Esophageal Dysmotility, Gastro-esophageal Reflux Disease, and Lung Transplantation: What Is the Evidence?

  • Richard K. WoodEmail author
Esophagus (J Clarke, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Esophagus


Lung transplantation is an effective and life-prolonging therapy for patients with advanced lung disease (ALD). However, long-term patient survival following lung transplantation is primarily limited by development of an inflammatory and fibrotic process involving the lung allograft known as bronchiolitis obliterans syndrome (BOS). Although the precise cause of BOS remains uncertain and is likely multifactorial, chronic aspiration of gastro-duodenal contents is one possible contributing factor. Multiple small, cross-sectional studies performed over the past two decades have reported a high prevalence of gastro-esophageal reflux disease (GERD) and esophageal dysmotility in the ALD population and several investigations suggest the prevalence may increase following lung transplantation. More recent studies evaluating the direct effect of gastro-duodenal contents on airways have demonstrated a possible biologic link between GERD and BOS. Despite the recent advances in our understanding of BOS, further investigations are needed to establish GERD as a causative factor in its development. This review will discuss the existing literature that has identified an association of GERD with ALD and post-transplant populations, with a focus on recent advances in the field.


Gastro-esophageal reflux disease Lung transplantation Obliterative bronchiolitis Bronchiolitis obliterans syndrome Esophageal dysmotility Fundoplication 


