Lung transplantation is an accepted treatment for

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1 Lung Transplantation, Gastroesophageal Reflux, and Fundoplication Andrew G. N. Robertson, MBChB(Hons), Chris Ward, PhD, Jeff P. Pearson, PhD, Paul A. Corris, FRCP, John H. Dark, FRCS, and S. Michael Griffin, MD, FRCS Northern Oesophago-Gastric Unit, Royal Victoria Infirmary, Newcastle, United Kingdom; Department of Cardiothoracic Surgery, Freeman Hospital, Immunobiology and Transplantation Group, Institute of Cellular & Molecular Biosciences, Newcastle University, Newcastle, United Kingdom Lung transplantation is an accepted treatment strategy for end-stage lung disease; however, bronchiolitis obliterans syndrome is a major cause of morbidity and mortality. This review explores the role of gastroesophageal reflux disease in bronchiolitis obliterans syndrome and the evidence suggesting the benefits of anti-reflux surgery in improving lung function and survival. There is a high prevalence of gastroesophageal reflux in patients post lung transplantation. This may be due to a high preoperative incidence, vagal damage and immunosuppression. Reflux in these patients is associated with a worse outcome, which may be due to micro-aspiration. Anti-reflux surgery is safe in selected lung transplant recipients; however there has been one report of a postoperative mortality. Evidence is conflicting but may suggest a benefit for patients undergoing anti-reflux surgery in terms of lung function and survival; there are no controlled studies. The precise indications, timing, and choice of fundoplication are yet to be defined, and further studies are required. (Ann Thorac Surg 2010;89:653 60) 2010 by The Society of Thoracic Surgeons Lung transplantation is an accepted treatment for end-stage lung disease and improvements in surgical technique, lung preservation, immunosuppression, and the treatment of ischemic-reperfusion injury have increased 1-year survival to 82%. Survival of lung allograft recipients is lower than other solid organ transplants. This is most commonly due to chronic allograft dysfunction manifested as bronchiolitis obliterans syndrome (BOS), the clinical equivalent of obliterative bronchiolitis (OB) [1, 2], the pathologic process of chronic rejection [1, 3]. BOS normally develops between 6 months and 2 years post transplant [4], affects 50% to 60% of patients at 5 years post-transplant, and accounts for 30% of deaths after postoperative year 3 [5, 6]. The pathology behind this process involves progressive fibrosis of the small airways, with sclerosis, intimal thickening, and destruction of the pulmonary vasculature [5, 6]. Clinically this is accompanied by a decreased forced expiratory volume in 1 second (FEV 1 ) and progressive dyspnea, which forms the basis of the BOS score. The accepted definition of BOS is a decreased FEV 1 from the best postoperative function, in the absence of other cause [7, 8]. Risk factors for BOS are both alloimmune and nonalloimmune [3, 5, 9, 10]. There has been no significant impact on BOS for the last 20 years, despite the use of newer immunosuppressive strategies with improved control of acute rejection [11]. Chronic aspiration, secondary to extra-esophageal reflux, may contribute to BOS, and as many as 75% of patients have gastroesophageal reflux disease (GERD) on Address correspondence to Prof Griffin, Northern Oesophago-Gastric Unit, Royal Victoria Infirmary, Queen Victoria Rd, Newcastle, NE1 4LP, United Kingdom; michael.griffin@nuth.nhs.uk. ph monitoring after lung transplantation [5]. The association between OB and aspiration has been known for some time. In 1991, a small series of heart-lung transplant autopsies showed 4 of 7 patients to have aspiration. These patients had developed early onset OB, which may have been associated with aspiration [12]. An implication of the integrated literature is that current therapies, predicated on augmenting immunosuppression, may harm patients through gastroparesis and subsequent aspiration [13]. The significance of this link is that GERD is a modifiable risk factor that can be successfully treated. Antireflux surgery in this population may be associated with increased survival and improved lung function [11]. Methods Literature searches using Ovid, MEDLINE, PubMed, and Embase. Search terms included lung transplantation, gastroesophageal reflux disease, fundoplication, pepsin, bile acids, and combinations thereof. Reference lists from important articles were examined to retrieve further articles. Only English articles were included. Results Gastroesophageal Reflux Disease Pre-Transplant There is an association between gastroesophageal reflux and lung disease, and GERD may contribute