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. Author manuscript; available in PMC: 2016 Jul 1.
Published in final edited form as: Curr Opin Gastroenterol. 2015 Jul;31(4):309–315. doi: 10.1097/MOG.0000000000000185

PPI-responsive esophageal eosinophilia and eosinophilic esophagitis: More similarities than differences

Swathi Eluri 1,2, Evan S Dellon 1,2
PMCID: PMC4586084  NIHMSID: NIHMS723711  PMID: 26039722

Abstract

Purpose of review

To discuss the clinical, endoscopic, and histologic features, pathogenesis, and disease mechanisms of proton pump inhibitor–responsive esophageal eosinophilia (PPI-REE), and to highlight similarities and differences with eosinophilic esophagitis (EoE).

Recent findings

PPI-REE is a condition in which patients have clinical and histologic findings similar to EoE, but achieve complete remission with proton pump inhibitor (PPI) treatment. More than one-third of patients who have esophageal symptoms associated with esophageal eosinophilia respond to PPI treatment. Emerging data elucidating the pathogenesis of PPI-REE have shown that Th2-related inflammatory factors such as IL-13, IL-5, eotaxin-3, and major basic protein (MBP) are elevated in PPI-REE, similar to EoE. PPI-REE also shares a genetic expression signature with EoE that reverses with PPI treatment. Mechanisms proposed to explain the PPI response include an acid-independent, anti-inflammatory action of PPIs and PPI-induced restoration of esophageal barrier function.

Summary

Multiple features of PPI-REE overlap extensively with EoE. This raises the question of whether PPI-REE is merely a subtype of EoE rather than an independent condition. This similarity may have future implications for algorithms informing evaluation and treatment of esophageal eosinophilia.

Keywords: eosinophilic esophagitis, gastroesophageal reflux disease, proton-pump inhibitor-responsive esophageal eosinophilia

Introduction

Eosinophilic esophagitis (EoE) is an immune-mediated clinicopathologic condition that presents with symptoms of esophageal dysfunction, and esophageal eosinophilia with ≥15 eosinophils per high-power field (eos/hpf) in the absence of other known causes (1, 2). Eosinophilic infiltration of the esophagus is not unique to EoE, but is present in gastroesophageal reflux disease (GERD) and a number of other conditions including proton pump inhibitor–responsive esophageal eosinophilia (PPI-REE) (3). Due to the presence of eosinophilia and response to PPI therapy, GERD and PPI-REE have become the most common alternate diagnoses for EoE (2, 4).

PPI-REE is a condition in which patients have clinical and histologic findings suggestive of EoE, but achieve complete remission of symptoms and esophageal eosinophilia with PPI treatment. PPI-REE was first described in 2006 when three patients with esophageal eosinophilia, dysphagia, food impaction, and vomiting were noted to have histologic and symptomatic responses to an 8-week course of PPI treatment (5). At that time, the authors raised the question of whether this clinical response could be attributed to allergic eosinophilic esophagitis or to peptic esophagitis. Since then, PPI-REE has been recognized as a distinct clinical entity, with subsequent studies demonstrating a histologic response to PPIs in 33–74% of patients with symptomatic esophageal eosinophilia (6–15). As a result, both the 2011 and 2013 EoE guidelines state that PPI-REE should be excluded in all patients with esophageal eosinophilia by treating with an 8-week course of any PPI, typically at a dose of 20–40 mg twice a day, followed by endoscopy to assess the histologic response (1, 2).

The well-documented overlap between PPI-REE, GERD, and EoE leads to challenges in differentiating these conditions (16). GERD can cause esophageal eosinophilia that responds to PPI therapy, similar to PPI-REE (7, 17). In addition to acid-peptic damage, cytokine-mediated pathways have been proposed to cause esophageal inflammation in GERD, and some of these pathways may overlap with EoE (18, 19). Therefore, it remains an unresolved question whether PPI-REE is a subtype of GERD, a subtype of EoE, or a different clinical entity altogether. The purpose of this paper is to discuss the clinical, endoscopic, and histologic features, pathogenesis, and disease mechanisms of PPI-REE, and to highlight similarities and differences with EoE.

