Early Fundoplication Prevents Chronic Allograft Dysfunction in Patients With Gastroesophageal Reflux Disease

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1 GENERAL THORACIC J. MAXWELL CHAMBERLAIN MEMORIAL PAPER Early Prevents Chronic Allograft Dysfunction in Patients With Gastroesophageal Reflux Disease Edward Cantu III, MD, James Z. Appel III, MD, Matthew G. Hartwig, MD, Hiwot Woreta, BA, Cindy Green, PhD, Robert Messier, MD, PhD, Scott M. Palmer, MD, MPH, and R. Duane Davis, Jr, MD Department of Surgery, Department of Medicine, Duke University Medical Center; Duke Clinical Research Institute, Durham, North Carolina 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. (Ann Thorac Surg 2004;78: ) 2004 by The Society of Thoracic Surgeons 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 Accepted for publication April 12, Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26 28, Address reprint requests to Dr Davis, Department of Surgery, Duke University Medical Center, Box 3864, Durham, NC 27710; davis053@mc.duke.edu. 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 FEV 1, 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 alloantigendependent and -independent processes have been suggested [3]. Although alloantigenic processes have been 2004 by The Society of Thoracic Surgeons /04/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg CHAMBERLAIN MEMORIAL PAPER CANTU ET AL 2004;78: EARLY FUNDOPLICATION PREVENTS CHRONIC ALLOGRAFT DYSFUNCTION 1143 we hypothesized that prevention of gastroesophageal reflux with early fundoplication ( 90 days) would prevent BOS and improve survival to a greater extent. GENERAL THORACIC Fig 1. Group segregation methods: (A) ICD-9 method and (B) ph method. (Hx history; ICD international classification of diseases.) 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, 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 FEV 1 measurements were obtained at each clinic visit or at any suggestion of clinical deterioration. The best postoperative FEV 1 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 FEV 1 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. 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

3 GENERAL THORACIC 1144 CHAMBERLAIN MEMORIAL PAPER CANTU ET AL Ann Thorac Surg EARLY FUNDOPLICATION PREVENTS CHRONIC ALLOGRAFT DYSFUNCTION 2004;78: Table 1. Lung Transplant Patients at Duke (ICD-9 Segregated) No Reflux History Reflux, No Reflux, Early Reflux, Late p Value Number of patients Age Male % (n) 55 (99) 46 (58) 57 (8) 60 (37) NS Principal Dx % (n) COPD/A1A def 55 (99) 50 (62) 7 (1) 40 (25) CF/Bronchiectasis 16 (28) 25 (31) 64 (9) 32 (20) IPF 10 (18) 13 (16) 14 (2) 21 (13) BO/RTx 2 (3) 2 (3) 0 (0) 3 (2) PPH 5 (9) 2 (3) 0 (0) 3 (2) Other 13 (23) 8 (10) 14 (2) 0 (0) Comorbidities % (n) Tobacco history 72 (129) 66 (83) 29 (4) 60 (37) GER Meds Preop 33 (59) 47 (59) 57 (8) 52 (32) DGE 6 (10) 10 (13) 7 (1) 10 (6) NS Hiatal Hernia 2 (4) 11 (14) 29 (4) 27 (17) Diabetes 7 (12) 7 (9) 29 (4) 15 (9) Hypertension 19 (35) 29 (36) 36 (5) 23 (14) NS Risk Factors CR % (n) PRA 8 (15) 6 (7) 14 (2) 8 (5) NS PCM 1 (1) 1 (1) 0 (0) 3 (2) NS Acute rejections NS All values reported as indicated except continuous variables, which are reported as mean SD. BO bronchiolitis obliterans; CR chronic rejection; DGE delayed gastric emptying; PCM positive cross-match; PRA panel reactive antibodies; RTx retransplant. 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. Initially, ph studies and decision to perform fundoplication was based on unexplained decrease in FEV 1 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. 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