to pulmonary pathophysiology (eg in asthma, cystic fibrosis, and pulmonary fibrosis). Furthermore, diffuse aspiration bronchiolitis has been described in elderly patients with dementia who suffer from chronic aspiration [14]. There is a high prevalence of foregut motility problems and 2010 by The Society of Thoracic Surgeons /10/$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 654 REVIEW ROBERTSON ET AL Ann Thorac Surg ANTIREFLUX SURGERY POSTLUNG TRANSPLANTATION 2010;89: GERD (78 of 104 patients, 68%) in patients with a range of end-stage lung disease including interstitial lung disease, and cystic fibrosis [3, 15]. There were 72% (56 of 78) of pre-transplant patients who had decreased lower esophageal sphincter pressure [16]. Another 33% to 47% had esophageal body dysmotility [15, 16]. In total, nearly 80% (60 in 78) of these patients had esophageal dysmotility, a hypotensive lower esophageal sphincter, or both [16]. Overall more than a third of the patients had impaired peristalsis, often associated with respiratory symptoms. Nearly half of the patients had prolonged gastric emptying for solids (16 of 36), and a quarter of the patients had prolonged gastric emptying for liquids (7 of 29) [16]. D Ovidio and associates suggested a 38% (29 of 76) prevalence of GERD in end-stage lung disease [16], which was often asymptomatic [15, 16], with no difference in the prevalence of reflux in patients with or without symptoms, and no relationship between the symptoms and DeMeester score [15]. As many as a third of patients have proximal reflux on ambulatory ph monitoring [15, 16]. This is potentially more dangerous, because presumably it predisposes to micro-aspiration. It is unclear whether GERD causes pulmonary pathology or whether disordered pulmonary function leads to GERD. Reflux in end-stage lung disease may be related to an increased negative intrathoracic pressure and increased positive abdominal pressure. Lung hyperinflation may interfere with the esophageal hiatus and also lower esophageal sphincter function [17]. Gastroesophageal Reflux Disease Post-Transplant Cause Diverse factors surrounding lung transplantation may increase the prevalence of reflux, including vagal damage, immunosuppression, changes in intrathoracic volume and postpneumonectomy reflux [18 20], although vagal damage is more likely to occur with the more extensive dissection needed for combined heart-lung transplant. Vagal Damage The recipient pneumonectomy requires meticulous hemostasis and injuries to the vagal nerves are common due to direct trauma and electrocautery, tending to occur near the lung hila [19]. Biomechanical vagal damage leads to delayed gastric emptying and distal esophagus dysmotility, promoting reflux post-transplantation [19]. Modification of surgical technique can decrease the risk of vagal injury, thus reducing morbidity. This involves circumspect or bipolar diathermy and stapling. Risk to the vagal nerve is reduced by performing bilateral sequential lung transplantation, which is the favored procedure in our unit. Therefore, dissection of the distal trachea and posterior mediastinum can be avoided [19]. Avoidance of vagal injury is likely to reduce the risk of foregut dysmotility. The American Gastroenterology Association has documented that lung transplant is a cause of gastroparesis. There are as many as 90% of patients who have experienced delayed gastric emptying post-lung transplant [5, 21]. An evaluation of foregut dysmotility post heart-lung transplantation showed vagal damage to occur in nearly one third of heart-lung transplant recipients [19]. In another study, one third of patients with GERD post-transplant had delayed gastric emptying and 13% (2 of 15) had incomplete relaxation of the lower esophageal sphincter [22]. D Ovidio and associates showed that 8 of 22 patients had abnormal liquid emptying at 3 months and 5 of 7 at 12 months post transplant [21]. Thirty-nine of 43 patients had prolonged gastric emptying to solids at 3 months, and 17 of 21 had prolonged gastric emptying at 12 months. Immunosuppression Gastrointestinal complications post-transplantation are common, often due to immunosuppressant therapy [23 25]. Historically, peptic ulcer disease is associated with high-dose steroids. However, the incidence of peptic ulceration has decreased with reduced doses of steroids and use of proton pump inhibitors [26]. After renal transplantation, 20% of patients had gastrointestinal complications develop [27]. These may be related to side effects of medication or infection. Nausea, vomiting, and dyspepsia (83%) are commonly reported [27, 28]. Nearly half of renal transplant patients report gastroesophageal reflux symptoms [28]. These may be related