Clinical Presentation of PPI-REE

Symptomatology and clinical features

The clinical presentation of EoE varies in adults and children, but multiple studies have shown that it is virtually identical to the presentation of PPI-REE (6–9, 20). Children with EoE typically present with upper gastrointestinal manifestations such as abdominal pain, nausea, vomiting, feeding intolerance, and poor growth (21, 22). In adults, common symptoms are solid food dysphagia (4, 23), food impaction (24–26), heartburn, and non-cardiac chest pain (23, 24, 27). Not only are these same presenting symptoms found in PPI-REE, but there is also a strong association with atopic diseases such as asthma and allergies in both conditions (6, 8, 9, 20).

Like EoE, PPI-REE tends to occur predominantly in white males (6, 7, 20, 28). While some studies have suggested that adult patients with PPI-REE might be slightly older than EoE patients, (6) a recent meta-analysis of 10 studies found that the two conditions are essentially indistinguishable clinically (28).

Endoscopic Findings

Esophageal rings, linear furrows, white plaques, and exudates, while not diagnostic (29), are characteristic endoscopic findings of EoE (1, 30). The esophagus can also be narrowed and develop strictures due to long standing fibrosis. In one large, prospective study, patients with PPI-REE had similar endoscopic findings, but were somewhat less likely to have rings, narrowing, furrows, and decreased vascularity than patients with EoE (6). However, these differences were not statistically significant in multivariate analysis, and could not be used to distinguish EoE from PPI-REE. Another study by Moawad et al also failed to show differences in endoscopic findings between PPI-REE and EoE (20).

Histologic Findings

Histologically, EoE is characterized by an esophageal eosinophilic infiltrate with ≥15 eosinophils per high-power field (2). Additional findings include eosinophil degranulation, eosinophil microabscesses, basal layer hyperplasia, elongation of the rete pegs, dilated intracellular spaces (also called spongiosis), and lamina propria fibrosis (4). Like the endoscopic and clinical features, there are no differences in initial eosinophil counts or other associated histopathologic features that distinguish PPI-REE (prior to PPI administration) from EoE (6–8, 20).

In summary, both retrospective and prospective studies of adults and children with esophageal eosinophilia have failed to show significant differences in the clinical, endoscopic, and histologic presentation of PPI-REE and EoE. While small differences in individual features have been noted in some studies, after multivariate analysis, none independently could distinguish EoE from PPI-REE. This lack of clinical discrimination has prompted investigations into alternate diagnostic modalities.

Role of GERD and utility of pH testing as a diagnostic tool for PPI-REE

Given the difficulties in distinguishing PPI-REE from EoE on clinical, endoscopic and histologic grounds, a logical question is whether pH monitoring would have any utility. The presence of intraepithelial eosinophils in esophageal biopsies was proposed as a diagnostic criterion for reflux esophagitis over 30 years ago (31) and, since then, it has been appreciated that GERD can be associated with high levels of esophageal eosinophilia (3). Therefore, one could hypothesize that GERD underlies PPI-REE. There can be a complex relationship between reflux, EoE, and esophageal eosinophilia (17), and the initial guidelines for EoE considered a PPI response to be a marker of GERD (30). While individual patients with PPI-REE might have some features suggestive of GERD (e.g. large hiatal hernia, erosive esophagitis, heartburn-predominant symptoms, older age, lack of atopy, response to PPI), the majority of reported patients with PPI-REE have more of an EoE clinical phenotype than a GERD picture (6, 7).