4 Ann Thorac Surg CHAMBERLAIN MEMORIAL PAPER CANTU ET AL 2004;78: EARLY FUNDOPLICATION PREVENTS CHRONIC ALLOGRAFT DYSFUNCTION Table 2. Lung Transplant Patients at Duke (ph Confirmed) Normal ph Study Reflux, No Reflux, Early Reflux, Late Unknown, No p Value Number of patients Age Male % (n) 49 (23) 52 (41) 57 (8) 60 (37) 52 (93) NS Principal Dx % (n) COPD/A1A def 57 (27) 49 (39) 7 (1) 40 (25) 53 (95) CF/Bronchiectasis 21 (10) 23 (18) 64 (9) 32 (20) 18 (32) IPF 4 (2) 18 (14) 14 (2) 21 (13) 10 (18) BO/RTx 0 (0) 0 (0) 0 (0) 3 (2) 3 (6) PPH 4 (2) 3 (2) 0 (0) 3 (2) 4 (8) Other 13 (6) 8 (6) 14 (2) 0 (0) 12 (21) Comorbidities % (n) Tobacco Hx 70 (33) 67 (53) 29 (4) 60 (37) 70 (126) GER Meds Preop 36 (17) 46 (36) 57 (8) 52 (32) 36 (65) NS DGE 6 (3) 13 (10) 7 (1) 10 (6) 6 (10) NS Hiatal Hernia 2 (1) 11 (9) 29 (4) 27 (17) 5 (9) Diabetes 4 (2) 9 (7) 29 (4) 15 (9) 7 (13) Hypertension 21 (10) 33 (26) 36 (5) 23 (14) 20 (36) NS ph studies Total Upright Supine Risk Factors CR % (n) PRA 11 (5) 5 (4) 15 (2) 8 (5) 7 (13) NS PCM 0 (0) 0 (0) 0 (0) 3 (2) 1 (2) NS Acute rejections 60 (28) 68 (53) 62 (8) 81 (50) 68 (122) NS 1145 GENERAL THORACIC All values reported as indicated except continuous variables, which are reported as mean SD. BO bronchiolitis obliterans; CR chronic rejection; DGE delayed gastric emptying; PCM positive cross-match; PRA panel reactive antibodies; RTx retransplant. 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. ph Studies Of the 457 patients transplanted who survived for at least 3 months, 202 were evaluated postoperatively with a 24-hour ambulatory ph probe. Those not evaluated by ph probe were labeled as unknowns and included for subgroup analysis below. Of those evaluated, 23 of 36 (63%) had abnormal ph study results preoperatively and 127 of 167 (76%) postoperatively. In patients with abnormal postoperative ph studies, the average total, upright and supine values were 12% 0.8%, 12% 0.9%, 13% 1.2%, respectively. Comparisons between subgroups with reflux demonstrated significant differences between average total, upright and supine values (Table 2), with more severe reflux among patients in both fundoplication groups. For the 40 of 167 (24%) patients with normal postoperative ph studies, the average total, upright and supine values were 2% 0.2%, 3% 0.3%, 1% 0.2%, respectively. 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 days (median 36, range 0 to 87 days) while those in the late surgery group underwent fundoplication at 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 fundo-