to gastroparesis, attributable to adverse effects of calcineurin inhibitors, steroids, and mycophenolate mofetil [27, 29]. Prevalence of GERD Post-Transplant There is increased prevalence and severity of GERD postlung transplantation [2, 22]. Due to this high prevalence of post transplant reflux, it is increasingly advocated to screen all lung transplant recipients for GERD [20]. In 2003, Young and colleagues [22] demonstrated an increase in reflux from 8 of 23 patients pre-transplantation to 15 in 23 post-transplant. Acid contact time increased by a mean of 3.7% (from 5.6% to 9.3%) in the upright position and 6.3% (from 5.1% to 11.4%) in the supine position [22]. Gastroesophageal reflux disease is associated with worse pulmonary function tests in the post-transplant population [2]. Twenty-six of 43 patients had BOS at the time of the study. Twenty of these 26 patients with BOS had abnormal esophageal ph, compared with 10 of 17 patients without BOS [2]. In another study of patients without BOS, abnormal distal or proximal ph was present in 16 of 50 patients at 3 months and 16 of 30 patients at 12 months [21]. The frequency and severity of reflux, especially the upright contact time is associated with chronic allograft dysfunction [2]. Recently it was demonstrated that 22 of 45 lung transplant patients have reflux after 1 year post-transplantation. It is of interest that nearly a third (6 of 22) of these patients had exclusively nonacid reflux as detected by phimpedance [30].

3 Ann Thorac Surg REVIEW ROBERTSON ET AL 2010;89: ANTIREFLUX SURGERY POSTLUNG TRANSPLANTATION 655 Reflux in the Pediatric Lung Transplant Population To date a single United Kingdom transplant center provides the only publication on reflux in pediatric lung transplant recipients. All patients had GERD post-lung transplant (9 in 10), except 1 patient with a prior fundoplication. All patients with acute rejection had moderate to severe GERD [31]. Evaluation of Reflux Symptoms do not always correlate with objective measurements of reflux [15], and the symptoms of reflux are often absent post-transplantation [11], possibly due to esophageal denervation. Specific reflux questionnaires have been developed and validated in patients with laryngopharyngeal reflux, and these may give information on reflux reaching the upper airway [32]. However no questionnaires have been validated in the lung transplant population, many of whom have asymptomatic reflux. We conclude that only investigating patients with symptoms is unreliable and will underestimate the prevalence of GERD. The consideration of the available literature would suggest that all patients should undergo objective physiologic evaluation postoperatively. Ambulatory ph monitoring has been used historically to evaluate GERD, but its main shortcoming is the inability to detect weakly acid and nonacid reflux. This method also fails to measure the proximal extent of reflux, although dual channel ph monitors have been designed to detect proximal reflux. To remove the difficulties of nasal catheterization, wireless ph probes have been developed, such as the Bravo capsule (Medtronic, Minneapolis, MN). These can be attached to the lower esophageal mucosa during endoscopy. This is tolerable and allows recording for more than 24 hours, but again it does not detect nonacid reflux [33]. The Bilitec 2000 device (Medtronic, Minneapolis, MN) has limited use and exclusively detects bile reflux [33]. The role of multichannel intraluminal impedance in detecting gastroesophageal reflux has been extensively reviewed elsewhere [34]. Standard ph monitoring may underestimate the degree of reflux, and therefore impedance has an important role in the detection of gastroesophageal reflux [34]. Combined ph-impedance can accurately measure the direction and the proximal extent of liquid and gas reflux [34]; it allows the measurement of acid, nonacid, and weakly acid reflux events. There is a higher detection rate with ph-impedance compared with ph monitoring. In one study, impedance detected 96% of reflux events compared with 28% detected by ph study using acid reflux event definition. At least a third of reflux events are nonacid or weakly acid reflux events, both in normal subjects and those with GERD [34]. Reflux is best evaluated by combined ph-impedance [33]; however, this does not document aspiration. Biomarkers of aspiration have therefore been evaluated [35]. Biomarkers of Aspiration Pepsin Pepsin, a proteolytic enzyme produced in the stomach, has been used as a marker of extra-esophageal reflux and is a marker of aspiration [9, 36 38]. Bronchoalveolar lavage pepsin levels were higher in the transplanted population when compared with normals, suggesting aspiration