Summary of the updated international consensus diagnostic criteria for eosinophilic esophagitis: AGREE conference
Introduction
Eosinophilic esophagitis (EoE) is a global health condition that has steady increased during the last few decades and is now reported on all continents, with an estimated incidence of 4 per 100,000 population. Diagnostic guidelines on EoE were published in 2007 and updated in 2011.1., 2. EoE is defined as a clinicopathologic condition that is likely immune or antigen driven and characterized clinically by symptoms of esophageal dysfunction and histologically by 15 eosinophils per high-power field (eos/hpf) or more. In the initial guidelines, inflammation related to gastroesophageal reflux disease (GERD) needed to be ruled out as an underlying cause, and expert consensus determined that the best approach would be to use either high-dose proton pump inhibitor (PPI) treatment or pH monitoring. EoE and GERD were believed to be mutually exclusive disorders for which response to a PPI trial or pathologic pH exposure was consistent with GERD and nonresponse and normal pH monitoring confirmed EoE. However, multiple investigators observed that a large proportion of patients with clinical symptoms suggestive of EoE and esophageal eosinophilia (≥15 eos/hpf) responded to treatment with a high-dose PPI.3 Even in these reports, there is heterogeneity and inconsistency of the definition of high-dose PPI. Because of this, diagnostic guidelines published in 2011, 2013, and 2014 defined a new condition termed PPI-responsive esophageal eosinophilia (PPI-REE).2 Lack of response to a PPI trial confirmed the diagnosis of EoE, and response was suggestive of GERD or PPI-REE.
An evolving body of research suggested that EoE and GERD were not mutually exclusive and instead had a complex relationship. In addition, multiple retrospective and prospective studies found that esophageal eosinophilia in patients with symptoms and endoscopic signs suggestive of EoE can respond to PPI therapy in both children and adults at a rate of 28% to 82% (summarized by Dellon et al3). In a meta-analysis by Lucendo and colleagues4 that assessed PPIs for treatment of symptomatic esophageal eosinophilia, the pooled histologic response to PPI was approximately 50%, although heterogeneity was high (I2 = 66%). Therefore, an estimated 50% of the patients with esophageal eosinophilia respond to a PPI, and in those who do not respond to a PPI, almost all (>90%) respond to an elemental diet. However, how many patients who respond to a PPI also respond to diet is an unanswered and important question (Fig 1).
In addition, similar studies examined the clinical, endoscopic, and histologic features at baseline (before a PPI trial) of EoE and PPI-REE cases and found that few, if any, of these factors that could distinguish the two.5., 6. However, a recent study7 found an increase in IgE-mediated food allergy in an EoE population compared with PPI-REE. RNA expression profiles were largely similar between the 2 conditions (and distinct from GERD), although some differences were particularly related to a potassium channel in PPI-REE.8., 9. Finally, 2 case reports have described individuals who respond to both diet and PPI.10., 11.
Potential non–acid-mediated anti-inflammatory mechanisms of PPIs were identified.12., 13., 14. For example, PPIs inhibit the expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, an adhesion molecule recognized by ligands on the eosinophil cell surface.15 PPIs also block the interleukin 13 and interleukin 4 stimulated increase in eotaxin-3 messenger RNA expression and protein secretion12 via STAT6 (signal transducer and activator of transcription 6) binding to the eotaxin-3 promoter.13 Finally, PPIs may improve the epithelial barrier function in the esophagus.16., 17.
Overall, these findings raised an important question of whether PPI-REE is a subset of EoE in both children and adults. A new European EoE guideline, published in 2017,18 suggested that PPI-REE and EoE were on the same spectrum and that PPIs could be considered a treatment for EoE. To develop an international consensus, the AGREE (A Working Group on PPI-REE) Conference was held on May 6, 2017, in Chicago, Illinois. The full report is published in Gastroenterology and the following are highlights of the report.
Section snippets
New Diagnostic Criteria
EoE is suspected on a clinical basis with chronic symptoms of esophageal dysfunction (dysphagia, food impaction, food refusal, failure to progress with food introduction, heartburn, regurgitation, vomiting, chest pain, odynophagia, abdominal pain, and failure to thrive, among others). The updated diagnostic algorithm for EoE is shown in Figure 2 based on the diagnostic criteria listed in Table 1.
When endoscopy is performed, the esophagus should be examined for features of EoE (including
Initial Treatment and Follow-up After EoE Confirmation
It is beyond the scope of this article to provide comprehensive recommendations for the treatment of EoE.18., 22. To date, no prospective, double-blind, randomized trial has compared the efficacies of steroids to PPI or diet to PPI. However, because of low cost, good safety profile, convenience, and a large body of literature describing response rates in patients with esophageal eosinophilia, a PPI should be considered as a potential initial treatment (especially if it has not been used
Conclusion
The new proposed diagnostic criteria are an international collaboration of pediatric and adult gastroenterologists, allergist-immunologists, pathologists, and researchers. The new criteria allow some flexibility because the clinical presentation and treatments can vary for patients and practitioners. The criteria allow for gastroenterologists to diagnose EoE without a PPI trial and also allow pediatricians to use PPIs to assess abdominal pain related to GERD without diagnosing EoE. These new
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Disclosures: Dr Spergel reported working as a consultant for Regeneron, DBV Technology, and Kaleo; receiving grants from DBV Technology, Aimmune Therapeutics, and Food Allergy Research Education; and receiving royalities from UpToDate Dr Dellon reported working as a consultant for Adare, Allakos, Alivio, Banner, Celgene/Receptos, Enumeral, GSK, Regeneron, and Shire; receiving research funding from Adare, Celgene/Receptos, Miraca, Meritage, Nutricia, Regeneron, and Shire; and receiving educational grants from Banner and Holoclara. Dr Liacouras reported working as a consultant for Shire, Adare, Abbott Nutrition, Receptos, and TEVA. Dr Hirano reported working as a consultant for Adare and Allakos. Dr Molina-Infante reported receiving research funding and working as a consultant for Dr. Falk Pharma. Dr Furuta reported being a founder of EnteroTrack, working as a consultant for Shire, and receiving royalties from UpToDate.
Funding Sources: This study was funded by the International Gastrointestinal Eosinophilic Diseases Researchers; the David and Denise Bunning Family; grant U54AI117804 (Consortium of Eosinophilic Gastrointestinal Disease Researchers), which is part of the Rare Disease Clinical Research Network, an initiative of the Office of Rare Disease Research, National Center for Advancing Translational Sciences, and is funded through collaboration of National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, and patient advocacy groups, including American Partnership for Eosinophilic Disorders, Campaign Urging Research for Eosinophilic Disease, and Eosinophilic Family Coalition (Drs. Spergel, Furuta, Liacouras, Dellon and Hirano); and grant K24DK100303 from the National Institutes of Health (Dr. Furuta).