Compliance with Ethical Standards

Conflict of Interest

The author declares that he has no competing interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Yusen RD et al. The registry of the international society for heart and lung transplantation: thirty-first adult lung and heart-lung transplant report--2014; focus theme: retransplantation. J Heart Lung Transplant. 2014;33(10):1009–24.PubMedCrossRefGoogle Scholar
  2. 2.
    Lodhi SA, Lamb KE, Meier-Kriesche HU. Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success. Am J Transplant. 2011;11(6):1226–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Belperio JA et al. Chronic lung allograft rejection: mechanisms and therapy. Proc Am Thorac Soc. 2009;6(1):108–21.PubMedCrossRefGoogle Scholar
  4. 4.
    Robertson AG et al. Lung transplantation, gastroesophageal reflux, and fundoplication. Ann Thorac Surg. 2010;89(2):653–60.PubMedCrossRefGoogle Scholar
  5. 5.
    Sato M et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011;30(7):735–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Gulack BC et al. Reflux and allograft dysfunction: is there a connection? Thorac Surg Clin. 2015;25(1):97–105.PubMedCrossRefGoogle Scholar
  7. 7.
    Estenne M et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant. 2002;21(3):297–310.PubMedCrossRefGoogle Scholar
  8. 8.
    Hartwig MG et al. Chronic aspiration of gastric fluid accelerates pulmonary allograft dysfunction in a rat model of lung transplantation. J Thorac Cardiovasc Surg. 2006;131(1):209–17.PubMedCrossRefGoogle Scholar
  9. 9.
    Cantu 3rd E et al. J. Maxwell chamberlain memorial paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease. Ann Thorac Surg. 2004;78(4):1142–51. discussion 1142–51.PubMedCrossRefGoogle Scholar
  10. 10.
    Burlingham WJ et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007;117(11):3498–506.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Holloway RH, Penagini R, Ireland AC. Criteria for objective definition of transient lower esophageal sphincter relaxation. Am J Physiol. 1995;268(1 Pt 1):G128–33.PubMedGoogle Scholar
  12. 12.
    Mittal RK et al. Transient lower esophageal sphincter relaxation. Gastroenterology. 1995;109(2):601–10.PubMedCrossRefGoogle Scholar
  13. 13.
    Patti MG et al. Hiatal hernia size affects lower esophageal sphincter function, esophageal acid exposure, and the degree of mucosal injury. Am J Surg. 1996;171(1):182–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Casanova C et al. Increased gastro-oesophageal reflux disease in patients with severe COPD. Eur Respir J. 2004;23(6):841–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Pandolfino JE et al. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology. 2006;130(3):639–49.PubMedCrossRefGoogle Scholar
  16. 16.
    Diener U et al. Esophageal dysmotility and gastroesophageal reflux disease. J Gastrointest Surg. 2001;5(3):260–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology. 1988;94(1):73–80.PubMedGoogle Scholar
  18. 18.
    Moraes-Filho J et al. Brazilian consensus on gastroesophageal reflux disease: proposals for assessment, classification, and management. Am J Gastroenterol. 2002;97(2):241–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Vakil N et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101(8):1900–20. quiz 1943.PubMedCrossRefGoogle Scholar
  20. 20.
    Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108(3):308–28. quiz 329.PubMedCrossRefGoogle Scholar
  21. 21.
    el-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology. 1997;113(3):755–60.PubMedCrossRefGoogle Scholar
  22. 22.
    Raghu G et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27(1):136–42.PubMedCrossRefGoogle Scholar
  23. 23.
    Salvioli B et al. Gastro-oesophageal reflux and interstitial lung disease. Dig Liver Dis. 2006;38(12):879–84.PubMedCrossRefGoogle Scholar
  24. 24.
    Sweet MP et al. The prevalence of distal and proximal gastroesophageal reflux in patients awaiting lung transplantation. Ann Surg. 2006;244(4):491–7.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Tobin RW et al. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158(6):1804–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Mokhlesi B et al. Increased prevalence of gastroesophageal reflux symptoms in patients with COPD. Chest. 2001;119(4):1043–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastro-oesophageal reflux in adult cystic fibrosis patients. J R Soc Med. 1998;91(1):7–9.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Bassotti G et al. Esophageal dysfunction in scleroderma: relationship with disease subsets. Arthritis Rheum. 1997;40(12):2252–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Marie I et al. Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum. 2001;45(4):346–54.PubMedCrossRefGoogle Scholar
  30. 30.
    Pellegrini CA et al. Gastroesophageal reflux and pulmonary aspiration: incidence, functional abnormality, and results of surgical therapy. Surgery. 1979;86(1):110–9.PubMedGoogle Scholar
  31. 31.
    Seccombe J et al. Esophageal motor disease and reflux patterns in patients with advanced pulmonary disease undergoing lung transplant evaluation. Neurogastroenterol Motil. 2013;25(8):657–63.PubMedCrossRefGoogle Scholar
  32. 32.••
    D'Ovidio F et al. The effect of reflux and bile acid aspiration on the lung allograft and its surfactant and innate immunity molecules SP-A and SP-D. Am J Transplant. 2006;6(8):1930–8. In this study of 31 post-transplant patients, the investigators found patients with abnormal proximal esophageal acid exposure had higher levels of bile acids, lower levels of pulmonary surfactant proteins A and D, and alterations of surfactant phospholipids. These findings support a plausible biologic mechanism for bile acid related pulmonary injury.PubMedCrossRefGoogle Scholar
  33. 33.
    Sweet MP et al. Gastro-oesophageal reflux and aspiration in patients with advanced lung disease. Thorax. 2009;64(2):167–73.PubMedCrossRefGoogle Scholar
  34. 34.
    Allaix ME et al. The pulmonary side of reflux disease: from heartburn to lung fibrosis. J Gastrointest Surg. 2013;17(8):1526–35.PubMedCrossRefGoogle Scholar
  35. 35.
    El-Serag HB et al. Obesity increases oesophageal acid exposure. Gut. 2007;56(6):749–55.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Young LR et al. Lung transplantation exacerbates gastroesophageal reflux disease. Chest. 2003;124(5):1689–93.PubMedCrossRefGoogle Scholar
  37. 37.
