Proton Pump Inhibitor-responsive Esophageal Eosinophilia: Still a Valid Diagnosis?

Javier Molina-Infante; Pedro L. Gonzalez-Cordero; Alfredo J. Lucendo


Curr Opin Gastroenterol. 2017;33(4):285-292. 

In This Article

Abstract and Introduction


Purpose of review To update rapidly evolving concepts regarding the controversial entity of 'proton pump inhibitor (PPI)-responsive esophageal eosinophilia,' referring to patients with clinical, endoscopic and histologic features of eosinophilic esophagitis (EoE) who achieve remission on PPI therapy.

Recent findings Up to half of pediatric and adult patients with typical EoE symptoms and histology achieve clinico-pathologic remission on PPI therapy, irrespective of whether esophageal pH monitoring demonstrates abnormal acid reflux. In patients with clinical and histologic features of EoE, genotypic and phenotypic features of PPI responders and nonresponders are virtually indistinguishable, and different from those of patients with gastroesophageal reflux disease. In PPI responders, PPIs effects on esophageal Th2 inflammation and gene expression are similar to those of topical steroids in PPI nonresponders. These therapies, along with diets, recently have been shown to be potentially interchangeable in two small series.

Summary Proton pump inhibitor-responsive esophageal eosinophilia is an inappropriate disease descriptor, arbitrarily based on a response to a single drug, and should be abandoned. Patients who have esophageal eosinophilia and esophageal symptoms that resolve with PPI therapy have phenotypic, molecular, mechanistic, and therapeutic features indistinguishable from similar patients who do not respond to PPIs. These patients with PPI responsiveness should be considered within the spectrum of EoE.


In the first consensus guidelines for the diagnosis and management of eosinophilic esophagitis (EoE) published in 2007, EoE diagnostic criteria included symptoms of esophageal dysfunction, esophageal eosinophilic infiltration [defined by ≥15 eosinophils per high power field (eos/HPF)], and either absence of response to proton-pump inhibitor (PPI) therapy or normal esophageal acid exposure on pH monitoring.[1] These guidelines suggested that symptomatic patients with esophageal eosinophilia who responded to PPIs or had abnormal acid reflux suffered from gastroesophageal reflux disease (GERD), not EoE. This dichotomous diagnostic criterion assumed that GERD and EoE were mutually exclusive disorder. However, this assumption was counterintuitive, since both diseases commonly affect young males, so the likelihood of their coexistence was a priori high.

In 2011, the first prospective series systematically evaluating PPI therapy in patients who had esophageal eosinophilia with EoE symptoms showed that up to 50% responded to PPIs.[2] Furthermore, clinical, endoscopic and histologic features were indistinguishable among the PPI responders and nonresponders. In disagreement with the 2007 consensus guidelines, the investigators found considerable overlap between GERD (determined by esophageal pH monitoring) and EoE. Among patients with abnormal acid reflux by pH monitoring, 20% did not respond to PPI therapy. Conversely, 33% of patients with normal esophageal pH monitoring results responded to PPIs. This study led to significant changes in subsequent EoE diagnostic guidelines,[3,4] and esophageal pH monitoring was eliminated as a negative diagnostic criterion for EoE.[3] Nevertheless, a response to PPI therapy was still considered sufficient to rule out EoE in 2011[3] and 2013,[4] even though evidence was mounting that PPI responders had virtually the same clinical, endoscopic, histologic, and molecular features as EoE patients who did not respond to PPIs.[5,6]

For these intriguing patients, who looked like EoE patients even though they did not have EoE according to the arbitrary consensus guidelines, the artificial term 'PPI-responsive esophageal eosinophilia' (PPI-REE) was coined. This disease descriptor was arbitrarily based on the response to a given drug, without considering the intrinsic characteristics of the condition. Thus, a dubious, provisional diagnostic category was created with the expectation that future research eventually would clarify the molecular and mechanistic basis of PPI-REE. Over the past 3 years (2014–2016), state-of-the-art research, mostly in adult patients, has confirmed that these patients are likely EoE patients. The evolving concepts on the diagnosis of these patients over the past decade are illustrated in Fig. 1. The aim of this review is to update knowledge on this controversial entity and, through our review of available data, we argue that the artificial and arbitrary term 'PPI-REE' should be discarded.

Figure 1.

Evolving considerations on the relationship between GERD, EoE, and response to PPI therapy over the past decade. EoE, eosinophilic esophagitis; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.