Eosinophilic esophagitis (EoE) is an emerging disease characterized by an anomalous esophageal allergic inflammatory response, triggered by food and/or environmental allergens. Currently, solid data currently confirm that up to half of EoE patients achieve symptom and inflammation remission on acid suppressive drugs like proton pump inhibitor (PPI) therapy1. This disease phenotype, first described in 2006, was then labelled as PPI-responsive esophageal eosinophilia (PPI-REE). A recent and growing body of research has challenged initial considerations of this entity.
The first consensus recommendations for the diagnosis and management of EoE were published in 20072. These guidelines advocated a diagnosis of EoE in patients with symptomatic oesophageal eosinophilia showing either lack of response to proton pump inhibitor (PPI) therapy or a normal acid exposure on oesophageal pH monitoring. Therefore, patients with a normal pH monitoring or remission on PPI therapy should be given a diagnosis of gastro-esophageal reflux disease (GERD). This distinction was based on the belief that only GERD, as an acid-related disorder, could respond to the acid suppressive effect of PPI therapy. A first prospective study in 2011 proved a high rate of response to PPI therapy (50%), which was present in patients with either normal or pathological pH monitoring3. Responders and non-responders to PPI therapy were indistinguishable upon clinic, endoscopic and histologic features3. Updated consensus recommendations in 2011 included the description of a novel phenotype, PPI-REE, different from GERD and the withdrawal of esophageal pH monitoring as a diagnostic tool, due to low accuracy to predict responsiveness to PPI4. PPI-REE and EoE, however, were still considered separate clinical entities in 2011 guidelines as they showed a different response to the PPI trial4. Over the past years, an increasing number of papers have tried to further characterize distinguishing features between PPI-REE and EoE. However, baseline gene expression of allergic Th2 inﬂammation5-7 and the hallmark EoE genes7 for eosinophil chemotaxis, mast cells, barrier molecules and tissue remodeling were virtually indistinguishable between both entities and radically different from that observed in GERD patients. Overall, these findings suggest PPI-REE and EoE are very alike and both associated with allergic inflammation.
Due to its acid suppressing ability, PPI therapy are the mainstay therapy for acid related disorders. However, recent clinical studies have shown that the effects of PPI therapy in PPI-REE might go beyond symptom improvement and histologic normalization. PPI alone in PPI-REE patients has been shown to almost completely reverse the Th2 signature5-7 and concurrently induce a normalization of the genetic transcriptome in esophageal tissue7. Since these effects are identically displayed by topical steroid therapy in EoE patients5,8, these striking data pose again the possibility that EoE and PPI-REE are the same disorder.
Finally, two recent and important series have proven that EoE patients responsive to diet/topical steroid therapy can also be responsive to response to PPI therapy, and viceversa9,10. These series demonstrate an allergic inflammatory cause in PPI-REE, besides underscoring that an approach considering that PPI merely suppress gastric acid might be simplistic. Based on all the aforementioned evolving research, an updated Position Paper on PPI-REE has recently recommended to consider this entity as a subphenotype of a true EoE11.
- Lucendo AJ, Arias A, Molina-Infante J. Efficacy of Proton Pump Inhibitor Drugs for Inducing Clinical and Histological Remission in Patients With Symptomatic Esophageal Eosinophilia: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2016;14:13-22.e1.
- Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007;133:1342-63.
- Molina-Infante J, Ferrando-Lamana L, Ripoll C, et al. Esophageal eosinophilic infiltration responds to proton pump inhibition in most adults. Clin Gastroenterol Hepatol 2011;9:110-117.
- Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: Updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011;128:3-20.
- Molina-Infante J, Rivas MD, Hernandez-Alonso M, et al. Remission in proton pump inhibitor-responsive esophageal eosinophilia correlates with down regulation of eotaxin-3 and TH2 cytokines, similarly to eosinophilic esophagitis after steroids. Aliment Pharmacol Ther 2014;40:955-65.
- van Rhijn BD, Weijenborg PW, Verheij J, et al. Proton Pump Inhibitors Partially Restore Mucosal Integrity in Patients With Proton Pump Inhibitor-Responsive Esophageal Eosinophilia but Not Eosinophilic Esophagitis. Clin Gastroenterol Hepatol 2014;12:1815-23.
- Wen T, Dellon ES, Moawad FJ, et al. Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation. J Allergy Clin Immunol 2015;135:187-97.
- Butz BK, Wen T, Gleich GJ, et al. Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis. Gastroenterology 2014;147:324-33.e5.
- Sodikoff J, Hirano I. Proton pump inhibitor-responsive esophageal eosinophilia does not preclude food-responsive eosinophilic esophagitis. J Allergy Clin Immunol 2016;137:631-3.
- Lucendo AJ, Arias A, Gonzalez-Cervera J, Olalla JM, Molina-Infante J. Dual response to Dietary/Topical Steroid and PPI therapy in Adult Patients with Eosinophilic Esophagitis. J Allergy Clin Immunol 2016;137:931-934.
- Molina-Infante J, Bredenoord AJ, Cheng E, et al PPI-REE Task Force of the European Society of Eosinophilic Oesophagitis (EUREOS). Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut 2016;65:524-31.