of gastric juice [9, 30]. Another study showed pepsin levels in bronchoalveolar lavage were raised in lung transplant patients without BOS, showing that pepsin can be present without airflow limitation [35]. The highest levels were present in patients with acute rejection and they had the highest grades of inflammation on pathology. This may suggest interaction between allo-immune and nonallo-immune mediated allograft damage [35]. Bile Acids The presence of bile acids in the lung is believed to reflect duodenogastroesophageal reflux and aspiration [6, 21, 35] and has been associated with severe pulmonary injury [6, 39] and BOS. A relationship between bronchoalveolar lavage bile acids and abnormal ph findings in lung transplant patient exists. Freedom from BOS was significantly reduced by the presence of bile acids, and an estimated 7 of 10 patients with high bile acids in bronchoalveolar lavage fluid (BALF) samples develop BOS within 12 months [5, 21]. Higher levels of bile acids are associated with early onset BOS [6, 30], and bile acids were present in bronchoalveolar lavage of half of the patients at 3 and 12 months [21]. Bile aspiration is cytotoxic, disrupts cellular membranes, and damages type II pneumocytes [40], which are responsible for surfactant protein and phospholipid production and homeostasis [5, 6, 21]. In the lungs, bile acids may disrupt the phospholipids in surfactant. Bile acids downregulate innate immunity by receptors on monocytes and macrophages [5, 21]. The presence of bile acids is associated with elevated neutrophils, interleukin-8, and the presence of bacteria [41], fungi, lower levels of pulmonary surfactant, and inflammation on transbronchial biopsies [21]. These lower levels of surfactant surface proteins will depress innate immunity and increase alveolar surface tension [21]. The role of bile acids in reflux related lung damage is open to interpretation, since lung levels of bile acid are difficult to accurately measure. Aspiration Gastroesophageal reflux may influence the lung in several ways. It may cause bronchoconstriction through a vagal reflex. Extra-esophageal reflux may lead to microaspiration and lung injury [17]. Aspiration leads to epithelial damage, stimulation of cytokine production, inflammation, and graft failure. There is impaired cough and mucociliary clearance post-transplant that have been shown to be less than 15% of normal. These factors may lead to a prolonged and increased contact between reflux

4 656 REVIEW ROBERTSON ET AL Ann Thorac Surg ANTIREFLUX SURGERY POSTLUNG TRANSPLANTATION 2010;89: material and lung parenchyma [3, 5, 6, 9, 22]. Little is known regarding the role of aspiration during disordered swallowing. In 2007, a study by Atkins and colleagues [42] showed that, in lung transplant recipients, 64% (67 of 105) of patients aspirate during swallowing, 78% (52 of 67) of these were asymptomatic. This was associated with a prolonged hospital stay and increased episodes of severe rejection [42]. In studies on rats, aspiration of gastric juice leads to lung damage [35, 43, 44], but such direct challenges can not be confirmed in humans. Pathophysiology Bronchiolitis obliterans syndrome is the pathophysiologic equivalent of obliterative bronchiolitis, the pathologic process of chronic rejection [1]. The pathophysiology of BOS is well reviewed elsewhere [1], but aspects that may be especially relevant to gastroesophageal reflux and aspiration are appropriate to consider. In brief, the pathophysiology of BOS is an inflammatory and fibrotic process of the small airways, underlied by neutrophilic inflammation and airway remodeling. Both alloimmune and nonallo-immune mechanisms, such as GERD, infection, and ischemia are involved [1]. There is an increasing recognition of the potential for complex interactions, including auto-immune mechanisms of damage [45], with BOS representing a common pathway, resulting from overall lung injury. It has recently been suggested that BOS is a heterogeneous condition with neutrophilic reversible allograft dysfunction representing a distinct patient subset. This may have therapeutic implications, and the definition of BOS, which currently is described as irreversible, may need to be revised [46]. The end result of the injuries that lead to BOS is fibrosis and airway remodeling. The fibroblasts that effect fibrosis may originate from recruited circulating fibrocytes and through in situ airway proliferation. It has been suggested by our group that fibroblasts may also originate from injured epithelium through epithelial mesenchymal transition [47]. Epithelial mesenchymal transition is recognized to occur in organogenesis, metastasis, and in chronic rejection of other transplant