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Nissen Fundoplication and Lung Transplantation

John C Haney, MD, MPH
Matthew G Hartwig, MD
Duke University
Durham, North Carolina, USA

"An ounce of prevention is worth a pound of cure" - Benjamin Franklin

If the esteemed Mr. Franklin were a lung transplant surgeon, certainly one at the writers' institution, he might have rephrased his sentiment "an early Nissen is better than a late retransplant".

Gastroesophageal reflux disease (GERD) is a common finding in patients with advanced lung disease. A recognized factor in diseases such as asthma and bronchitis, it has been found with high incidence in end-stage lung diseases such as cystic fibrosis and pulmonary fibrosis [1]. More impressively, the incidence of GERD as defined by abnormal esophageal acid contact time increases after lung transplantation, detectable in up to 65-75% of patients [1,2]. Proposed mechanisms for this increase include vagal nerve irritation or injury, altered diaphragm mechanics and the effects of post-transplant immunosuppression, especially by corticosteroids, on lower esophageal sphincter (LES) function [1]. None of these mechanisms have been clearly elucidated and the increased incidence is not explained entirely by altered esophageal or gastric motility. Importantly, the majority of transplant patients remained asymptomatic.

Early studies on transplant patients found a relationship between GERD and the development of bronchiolitis obliterans syndrome (BOS) and diminished graft function as determined by forced expiratory volume in one minute (FEV1) [3]. Corresponding animal work has shown the development of airway inflammation and remodeling in response to the induced aspiration of gastric contents, leading to the development of obliterative bronchiolitis lesions by neutrophil-derived inflammatory mediators [4]. Critically, these results are not entirely explained by acid exposure [5]. While neutralization of acid ameliorates some of the inflammatory activity, perhaps by preventing the activation of acid-dependent proteases such as pepsin within the aspirate, alkalinization alone does not ameliorate all of the deleterious effects. As a result, our group and others have taken an aggressive stance towards the surgical management of reflux, advocating uniform screening and fundoplication as a physical barrier to reflux. It has been a decade since initial results of early fundoplication found an association with improved FEV1 and delayed onset of BOS [6]. Our most recent examination of the largest cohort to date of nearly 300 patients found an association between early fundoplication and preserved graft function, as patients undergoing fundoplication within the first year of transplantation had 1-year percent predicted FEV1 nearly 10 percentage points higher than those with abnormal acid contact times who did not undergo fundoplication [2]. The laparoscopic fundoplication has evolved into the clear technique choice for fundoplication, and studies have found this to be safely performed in transplant and non-transplant patients alike [7]. Compared to non-transplant recipients, transplant patients have a longer postoperative stay after fundoplication and higher rates of readmission as one would surmise. It has been our bias to perform 360°, or Nissen fundoplication, on these patients provided esophageal motility and gastric anatomy allow for that. This is occasionally combined with a laparoscopic pyloroplasty or gastrojejunostomy for those with severe gastric emptying problems.

Similar studies by Pittsburgh [8] and Loyola [9] also found protective effects of anti-reflux surgery in lung transplant recipients. Hoppo and colleagues found improvement in FEV1 in 90% of patients following anti-reflux surgery and a statistically significant reduction in episodes of acute rejection, while Fisichella and colleagues also found a reduction in reflux and episodes of acute rejection and progression to BOS. Enrollment has recently concluded in the RESULT trial, Reflux Surgery in Lung Transplantation, a multicenter prospective trial of over 600 patients designed to identify clinically useful markers of GERD-induced lung injury that correlate with adverse outcomes. The trial has an additional goal of a future randomized multicenter trial to definitively establish these relationships and identify the best means of preventing them. RESULT has recently closed enrollment and data are being processed.

The argument for fundoplication in lung transplantation may be summarized as follows: Gastroesophageal reflux disease is quite common post-transplantation, detectable in up to three-quarters of transplant recipients [2]. Animal models of lung transplantation have shown a role for aspirated gastric contents in causing bronchiolitis obliterans-like pathology [4], and retrospective observational human studies have shown an association between reflux and progressive graft dysfunction and bronchiolitis obliterans syndrome [3]. Further evidence suggests that the ubiquitous medical management of reflux by pH neutralization is likely ineffective at eliminating all of the deleterious effects [5]. Surgical fundoplication reduces reflux and may be performed safely in the lung transplant population [7]. Finally, multiple retrospective studies have found an association between early fundoplication and preserved graft function and delayed development of BOS [2,8,9]. With a median survival hovering at five years, a lung transplant recipient's long-term outcome is still driven primarily by graft function. A laparoscopic fundoplication performed safely offers the potential to extend graft function in a low-risk, high-reward fashion. After all, can we really argue with our Founding Father?

Disclosure Statement: The authors have no conflicts of interest to disclose.


  1. Young LR, Hadjiliadis D, Davis RD, et al. Lung transplantation exacerbates gastroesophageal reflux disease. Chest. 2003;124(5):1689-93.
  2. Hartwig MG, Anderson DJ, Onaitis MW et al. Fundoplication after lung transplantation prevents the allograft dysfunction associated with reflux. Ann Thorac Surg 2011;462-9.
  3. Palmer SM, Miralles AP, Howell DN, et al. Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation. Chest. 2000;118(4):1214-7.
  4. Li B, Hartwig MG, Appel JZ, et al. Chronic aspiration of gastric fluid induces the development of obliterative bronchiolitis in rat lung transplants. Am J Transplant. 2008;8(8):1614-21.
  5. Tang T, Chang JC, Xie A, et al. Aspiration of gastric fluid in pulmonary allografts: effect of pH. J Surg Res 2013;181(1):e31-8.
  6. Cantu E, Appel JZ, Hartwig MG, et al. J. Maxwell Chamberlain memorial paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease. Ann Thorac Surg 2004;78:1142-51.
  7. Robertson AGN, Ward C, Pearson JP, et al. Lung transplantation, gastroesophageal reflux and fundoplication. Ann Thorac Surg 2010;89:653-60.
  8. Hoppo T, Jarido V, Pennathur A, et al. Antireflux surgery preserves lung function in patients with gastroesophageal reflux disease and end-stage lung disease before and after lung transplantation. Arch Surg 2011; 146:1041-47.
  9. Fisichella PM, Davis CS, Lundberg PW, et al. The protective role of laparoscopic antireflux surgery against aspiration of pepsin after lung transplantation. Surgery 2011; 150:598-606.

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