majority of rejections took place.
We demonstrated a survival advantage in the early fundoplication group. This might be a consequence of a predominantly younger group yet this population tended to have more risk factors for reflux and more comorbidities. Taken together with the BOS data there seems some suggestion that immune and nonimmune interactions may be taking place that account for the development of BOS and ultimately death. Certainly, more follow-up and a larger cohort will need to be analyzed to confirm that prolonged freedom from BOS and survival is sustained.
Our analysis also uncovered a somewhat unexpected observation. In the cohort of patients with reflux and no surgery, freedom from BOS was similar to those with a normal pH study. This may be consequent to our definition of a positive reflux study which utilizes standardized acid contact times from normal healthy adults. In the lung transplant patient, the question remains what is too much reflux? In the individuals with normal studies, there is still some acid exposure (even as high as 7.9% of the time). Our experience and previous reports have demonstrated that fundoplication reduces acid contact times significantly as compared to those with normal pH studies. Therefore our study suggests that in lung transplant patients any reflux may be detrimental to allograft function.
Our study has several significant limitations. First, the retrospective nature and nonrandom patient selection certainly introduce selection bias. This becomes most evident with respect to intergroup differences in demographics, particularly age and diagnosis. These differences are problematic and make it difficult to adequately control for all covariates. Second, as our experience with fundoplication in these patients has improved, we have progressed through several iterations of earlier and more aggressive intervention. Therefore, the number of patients undergoing early fundoplication is small and the follow-up is limited to only a few years in this group.
Although this study does not conclusively demonstrate early fundoplication in patients with gastroesophageal reflux prevents BOS and ultimately prolongs survival, it suggests that early fundoplication is safe and may retard the development of BOS and as a consequence extend survival. Reflux appears to be a nonalloimune factor that contributes to lung allograft injury through a process that is treatable and possibly preventable. Whether clinical practice should require prevention of reflux in lung transplant patients through fundoplication remains unclear and further inquiry should be made as part of a multicenter initiative.
Discussion
DR TOM R. DEMEESTER (Los Angeles, CA): Dr Cantu, I compliment you on a very clear and provocative presentation. I also congratulate you on getting the Maxwell Chamberlain Award. It is a great achievement.
Certainly, Dr Cantu and his group have given us further convincing evidence that gastroesophageal reflux disease and its prevention by fundoplication plays an important role in the outcome of lung transplantation. That it does isn't too surprising for two reasons. First, gastroesophageal reflux disease has been implicated in a number of diseases that lead to lung transplantation, such as chronic pulmonary fibrosis, bronchiectasis, and primary pulmonary hypertension. All three have a high incidence of gastroesophageal reflux.
Further, our group has shown that when one augments the inspiratory gradient between the stomach and the esophagus, as occurs in late pulmonary disease, one can induce gastroesophageal reflux in patients, and your studies show in the group of such patients that you tested prior to transplantation, you had a 65% incidence of increased esophageal acid exposure on 24-hour pH monitoring.
One might say, and I would like to hear your comments on this, that your studies are driving us to the conclusion that we should suspect gastroesophageal reflux disease in these pulmonary conditions and encourage fundoplication early in the process and maybe preempt the need for transplantation.
Now, regarding bronchiolitis obliterans, there are a number of conditions that lead to it. They have been elucidated in the literature, and certainly regurgitation and aspiration has to be one. What would convince me greatly, and I would like to hear your thoughts regarding this, would be a low incidence of bronchiolitis obliterans in patients who have normal esophageal acid exposure on 24-hour pH monitoring.
I would like you to comment also about the evidence you used to determine that you had increased esophageal acid exposure. Your determination of that is a bit unconventional. Did you use just percent times pHs less than four for the total period and that was it, and if so, then what would you say about a patient who had normal acid exposure for the total period but had high acid exposure during just the supine period? Please tell us a little bit more on how you determined increased esophageal acid exposure.
Now that you have come to the point where you are doing 24-hour pH monitoring on every patient that you evaluate for lung transplantation, are you uncomfortable in going forward with transplantation without doing a fundoplication if the 24-hour pH is abnormal?
Dr Cantu, your group has done a great work in obtaining and reporting these observations. I think your study has broad implications. Not only has it told us that reflux is important in the outcome of lung transplantation, that you have made very clear, but I think it also underscores how pulmonary disease and esophageal disease are intermingled. The latter may be your greatest contribution.
I really appreciated the paper, the slides were excellent, and I thank the Society for the opportunity of discussing this award-winning presentation.
DR CANTU: Dr DeMeester, thank you for your kind, insightful and poignant comments. With respect to your first question, it has been our experience that patients that present to us with end-stage lung disease commonly have reflux. While patients with cystic fibrosis and pulmonary fibrosis are more likely to have significant reflux disease, patients with other causes of pulmonary failure also are more likely to have gastroesophageal reflux disease than the general population. Though not presented, our experience, based on our referral pattern, has about a 63% preoperative incidence of reflux, and likely explains why we see such a high prevalence of postoperative reflux. It is true, as you have already mentioned that many pulmonary diseases are associated with reflux; however, whether prophylactic fundoplication would alter the natural course of the disease is unknown. We have anecdotal experience with patients suffering from UIP, referred early in their disease course for transplant evaluation, who had significant reflux and underwent fundoplication. Their disease progression appeared to be much slower than what would be expected. Unfortunately, most patients referred for lung transplant are poor candidates for general anesthesia and fundoplication prior to their lung transplant. In lung transplant patients with gastroesophageal reflux disease who undergo early fundoplication, evidence from this study suggests that the natural history of chronic lung dysfunction is significantly delayed.
The incidence of bronchiolitis obliterans in patients with normal pH studies is 49% (23 of 47). Among all patients with bronchiolitis obliterans, those patients with normal pH studies only comprise 13% (23 of 182) of the total.
At Duke, our pH laboratory reports total, upright, and supine acid contact times. As long as the patients were above our normal ranges, they were considered positive. Our definition of those patients with reflux is somewhat unconventional. As you have pointed out, using the total acid contact time exclusively is problematic in that it creates a subpopulation of patients with a negative total but a positive supine or upright study. In putting this study together, our goal was to include those patients who would be at risk of reflux-mediated injury. Toward this end, our definition of a positive study included all individuals with any abnormally elevated value. Utilizing this method we did not experience the scenario you described.
The patients in this study demonstrate the safety of an approach of transplantation followed by early fundoplication. In this study, the survival and freedom from BOS in the early fundoplication group was excellent and better than the other cohort groups. The risk of aspiration is high in these patients and we are very aggressive in mechanical and pharmacologic treatments until fundoplication can be performed. We use G-J tubes liberally with feeding only through the jejunostomy port until fundoplication can be performed. With increasing experience, we are moving to earlier fundoplication, often within the initial transplant hospitalization.
Acknowledgments
Dr Cantu was supported by a grant from the National Institutes of Health (1F32 HL 71457–01).
References
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= no history of reflux; 
= reflux, no surgery; 
= reflux, early surgery; 
= reflux, late surgery. (BOS = bronchiolitis obliterans syndrome; ICD = international classification of diseases.)
= unknown. (BOS = bronchiolitis obliterans syndrome.)