organs, and it is denoted by loss of epithelial markers, for example E- cadherin, as well as upregulation of mesenchymal properties. Reflux injury is associated with the loss of E- cadherin in the esophageal epithelium of patients with Barrett s esophagus. This loss is more marked in esophageal adenocarcinoma [48], and this occurs, despite the presence of defenses such as carbonic anhydrase, evolved in the esophagus to protect against reflux. The airway epithelia without such defences might be expected to be more vulnerable to aspiration injury, and we hypothesize that micro-aspiration may directly injure the allograft, and that along with additional injuries from infection, allo-immunity and auto-immunity [48], this leads to epithelial mesenchymal transition, fibrosis, and BOS. A translational implication of this hypothesis is that treatments of GERD may reduce micro-aspiration, epithelial injury, and epithelial mesenchymal transition, impacting favorably on BOS. Therapy Conservative Therapy Maintenance, prophylactic proton pump inhibitor usage is common in lung transplant patients, but it is a widespread misconception that this may prevent reflux. There is growing recognition that as well as acid reflux, weakly acid, neutral, or alkaline reflux may be an important issue. Treatment with proton pump inhibitor therapy may also have deleterious effects by increasing intragastric ph leading to an increase of bacterial flora. This may potentiate the effects of aspiration and introduce bacteria into the lungs [49]. Blondeau and colleagues [30] showed that lung transplant patients on proton pump inhibitor treatment still had increased nonacid reflux and elevated pepsin and bile acid levels in the bronchoalveolar lavage fluid, suggesting that there may still be occult aspiration of gastric contents. Azithromycin, a pro-motility agent, may be of benefit for these patients, as it improves airflow limitation even in those patients with longstanding BOS [50]. Macrolides have multiple potential beneficial activities, with anti-inflammatory, antibacterial, and pro-motile effects [50 52]. This improvement in lung function may partially be through an amelioration of GERD [52]. Endoluminal Anti-Reflux Therapies Endoscopic reflux therapies include endoluminal gastroplication, suturing, radiofrequency ablation, or injecting the esophagogastric junction [53, 54]. The data supporting these procedures is limited with none reported in the lung transplant population [53]. There have been reports of complications [54] and of mortality. Endoscopic procedures reduce but fail to abolish both reflux and symptoms [53, 54], and therefore would not be expected to prevent aspiration. Their role, if any, is yet to be fully determined in the nontransplant population, and combined with its limitations it is our recommendation that these procedures should not be attempted in the lung transplant population. Anti-Reflux Surgery Anti-reflux surgery has been used as a treatment for laryngopharyngeal reflux [55] and has been performed for extra-esophageal reflux in end-stage lung disease [17, 56, 57]. The first documented case of GERD as a reversible cause of decreasing lung function was reported in 2000 by Palmer and colleagues [4]. After anti-reflux surgery, the patient had improved FEV 1 and resolution of bronchial inflammation [4]. Several articles have been published by the Duke University Transplant Group since then [3, 5, 20, 58, 59], with each as an update of a continuing program, suggesting that anti-reflux surgery

5 Ann Thorac Surg REVIEW ROBERTSON ET AL 2010;89: ANTIREFLUX SURGERY POSTLUNG TRANSPLANTATION 657 may lead to increased survival and improved lung function post-transplantation by preventing lung damage through reflux [5, 20]. Timing of Surgery: A Role for Fundoplication Before Lung Transplant? Introduction of fundoplication has not been systematic, but has been considered in patients with end-stage lung disease [17, 57]. There is the risk of morbidity and mortality, and some patients derive little benefit. However, there are potential benefits to performing this before transplant. Potentially this allows immediate protection from micro-aspiration, and a decreased risk of perioperative aspiration. Perhaps, with time, it may allow an improvement, stabilization, or reduced decline in function [17]. A small series of antireflux surgery in patients with end-stage lung disease have been described. In one series, there was no statistically significant decrease in pulmonary function for 15 months postoperatively, although 4 patients died before lung transplant (2 to 19 months) and after fundoplication, due to progressive respiratory failure. One patient with pulmonary fibrosis had a