Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis

Abstract

Consensus diagnostic recommendations to distinguish gastro-oesophageal reflux disease (GORD) from eosinophilic oesophagitis (EoE) by response to a trial of proton pump inhibitors (PPI) unexpectedly uncovered an entity called “PPI-responsive oesophageal eosinophilia” (PPI-REE). PPI-REE refers to patients with clinical and histologic features of EoE that remit with PPI treatment. Recent and evolving evidence, mostly from adults, shows that PPI-REE and EoE patients at baseline are clinically, endoscopically and histologically indistinguishable, and have significant overlap in terms of features of Th2 immune-mediated inflammation and gene expression. Furthermore, PPI therapy restores oesophageal mucosal integrity, reduces Th2 inflammation and reverses the abnormal gene expression signature in PPI-REE patients, similar to the effects of topical steroids in EoE patients. Additionally, recent series have reported that EoE patients responsive to diet/topical steroids may also achieve remission on PPI therapy. This mounting evidence supports the concept that PPI-REE represents a continuum of the same immunologic mechanisms that underlie EoE. Accordingly, it seems counterintuitive to differentiate PPI-REE from EoE based on a differential response to PPI therapy when their phenotypic, molecular, mechanistic, and therapeutic features cannot be reliably distinguished. For patients with symptoms and histologic features of EoE, it is reasonable to consider PPI therapy not as a diagnostic test, but as a therapeutic agent. Due to its safety profile, ease of administration and high response rates (up to 50%), PPI can be considered a first-line treatment, before diet and topical steroids. The reasons why some EoE patients respond to PPI, while others do not, remain to be elucidated.

Diagnosis and treatment of eosinophilic esophagitis in clinical practice

“…No significant difference has been shown regarding the treatment efficacy between children and adults, between the dose and number of PPI administered, or between the absence and the presence of GERD [122]. Although evidence of the pathogenesis of PPI-REE and EoE is accumulating, the two entities cannot be clearly differentiated solely based on patient characteristics, symptoms, endoscopic findings, histological findings with immunostaining, or molecular findings [116,123,124]. Thus, some experts have proposed that the responsiveness to PPI should not be included in the diagnostic criteria for EoE, and that use of the term PPI-REE should be avoided [116].…”

“…Consequently, PPI is a reasonable first-line therapeutic agent for symptomatic EE due to its feasibility, tolerability, and paucity of side effects compared with diet or steroid therapy [116]. No significant difference has been shown regarding the treatment efficacy between children and adults, between the dose and number of PPI administered, or between the absence and the presence of GERD [122].…”

“…Although evidence of the pathogenesis of PPI-REE and EoE is accumulating, the two entities cannot be clearly differentiated solely based on patient characteristics, symptoms, endoscopic findings, histological findings with immunostaining, or molecular findings [116,123,124]. Thus, some experts have proposed that the responsiveness to PPI should not be included in the diagnostic criteria for EoE, and that use of the term PPI-REE should be avoided [116]. High doses of PPIs (e.g., omeprazole 40 mg twice daily) are initially used in PPI therapy; however, 70-80% of patients may maintain histological remission with lower doses of PPI (e.g., omeprazole 20 mg twice or once daily) [125,126].…”

“…Subsequently reported retrospective and prospective studies have demonstrated that about 30-70% of adult EoE patients exhibited both symptomatic and histologic improvement of EE by PPI therapy [115]. A high dose of PPI is conventionally used twice daily or once daily for 8 weeks [116]. In the consensus recommendation for EoE in 2011, it was proposed that those conditions should be discriminated from EoE as a new potential disease entity termed ''PPI-REE.''…”

Letter: proton pump inhibitor‐responsive oesophageal eosinophilia – more than just gastro‐oesophageal reflux disease

“…A recent position paper on PPI-REE underscored that EoE and PPI-REE are virtually indistinguishable from one another, even at the genetic level (and very different from GERD without oesophageal eosinophilia). 6 Two recent series of patients with suspected EoE demonstrated dual response to PPI therapy and either diet or topical steroid therapy, 7,8 suggesting a common allergic pathogenesis for EoE and PPI-REE, very different from that of GERD. We do agree with Savarino et al that GERD may play a role in PPI-REE by being the triggering event in an antigen-driven oesophageal eosinophilia.…”