Several studies examining pH testing in PPI-REE demonstrate that the presence or absence of pathologic esophageal acid exposure does not reliably predict PPI response (7, 8, 11). In a prospective study by Francis et al of 51 subjects with >15 eos/hpf, those with an abnormal pH study were treated with high dose (twice a day) PPI therapy, while those with a normal pH study were treated with topical steroids (11). Approximately two-thirds of the patients had a normal esophageal pH monitoring test, indicating that acid reflux was likely not the cause of esophageal eosinophilia. Among those with abnormal acid reflux, almost 40% did not respond histologically to PPI treatment. Similar results were seen in a retrospective cohort study by Dranove et al, in which 59% of patients with a positive esophageal pH monitoring study did not respond histologically to PPI therapy (8). Therefore, abnormal acid exposure does not account for many cases of PPI-REE, and a positive pH test does not accurately predict the response of esophageal eosinophilia to PPIs.

Normal esophageal pH testing is also a poor predictor of PPI response for patients with esophageal eosinophilia. In a number of studies of patients who had esophageal biopsies with ≥15 eos/hpf and no pathologic acid reflux by esophageal pH monitoring, 18–45% nevertheless responded to PPI therapy (7, 8, 32). This level of PPI response with a normal pH study argues against a GERD or acid-based etiology in many cases. Therefore, existing data do not support pH testing as a useful predictor of PPI response for patients with esophageal eosinophilia.

PPI-REE Pathogenesis

Since PPI-REE is clinically indistinguishable from EoE, and since esophageal acid exposure does not reliably explain the PPI response, could the pathogenesis of PPI-REE be similar to EoE? EoE is an immune mediated condition, where in genetically predisposed individuals, food or environmental antigens trigger a type 2 T-helper (Th2) mediated response though cytokines such as interleukin (IL)-4, IL-5 and IL-13, which stimulate esophageal production of eotaxin-3 (an eosinophil chemoattractant) and subsequent recruitment and activation of eosinophils in the esophageal mucosa (33). Other mediators involved in the pathogenesis of EoE include transforming growth factor-β1, fibroblast growth factor, and thymic stromal lymphopoietin (34–38). Esophageal eotaxin-3 is a key factor promoting eosinophil chemotaxis, activation and subsequent release of intracellular granules such as major basic protein (MBP) (33, 39–41) and other pro-inflammatory mediators (42, 43). Prior investigations showed that MBP and eotaxin-3 were significantly upregulated in the esophageal epithelium of EoE patients compared to GERD controls, and could be used clinically to predict EoE case status (44, 45). Staining mast cells for tryptase has also been successful in distinguishing EoE from GERD (45, 46).

Recent studies have shown that these same markers are also increased in PPI-REE, and while there is a differential expression between EoE and GERD, there is no difference between EoE and PPI-REE (45, 47). In one prospective study of 23 patients with PPI-REE, 50 with EoE, and 123 controls, immunohistologic staining of esophageal biopsies for MBP, eotaxin-3, and mast cell tryptase showed high levels of all three markers in both EoE and PPI-REE (45). After a PPI trial, these markers returned to normal in PPI-REE, but remained elevated in EoE subjects. A similar prospective study by Molina-Infante et al comparing EoE and PPI-REE patients showed no significant differences in the gene expression levels of eotaxin-3 and IL-13 in the entire esophagus, and of IL-5 in the distal esophagus (47). Expression levels of all three cytokines also decreased after PPI therapy in the PPI-REE group. Thus, the existing immunologic data comparing EoE and PPI-REE suggests that similar inflammatory factors may be involved in their pathogenesis.

Genetic expression in PPI-REE

Since EoE and PPI-REE are clinically and histologically indistinguishable, useful molecular biomarkers would be desirable. The EoE diagnostic panel (EDP) is a genetic test comprised of 94 genes that are differentially expressed in EoE, and can reliably identify EoE patients (48). When the EDP was first assessed in PPI-REE (49), the gene expression pattern of the PPI-REE patients before PPI use was very similar to the pattern in EoE, and included key EoE-associated genes for eosinophil chemotaxis (CCL26), mast cell genes (CPA3 and TPSAB2), Th2 inflammatory markers, epithelial barrier genes, and tissue fibrosis markers. Furthermore, this genetic signature in PPI-REE reversed after PPI treatment in a manner similar to what is seen in EoE patients after diet or steroid treatment (48, 50). In contrast, PPIs do not reverse molecular characteristics in EoE.