significant improvement in FEV 1 from 77% of predicted to 103%. Subsequently he had decreased oxygen requirements and was taken off the transplant list. Patients with pulmonary fibrosis who underwent fundoplication had decreased oxygen requirements when compared with those who had no surgery [17]. The second series demonstrates that antireflux surgery can be safe for pre-lung transplant (n 15) and post lung transplant (n 17) in selected patient populations [57]. Early Versus Late Fundoplication in Lung Transplantation The early work from the Duke Group suggested that decreased FEV 1 post-transplant was reversible if fundoplication was performed early. Therefore, in 2004, Cantu and colleagues evaluated the effect of early versus late fundoplication. In 76 patients, fundoplication was performed if their ph studies showed a total acid time of 10% or if there was an unexplained decrease in FEV 1. All post-transplant patients were divided into five groups: (1) normal ph study; (2) reflux with no fundoplication; (3) reflux and early fundoplication (within 90 days); (4) reflux and late fundoplication (after 90 days), and (5) unknown reflux status. There was no significant difference between groups for the episodes of acute rejection. However, freedom from BOS was significantly better at both 1 year (100% vs 90% to 92%) and 3 years (100% vs 47% to 62%) in patients undergoing early fundoplication. This was further reflected in survival, with a significant difference after 1 year in patients who underwent early fundoplication (100%) when compared with the rest of the patients (90% to 98%). This was more pronounced at 3 years (100% vs 69% to 86%) [3]. This early fundoplication survival effect was present compared with patients who had a normal ph study. The normal patient group included patients with mild acidic reflux and a mean acid exposure of 7.9%, which was above normal limits ( 4.5%). This may explain the anomalous beneficial effect of early antireflux surgery compared with patients who had normal ph studies. There were several significant limitations to this study. First, it was retrospective and unrandomized; second, the group who underwent early fundoplication surgery was small (n 14) and had only been followed-up for a short time [3]. The most recent data (abstract publication) demonstrated that 16% of those undergoing early fundoplication (n 67) developed BOS compared with 48% in those undergoing late fundoplication (n 117) (p ) at 1-year post transplant [59]. This is the most up-to-date data available on this study and this shows no difference in 1-year survival. A recent study of late fundoplication (mean, 768 days post-transplant) suggests late intervention may stabilize lung function and slow decline, but it does not improve FEV 1 [60]. Choice of Procedure Open approaches to anti-reflux surgery in the non-lung transplant population have an excellent long-term success rate (25-year success rate of 70% to 80%) in controlling reflux [61]. The laparoscopic approach, first performed in 1991, is now the procedure of choice and has been shown to be as successful in the control of reflux as open procedures in the medium-term to long-term [62]. Although laparoscopic surgery requires an increased operative time, it has the advantage of a lower operative morbidity, hospital stay, and faster time to recovery when compared with an open approach [63]. These are important in the lung-transplant population. Published studies in the lung-transplant population have favored laparoscopic Nissen fundoplication, as the procedure of choice, unless esophageal dysmotility was present [3, 11]. This is based on the belief that a 360 wrap provides a more effective barrier against reflux. It is suggested that fundoplication should be performed with a slightly tighter wrap to ensure no microaspiration occurs [64]. However, a complete wrap may be obstructive to patients with impaired motility leading to dysphagia [11, 63]. Recent randomized control trials in nontransplant patients suggest that a wrap need not be tailored for dysmotility [65, 66], and this may be acceptable for mild esophageal dysmotility. However, it is believed that in the presence of severe esophageal dysfunction, the approach should be modified [11, 63] and a partial fundoplication should be considered [3, 58, 63]. Division of the short gastrics is performed routinely by some surgeons to allow full mobilization and a loose wrap, preventing dysphagia [67]. This is not however substantiated by recent trials; there is some evidence to suggest that this increases gas bloat and flatulence [68, 69], although it is the authors opinion that when the stomach is difficult to mobilize, then this can make the operation easier to perform. If present, a hiatus hernia and crural defects should be repaired [11]. In the trans-

