Review
Lung Transplantation, Gastroesophageal Reflux, and Fundoplication

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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.

Section snippets

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.

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 GERD (78 of 104 patients, 68%) in patients with a range of end-stage lung disease including interstitial lung

Cause

Diverse factors surrounding lung transplantation may increase the prevalence of reflux, including vagal damage, immunosuppression, changes in intrathoracic volume and postpneumonectomy reflux [18, 19, 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

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

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, 37, 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

Aspiration

Gastroesophageal reflux may influence the lung in several ways. It may cause bronchoconstriction through a vagal reflex. Extra-esophageal reflux may lead to micro-aspiration 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

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

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

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

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 FEV1 and resolution of bronchial inflammation [4]. Several articles have been published by the Duke University Transplant Group since then

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

Early Versus Late Fundoplication in Lung Transplantation

The early work from the Duke Group suggested that decreased FEV1 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 FEV1. All post-transplant patients were divided into five groups: (1) normal pH study; (2) reflux with no fundoplication;

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

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 FEV1 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

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

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 FEV1 [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

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