Although the aforementioned study found largely overlapping transcriptomes between patients with PPI-REE and those with EoE, the investigators did find some significant differences between EoE patients and PPI-REE patients (prior to their PPI trial) in the baseline expression of a cluster of 10 genes (49). One gene, KCNJ2, passed the false detection rate and was investigated further. KCNJ2 was expressed at high levels in the EoE group, but at low levels in normal controls and PPI-REE patients, and could predict PPI-REE versus EoE with a 72% sensitivity and 72% specificity. KCNJ2 encodes the potassium channel Kir2.1, which is abundant in gastrointestinal mucosa and co-localizes with the H1–K1 ATPase/proton pump (51, 52). The role of Kir2.1 in acid secretion may explain the PPI response, and additional studies are underway to assess the clinical utility of this marker. These new findings are provocative and support a potential shared immune mediated pathogenesis between EoE and PPI-REE.

Mechanism of PPI response in PPI-REE

As there may be a shared pathogenesis between EoE and PPI-REE, mechanisms that underlie the PPI response in esophageal eosinophilia have also been recently investigated. Given the relation between GERD and eosinophilia, one hypothesis has been that the PPI response in PPI-REE is through an acid reducing mechanism, treating underlying GERD that is not clinically apparent (53). Even in the absence of symptoms, acid exposure from GERD could cause esophageal epithelial damage, allowing penetration of allergic antigens that trigger an eosinophilic response in the mucosa (17, 54, 55). One prospective study compared barrier integrity in 8 PPI-REE and 8 EoE patients, as measured by dilated intracellular spaces, electrical tissue impedance, and transepithelial electrical resistance and molecule flux (53). The investigators found that, prior to a PPI trial, barrier function was reduced in both PPI-REE and EoE, but was restored only in the PPI-REE group after the PPI trial. Further work is needed, however, to elucidate the mechanisms of this improved barrier function.

Another novel potential mechanism for PPI-REE is based on the anti-inflammatory effects of PPIs (56). Two studies have recently demonstrated reduced Th2-related mediators in EoE cell lines treated with omeprazole (19, 57), similar to findings in a study of a murine lung model of asthma (58). Omeprazole blocked both IL-4- and IL-13-stimulated eotaxin-3 secretion from two EoE squamous cell lines in an experimental system devoid of acid (19). This was a strong demonstration of a proof-of-principle that PPIs could have an anti-inflammatory mechanism in esophageal eosinophilia. Furthermore, these studies showed that the mechanism by which omeprazole prevented cytokine-stimulated eotaxin-3 secretion was by preventing STAT6 from binding to the promoter region of the eotaxin-3 gene (57). These investigators also described a differential PPI effect by esophageal location in clinical biopsy specimens, with more prominent suppression of eotaxin-3 in the proximal esophagus (59). Interestingly, unlike the eotaxin-3 secretion by epithelial cells, eotaxin-3 secretion by fibroblasts is not blocked by PPIs (60), suggesting that there are additional processes contributing to the pathogenesis of EoE and PPI-REE.

A third mechanism, which is just beginning to be studied, addresses differential PPI metabolism as a potential mechanism of PPI response (61). An earlier case series described four children with PPI-REE who lost their PPI responsiveness (i.e. they developed recurrent symptoms and esophageal eosinophilia) despite being maintained on a stable dose of PPI and in the absence of other confounding factors, and who eventually met diagnostic criteria for EoE (10). In a study presented in abstract form by Molina-Infante et al, 72% of 46 PPI-REE patients with long-term follow-up had a sustained PPI response. Eight patients who relapsed with decrease of their PPI dose subsequently responded to increased PPI dosing, and also had a rapid PPI metabolism phenotype on CYP450 enzyme testing (61). While all of these potential mechanisms of PPI response require more study, they show several diverse and acid-independent ways that PPIs can reduce esophageal eosinophilia.