5 GENERAL THORACIC 1146 CHAMBERLAIN MEMORIAL PAPER CANTU ET AL Ann Thorac Surg EARLY FUNDOPLICATION PREVENTS CHRONIC ALLOGRAFT DYSFUNCTION 2004;78: Fig 2. Freedom from BOS in ICD-9 segregated groups. no history of reflux; reflux, no surgery; Πreflux, early surgery; reflux, late surgery. (BOS bronchiolitis obliterans syndrome; ICD international classification of diseases.) plication 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%). However, we have noted several instances where occult reflux was occurring and therefore we adopted more rigid criteria, requiring ph confirmation of ICD-9 diagnoses of gastroesophageal reflux. There was a 100% concordance in patients with ph confirmed reflux and ICD-9 diagnosis; however, 21 patients with ICD-9 diagnosis of reflux were not confirmed by ambulatory ph monitoring. Subgroup analysis reconfirmed the superior freedom from BOS in the early surgery group at 1 and 3 years (100%; 100%) as compared to those with a normal ph study (91%; 46%), reflux and no surgery (96%; 60%), reflux and late surgery (90%; 47%) and unknowns (90%; 66%; Fig 3). Acute Rejection Groups were analyzed with respect to number, severity and timing of rejection episodes. Rejection episodes were standardized and are reported as number of rejections per year of patient follow-up standard deviation (SD). Looking at all grades of rejection, there were no significant differences between groups (Table 3). The normal ph study group experienced rejection episodes when compared with reflux no surgery ( ), reflux early surgery ( ), reflux late surgery ( ), and unknown groups ( ). When divided into early and late rejection episodes with no regard to severity, the normal ph study group experienced early rejection episodes and late rejection episodes compared with the reflux no surgery ( ; ), reflux early surgery ( ; ), reflux late surgery ( ; ), and unknown groups ( ; ). When analyzing only rejection grades 2 or higher, the normal ph study group experienced early rejection episodes and late rejection episodes when compared with the reflux no surgery ( ; ), reflux early surgery ( ; ), reflux late surgery ( ; ), and unknown groups ( ; ). Lastly, when evaluating only moderate rejection episodes, the normal ph study group experienced early rejection episodes and 0 late rejection episodes compared with the reflux no surgery ( ; ), reflux early

6 Ann Thorac Surg CHAMBERLAIN MEMORIAL PAPER CANTU ET AL 2004;78: EARLY FUNDOPLICATION PREVENTS CHRONIC ALLOGRAFT DYSFUNCTION 1147 Fig 3. Freedom from BOS in ph confirmed subgroups. normal ph study; reflux, no surgery; Πreflux, early surgery; reflux, late surgery; unknown. (BOS bronchiolitis obliterans syndrome.) GENERAL THORACIC surgery ( ; 0), reflux late surgery ( ; ), and unknown groups ( ; ). Survival Survival analysis by Kaplan-Meier method based on ICD-9 diagnosis of gastroesophageal reflux without regard to ph studies demonstrated significant differences between groups (p 0.02; Fig 4). Overall survival was significantly better in the reflux early surgery group (100%) at 1 year than all other groups (89%; 89%; 98%). Further, by 3 years the early surgery group survival was significantly better (100%) than those with a no reflux history (71%), reflux and no surgery (69%), and reflux and late surgery (86%). Survival analysis on these ph confirmed subgroups still demonstrated significant differences (p 0.03, Fig 5). The 1- and 3-year survival in the early surgery group (100%; 100%) continued to be significantly better than those with a normal ph study (98%; 82%), reflux and no surgery (92%; 76%), reflux and late surgery (98%; 86%), and unknowns (86%; 66%). Comment 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 Table 3. Adjusted Acute Rejection Episodes (ph Confirmed Subgroups) Normal ph Study Reflux, No Reflux, Early Reflux, Late Unknown, No p Value All grades Total NS Early ( 6 mo) NS Late ( 6 mo) NS Mild and moderate Early ( 6 mo) NS Late ( 6 mo) NS Moderate Early ( 6 mo) NS Late ( 6 mo) NS All values reported as mean number of rejections per patient year of follow-up SD. Values were obtained by dividing number of specified rejections by the length of follow-up.

7 GENERAL THORACIC 1148 CHAMBERLAIN MEMORIAL PAPER CANTU ET AL Ann Thorac Surg EARLY FUNDOPLICATION PREVENTS CHRONIC ALLOGRAFT DYSFUNCTION 2004;78: Fig 4. Survival in ICD-9 segregated groups. no history of reflux; reflux, no surgery; Πreflux, early surgery; reflux, late surgery. (BOS bronchiolitis obliterans syndrome; ICD international classification of diseases.) 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 Fig 5. Survival in ph confirmed subgroups. normal ph study; reflux, no surgery; Πreflux, early surgery; reflux, late surgery; unknown.