6 658 REVIEW ROBERTSON ET AL Ann Thorac Surg ANTIREFLUX SURGERY POSTLUNG TRANSPLANTATION 2010;89: plant population, pre-existing fibrotic scar tissue at the hiatus and increased fatty or friable tissue leads to more difficult dissection, which may require conversion to an open procedure [64]. In a series from Duke University, extra surgical procedures were sometimes required with 9% of patients having a pyloroplasty for gastroparesis and 15% needing a jejunal feeding tube. A distal gastrectomy has been reported for a perforated peptic ulcer [11], and in our unit several percutaneous endoscopic gastrostomy fistulae have been closed simultaneously. In summary, the evidence to support a partial versus Nissen repair in the nontransplant population is both conflicting and confusing, but in the lung transplant population, the evidence for improved lung function and survival is based predominantly on Nissen fundoplication. Further evidence is required to demonstrate whether partial fundoplication has the same efficacy. Safety of Surgery In 2004, O Halloran and associates [64] studied the safety of anti-reflux surgery in the lung transplant population. No intraoperative or perioperative deaths were reported [64], although recently one postfundoplication death occurred. The patient had a preoperative FEV 1 of 30% predicted and developed chronic vascular rejection with atypical antibodies and pneumonia, subsequently dying 17 days postoperatively [60]. Compared with the nontransplant population, there were no significant differences in the intraoperative data [64]. The transplant population had an increased length of stay (2.89 days vs 0.71 days) and a higher readmission rate (25% [7 of 28] versus 3% [2 of 63]), generally due to transplant comorbidity [64]. Quality of Life In a study of laparoscopic Toupet fundoplication in transplant recipients, three quarters of patients had an improvement in quality of life and reflux scores. In this study, 88% rated the results of their surgery as excellent or good. Reported side effects included mild dysphagia (60%), belching, and increased flatulence. Mean body mass index decreased during the first 6 months postfundoplication [60]. This suggests that fundoplication may improve the quality of life in selected symptomatic transplant patients; however, in the first 6 months there was a reduction in weight. Postfundoplication dietary advice is important in this patient group. Antireflux Surgery in the Pediatric Population Again, a single study of 5 patients is the only available evidence in this patient group. These patients were operated on between 104 to 202 days post-transplant. No major complications were encountered. For a 6-month follow-up, no episodes of acute rejection occurred. However there was no improvement in FEV 1 [31]. The paucity of the available evidence prevents conclusions from being drawn from this population, and further studies are needed. Comment Bronchiolitis obliterans syndrome is a multifactorial problem, but reflux with aspiration has been consistently implicated as a significant contributing factor. Early fundoplication is safe in selected patients, although a recent mortality has been reported [60]. Results suggest that fundoplication may retard the development of BOS, and extend survival [3]. Several fundamental questions remain unanswered however, including: how should one confirm aspiration? and what are the indications for anti-reflux surgery [5]? In particular, the criteria for selection to surgery are yet to be defined and vary greatly from unit to unit. It may be the case that some reflux is physiological, but safe levels are unknown. Most of the available data supporting anti-reflux surgery in lung transplant recipients is derived from a single center; however, our center and others are also actively studying the role of fundoplication. The current data from different units, and even from the same unit, is conflicting. Although there are some early promising studies, we suggest there is a need for appropriate trials and solid evidence-based guidelines [70]. The authors wish to thank the European Society for Organ Transplantation and British Lung Foundation (AGNR), Medical Research Council (CW, PAC). References 1. Belperio JA, Weigt SS, Fishbein MC, Lynch JP, 3rd.Chronic lung allograft rejection: mechanisms and therapy. Proc Am Thorac Soc 2009;6: Hadjiliadis D, Duane Davis R, Steele MP, et al. Gastroesophageal reflux disease in lung transplant recipients. Clin Transplant 2003;17: Cantu E, Appel JZ, Hartwig MG, et al. J. Maxwell Chamberlain Memorial Paper. 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