Conclusions

PPI-REE has only been recognized recently, and knowledge about this condition is rapidly evolving. Initially, PPI-REE was thought to have a very close relationship with, or to be frankly a manifestation of GERD. Within this initial framework, GERD and EoE were considered separate conditions, and PPI-REE could overlap with GERD but not with EoE (62, 63). However, the interplay between GERD, EoE, PPI-REE, and esophageal eosinophilia is now known to be complex with significant overlap, and can potentially be re-conceptualized in a number of ways (Figure 1). Newly emerging data suggest that PPI-REE has many similarities to EoE. and is in fact indistinguishable from EoE in its clinical, endoscopic, and histologic presentation. Mechanistically, the tissue expression of inflammatory markers such as MBP, eotaxin-3, and tryptase are the same as in EoE. Both conditions share a very similar genetic expression profile, but there is the possibility that selected genes that are differentially expressed in PPI-REE and EoE may predict a PPI response. While there is accumulating evidence that suggests PPI-REE may be a sub-type of EoE, there needs to be further elucidation of the disease’s natural history, immune-mediated basis, optimal dosing of PPI regimens, and the long term efficacy of PPI use. More importantly, characterizing PPI-REE as a sub-type of EoE could have clinical implications in terms of disease management, which may involve PPIs as the first line treatment for all EoE patients, and only moving to steroids and dietary therapy in the non-responders. While the data do not yet fully support such a definitive paradigm shift, the rapid evolution of EoE definitions and change in the understanding of PPI-REE implies that revisions to diagnosis and management algorithms will likely occur in the future.

Figure 1.

Figure 1

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Rethinking the complex relation between GERD, EoE, PPI-REE, and esophageal eosinophilia for the future. The pink circle represents all cases of esophageal eosinophilia. Some may be due to other, non-esophageal causes. However, the majority are likely due to EoE (red circle). Given the similarities between EoE and PPI-REE, it is possible that the majority of PPI-REE cases are due to EoE, and these EoE patients respond to PPIs as a first-line agent (orange circle). The impact of GERD can be seen as well. Many GERD cases do not have significant esophageal eosinophilia (blue circle). There are some cases where esophageal eosinophilia is caused by GERD and responds to a PPI (yellow semi-circle), some cases where GERD and EoE overlap and where the eosinophilia is due to EoE (light blue area), and some cases where there is GERD and esophageal eosinophilia, but not PPI-response (purple area).

Key points.

  • PPI-REE is common in patients with esophageal symptoms and eosinophilia (≥15 eos/hpf), with response to PPI treatment observed in more than one third of such patients.

  • Currently, all patients with esophageal eosinophilia and EoE symptoms should have a PPI trial to identify PPI-REE.

  • There are no significant clinical, histological and endoscopic characteristics that distinguish PPI-REE from EoE.

  • Based on inflammatory, molecular, and genetic markers, both disease conditions appear to share a similar pathogenesis.

  • In the future, PPI-REE may be re-defined as a subtype of EoE, but additional data are required for this paradigm shift.

Acknowledgements

This work is funded, in part, by NIH awards T32DK007634 (SE), K23DK090073 (ESD), R01DK101856 (ESD), and U54AI117804 (Consortium of Eosinophilic Gastrointestinal Disease Researchers [CEGIR]).

Dr. Dellon receives research funding from Meritage Pharma and Receptos, and is a consultant for Aptalis, Novartis, Receptos, and Regeneron, and has received an educational grant from Diagnovus.

None.

Abbreviations

EoE

eosinophilic esophagitis

GERD

gastroesophageal reflux disease

MBP

major basic protein

PPI

proton pump inhibitor

PPI-REE

proton pump inhibitor-responsive esophageal eosinophilia

Footnotes

Conflict of Interest:

Eluri – none

Dellon – none pertaining to this article.

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