8 Ann Thorac Surg CHAMBERLAIN MEMORIAL PAPER CANTU ET AL 2004;78: EARLY FUNDOPLICATION PREVENTS CHRONIC ALLOGRAFT DYSFUNCTION 1149 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. GENERAL THORACIC

9 GENERAL THORACIC 1150 CHAMBERLAIN MEMORIAL PAPER CANTU ET AL Ann Thorac Surg EARLY FUNDOPLICATION PREVENTS CHRONIC ALLOGRAFT DYSFUNCTION 2004;78: Dr Cantu was supported by a grant from the National Institutes of Health (1F32 HL ). References 1. Hardy JD, Webb WR, Dalton ML Jr, Walker GR Jr. Lung Homotransplantation in Man. JAMA 1963;186: Trulock EP, Edwards LB, Taylor DO, et al. The registry of the International Society for Heart and Lung Transplantation: Twentieth official adult lung and heart-lung transplant report J Heart Lung Transplant 2003;22: Boehler A, Kesten S, Weder W, Speich R. Bronchiolitis obliterans after lung transplantation: a review. Chest 1998; 114: Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. J Heart Lung Transplant 1993;12: van Den BJ, Geertsma A, van Der BW, et al. Bronchiolitis obliterans syndrome after lung transplantation and healthrelated quality of life. Am J Respir Crit Care Med 2000;161: Palmer SM, Alexander BD, Sanders LL, et al. Significance of blood stream infection after lung transplantation: analysis in 176 consecutive patients. Transplantation 2000;69: Palmer SM Jr, Henshaw NG, Howell DN, Miller SE, Davis RD, Tapson VF. Community respiratory viral infection in adult lung transplant recipients. Chest 1998;113: Matar LD, McAdams HP, Palmer SM, et al. Respiratory viral infections in lung transplant recipients: radiologic findings with clinical correlation. Radiology 1999;213: UNOS. Annual Report. Richmond, VA: US Department of Health and Human Sevices, Kesten S, Chaparro C, Scavuzzo M, Gutierrez C. Tacrolimus as rescue therapy for bronchiolitis obliterans syndrome. J Heart Lung Transplant 1997;16: Iacono AT, Keenan RJ, Duncan SR, et al. Aerosolized cyclosporine in lung recipients with refractory chronic rejection. Am J Respir Crit Care Med 1996;153: Speich R, Boehler A, Thurnheer R, Weder W. Salvage therapy with mycophenolate mofetil for lung transplant bronchiolitis obliterans: importance of dosage. Transplantation 1997;64: Speich R, Boehler A, Russi EW, Weder W. A case report of a double-blind, randomized trial of inhaled steroids in a patient with lung transplant bronchiolitis obliterans. Respiration 1997;64: Kesten S, Rajagopalan N, Maurer J. Cytolytic therapy for the treatment of bronchiolitis obliterans syndrome following lung transplantation. Transplantation 1996;61: Snell GI, Esmore DS, Williams TJ. Cytolytic therapy for the bronchiolitis obliterans syndrome complicating lung transplantation. Chest 1996;109: Sharples LD, Tamm M, McNeil K, Higenbottam TW, Stewart S, Wallwork J. Development of bronchiolitis obliterans syndrome in recipients of heart-lung transplantation early risk factors. Transplantation 1996;61: Bando K, Paradis IL, Similo S, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. An analysis of risk factors and management. J Thorac Cardiovasc Surg 1995;110: Yousem SA, Dauber JA, Keenan R, Paradis IL, Zeevi A, Griffith BP. Does histologic acute rejection in lung allografts predict the development of bronchiolitis obliterans? Transplantation 1991;52: Keenan RJ, Lega ME, Dummer JS, et al. Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation. Transplantation 1991;51: Palmer SM, Miralles AP, Howell DN, Brazer SR, Tapson VF, Davis RD. Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation. Chest 2000; 118: Rinaldi M, Martinelli L, Volpato G, et al. Gastro-esophageal reflux as cause of obliterative bronchiolitis. A case report. Transplant Proc 1995;27: Hunt RH. Importance of ph control in the management of GERD. Arch Intern Med 1999;159: Harding SM, Richter JE. The role of gastroesophageal reflux in chronic cough and asthma. Chest 1997;111: Feigelson J, Girault F, Pecau Y. Gastro-oesophageal reflux and esophagitis in cystic fibrosis. Acta Paediatr Scand 1987; 76: Tobin RW, Pope CE, 2nd, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;158: Suen HC, Hendrix H, Patterson GA. Physiologic consequences of pneumonectomy. Consequences on the esophageal function. Chest Surg Clin N Am 1999;9:475 83, xiii. 27. Herve P, Silbert D, Cerrina J, Simonneau G, Dartevelle P. Impairment of bronchial mucociliary clearance in long-term survivors of heart/lung and double-lung transplantation. The Paris-Sud Lung Transplant Group Chest 1993;103: Davis RD Jr, Lau CL, Eubanks S, et al. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg 2003;125: Palmer SM, Baz MA, Sanders L, et al. Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection. Transplantation 2001;71: Hadjiliadis D, Howell DN, Davis RD, et al. Anastomotic infections in lung transplant recipients. Ann Transplant 2000;5: Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21: Richter JE. Ambulatory esophageal ph monitoring. Am J Med 1997;103:130S 134S. 33. Reid KR, McKenzie FN, Menkis AH, et al. Importance of chronic aspiration in recipients of heart-lung transplants. Lancet 1990;336: Au J, Hawkins T, Venables C, et al. Upper gastrointestinal dysmotility in heart-lung transplant recipients. Ann Thorac Surg 1993;55: Lubetkin EI, Lipson DA, Palevsky HI, et al. GI complications after orthotopic lung transplantation. Am J Gastroenterol 1996;91: Berkowitz N, Schulman LL, McGregor C, Markowitz D. Gastroparesis after lung transplantation. Potential role in postoperative respiratory complications. Chest 1995;108: Rivero DH, Lorenzi-Filho G, Pazetti R, Jatene FB, Saldiva PH. Effects of bronchial transection and reanastomosis on mucociliary system. Chest 2001;119: Tomkiewicz RP, App EM, Shennib H, Ramirez O, Nguyen D, King M. Airway mucus and epithelial function in a canine model of single lung autotransplantation. Chest 1995;107: Veale D, Glasper PN, Gascoigne A, Dark JH, Gibson GJ, Corris PA. Ciliary beat frequency in transplanted lungs. Thorax 1993;48: Higenbottam T, Jackson M, Woolman P, Lowry R, Wallwork J. The cough response to ultrasonically nebulized distilled water in heart-lung transplantation patients. Am Rev Respir Dis 1989;140: Lau CL, Palmer SM, Howell DN, et al. Laparoscopic antireflux surgery in the lung transplant population. Surg Endosc 2002;16: Tullius SG, Hancock WW, Heemann U, Azuma H, Tilney NL. Reversibility of chronic renal allograft rejection. Critical

10 Ann Thorac Surg CHAMBERLAIN MEMORIAL PAPER CANTU ET AL 2004;78: EARLY FUNDOPLICATION PREVENTS CHRONIC ALLOGRAFT DYSFUNCTION effect of time after transplantation suggests both host immune dependent and independent phases of progressive injury. Transplantation 1994;58: Izutani H, Miyagawa S, Shirakura R, et al. Evidence that graft coronary arteriosclerosis begins in the early phase after transplantation and progresses without chronic immunoreaction. Histopathological analysis using a retransplantation model. Transplantation 1995;60: Brazelton TR, Adams BA, Cheung AC, Morris RE. Progression of obliterative airway disease occurs despite the removal of immune reactivity by retransplantation. Transplant Proc 1997;29: al-dossari GA, Jessurun J, Bolman RM 3rd, et al. Pathogenesis of obliterative bronchiolitis. Possible roles of plateletderived growth factor and basic fibroblast growth factor. Transplantation 1995;59: GENERAL THORACIC DISCUSSION 12 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 awardwinning 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.