    Hadjiliadis D et al. Gastroesophageal reflux disease in lung transplant recipients. Clin Transplant. 2003;17(4):363–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Lo WK et al. Pre-transplant impedance measures of reflux are associated with early allograft injury after lung transplantation. J Heart Lung Transplant. 2015;34(1):26–35.PubMedCrossRefGoogle Scholar
  39. 39.
    Robertson AG et al. Longitudinal changes in gastro-oesophageal reflux from 3 months to 6 months after lung transplantation. Thorax. 2009;64(11):1005–7.PubMedCrossRefGoogle Scholar
  40. 40.••
    Blondeau K et al. Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J. 2008;31(4):707–13. In this study, the authors reported results of impedance/pH testing and BALF sampling in 45 patients at a mean of 36 months following transplantation. They found a lower level of post-transplant GERD (49 %) when compared to other studies and importantly, the authors did not identify an association between patients with abnormal levels of GERD and BOS. Pepsin was ubiquitous in BALF samples. Patients with BOS were more likely to have bile acids detected in BALF (70 %) compared to patients without BOS (31 %).PubMedCrossRefGoogle Scholar
  41. 41.••
    King BJ et al. Gastroesophageal reflux in bronchiolitis obliterans syndrome: a new perspective. J Heart Lung Transplant. 2009;28(9):870–5. The authors of this study reported on post-transplant impedance/pH findings in 59 patients. They found no significant association between elevated levels of acid exposure and BOS development. However, they reported patients with a higher than normal liquid reflux exposure measured by impedance had a 2.8 increased risk of developing BOS.PubMedCrossRefGoogle Scholar
  42. 42.
    Li B 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.PubMedCrossRefGoogle Scholar
  43. 43.
    Samloff IM. Peptic ulcer: the many proteinases of aggression. Gastroenterology. 1989;96(2 Pt 2 Suppl):p586–95.Google Scholar
  44. 44.
    Ward C et al. Pepsin like activity in bronchoalveolar lavage fluid is suggestive of gastric aspiration in lung allografts. Thorax. 2005;60(10):872–4.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Stovold R et al. Pepsin, a biomarker of gastric aspiration in lung allografts: a putative association with rejection. Am J Respir Crit Care Med. 2007;175(12):1298–303.PubMedCrossRefGoogle Scholar
  46. 46.
    D'Ovidio F, Keshavjee S. Gastroesophageal reflux and lung transplantation. Dis Esophagus. 2006;19(5):315–20.PubMedCrossRefGoogle Scholar
  47. 47.
    Oelberg DG, Downey SA, Flynn MM. Bile salt-induced intracellular Ca++ accumulation in type II pneumocytes. Lung. 1990;168(6):297–308.PubMedCrossRefGoogle Scholar
  48. 48.
    Chen X et al. Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins. Am J Physiol Gastrointest Liver Physiol. 2011;301(2):G203–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Chang KO et al. Bile acids are essential for porcine enteric calicivirus replication in association with down-regulation of signal transducer and activator of transcription 1. Proc Natl Acad Sci U S A. 2004;101(23):8733–8.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Meers CM et al. A porcine model of acute lung injury by instillation of gastric fluid. J Surg Res. 2011;166(2):e195–204.PubMedCrossRefGoogle Scholar
  51. 51.
    Blondeau K et al. Nocturnal weakly acidic reflux promotes aspiration of bile acids in lung transplant recipients. J Heart Lung Transplant. 2009;28(2):141–8.PubMedCrossRefGoogle Scholar
  52. 52.••
    D'Ovidio F et al. Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg. 2005;129(5):1144–52. In this study, the authors measured bile acids in BALF from 120 post-transplant patients and found higher bile acid levels were associated with an increased risk of BOS. Further, the highest BAL bile acid levels were strongly correlated with increase alveolar neutrophilia and higher concentrations of IL-8, suggesting a biochemical link between gastro-duodenal reflux and lung injury mechanisms.PubMedCrossRefGoogle Scholar
  53. 53.•
    Neujahr DC et al. Bile acid aspiration associated with lung chemical profile linked to other biomarkers of injury after lung transplantation. Am J Transplant. 2014;14(4):p841–8. This study used metabolomic profiling to link bile acid presence in lung allografts with inflammatory pathways known to segegrate with worsening allograft outcome. This novel approach to identifying patients at risk for lung injury may provide an alternative method of selecting patients at greatest risk for BOS.CrossRefGoogle Scholar
  54. 54.
    Davis Jr RD et al. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg. 2003;125(3):533–42.PubMedCrossRefGoogle Scholar
  55. 55.
    Hartwig MG et al. Fundoplication after lung transplantation prevents the allograft dysfunction associated with reflux. Ann Thorac Surg. 2011;92(2):p462–8. discussion; 468–9.CrossRefGoogle Scholar
  56. 56.
    Fisichella PM et al. The protective role of laparoscopic antireflux surgery against aspiration of pepsin after lung transplantation. Surgery. 2011;150(4):598–606.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.•
    Abbassi-Ghadi N et al. Anti-reflux surgery for lung transplant recipients in the presence of impedance-detected duodenogastroesophageal reflux and bronchiolitis obliterans syndrome: a study of efficacy and safety. J Heart Lung Transplant. 2013;32(6):p588–95. This study evaluated pulmonary function prior to and following fundoplication in 40 post-transplant patients and repored a reduced rate of decline in pulmonary function following fundoplication, suggesting that the course of BOS may be modified by anti-reflux therapy.CrossRefGoogle Scholar
  58. 58.••
    Fisichella PM et al. Pulmonary immune changes early after laparoscopic antireflux surgery in lung transplant patients with gastroesophageal reflux disease. J Surg Res. 2012;177(2):e65–73. This study evaluated the biologic effect of fundoplication on the immunologic enviroment of the lung allograft over the course of one year. The authors reported normalization of the pulmonary leukocyte differential coinciding with a reduced pro-inflammatory enviroment post-fundoplication. This prelminary study is the first to demonstrate a reduced inflammatory milieu in the lung allograft following fundoplication.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hayes Jr D et al. Reduction of lipid-laden macrophage index after laparoscopic Nissen fundoplication in cystic fibrosis patients after lung transplantation. Clin Transplant. 2013;27(1):121–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Division of GastroenterologyDuke University Medical CenterDurhamUSA

Personalised recommendations