Symptoms, Endoscopy, and Histology: Deciphering Diagnostics for EoE

With the incidence and prevalence of eosinophilic esophagitis (EoE) on the rise, the importance of timely diagnosis, histopathologic characterization and standardization of endoscopic assessment is crucial.

In updated clinical guidelines published in the American Journal of Gastroenterology, Evan S. Dellon at the Center for Esophageal Diseases and Swallowing, Department of Medicine, University of North Carolina School of Medicine, and the Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology Swallowing, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, and colleagues noted that EoE is diagnosed with 3 primary criteria:

• A patient presents with symptoms of esophageal dysfunction (eg dysphagia, food bolus impaction, adaptive behaviors for adults; poor growth, failure to thrive, food refusal, feeding intolerance for infants; abdominal pain, vomiting, heartburn for children).
• At least 15 eosinophils per high power field (15 eos/hpf) on esophageal biopsy.
• Evaluation of non-EoE conditions that may contribute to EoE.

But not all biopsies consistently detect peak eosinophil count when assessment of endoscopic features isn’t standardized.

"EoE is a patchy disease histologically. Previous studies have shown marked variability in eosinophil counts both between and within biopsies, with some microscope fields appearing normal and others appearing highly inflamed. Therefore, it is possible to miss the diagnosis if too few biopsies are obtained," Dellon and colleagues noted.

"In order to address an unmet need, the validated Endoscopic Reference System (EREFS; edema, rings, exudates, furrows, and strictures) was developed to describe endoscopic features of EoE," Alain M. Schoepfer, MD, at the Department of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland, and colleagues wrote in their 2023 review published in Immunology and Allergy Clinics of North America.

EREFS was codified by the seminal work of Ikuro Hirano MD, at the Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago.

Using the EREFS scoring system to standardize endoscopy and find ideal biopsy locations has been shown to considerably improve detection.

Schoepfer and colleagues echoed Dellon and colleagues by noting in early studies (Mackenzie et al., Liacouras et al.), there was "considerable variability" in sensitivity to detect endoscopic features to diagnose EoE, and it may be due (in part) to the experience level of the endoscopist. However, "several randomized controlled trials, in which endoscopic features were prospectively assessed, showed EREFS criteria to have sensitivities over 90% to diagnose EoE."

So, how do clinicians identify and score EREFS?

Schoepfer and colleagues described EREFS scoring, and break it down by the letter:

• Edema: Evaluation of mucosal pallor and vascular visibility, where 0 indicates distinct, visible vascular markings and 1 indicates absent or obscured vascularity.
• Rings: Assessment of concentric circular ridges, where 0 is none, 1 is mild or transient, 2 is distinct and fixed, and 3 is severe enough to impede the passage of a standard endoscope.
• Exudates: White plaques on the mucosal tissue that indicate high eosinophil density; scored 0-2 where 0 is no exudates, 1 is less than 10% of esophageal surface area, and 2 is more than 10% of the surface area.
• Furrows: Distinct vertical lines, folding of the edematous mucosa; scored 0 (absent) or 1 (present).
• Stricture: Abnormal narrowing of the esophagus; Scored 0 (absent) or 1 (present).

The authors also describe minor features graded 1 or 0 as "crepe paper esophagus," which they define as mucosal fragility or laceration after passage of the diagnostic endoscope but not after esophageal dilation. They additionally noted that in clinical practice, the EREFS with the highest scores should be the targets for assessment of the entire esophagus.

Schoepfer and colleagues offer a few modifications to EREFS to avoid grading confusion. They suggested that "E" should remain for edema, and "Ex" should be used for exudations.

"A simple way to integrate EREFS into daily clinical practice is to annotate the letters of the acronym followed by the grading. As such, the grading E1R2Ex1F1S1 would be decoded as edema present, rings moderate, exudates mild, furrows present, and stricture present," the authors explained.

The authors additionally suggested to remove simple integer grading for exudation and replace it with the percentage coverage (eg Ex8% or Ex50%).

"For example, using the aforementioned example, E1R2Ex40%F1S1 would describe an esophagus in which 40% of the mucosal surface is affected by white exudates," Schoepfer and co-authors added.

They noted that in 2022, The American Society for Gastrointestinal Endoscopy published a consensus paper that recommended EREFS should be routine for the assessment of EoE activity, and they outlined 4 major arguments to support the recommendation:

• To include endoscopic activity as a reliable physician-reported endpoint to improve the relatively low correlation between symptoms and histopathologic assessments which are otherwise poorly correlated. Particularly, they describe that variability in presentation for adults and children can be underestimated with histopathologic assessment and symptom presentation alone. This is most true for younger and pediatric patients where correlating symptoms to histology is most difficult.
• Current histopathologic assessments struggle with taking into account the "patchiness" of peak eosinophil numbers, where routine EREFS could monitor with a more "global view of inflammatory and fibrotic esophageal alterations than the histopathologic assessment that is often limited to the assessment of inflammatory changes," they wrote. For example, stricture can predict future food bolus impaction, therefore indicating a need for esophageal dilation.
• When it comes to interobserver agreement of EREFS features, EREFS is found to be easy to learn and is not complicated to include in routine practice. "Furthermore, interobserver and intraobserver agreement was not substantially different between expert and trainee endoscopists," the authors noted. This offers an opportunity to guide less experienced endoscopists into a focused point-by-point assessment that does not require lengthy descriptions.
• "The usefulness of using EREFS as an objective therapeutic endpoint is highlighted by the low rate of change in EREFS score seen within placebo arms. Improvement of inflammatory endoscopic features several weeks after the introduction of an anti-eosinophil treatment [eg, fluticasone; corticosteroid] provides the endoscopist with important information regarding the effectiveness of the treatment beyond that achieved by histology," Schoepfer and colleagues wrote.

However, the authors also noted the limitations of the EREFS grading system, noting that the system identifies the majority of patients with EoE, some features of EoE may not be pathognomonic and could be found in other esophageal conditions.

"Thus, the EREFS grading system should be used together with, and not in place of histologic findings to accurately assess physiologic disease activity in EoE. The role of endoscopy in the follow-up of EoE patients has also been highlighted in a recent consensus paper from an international expert group," the authors concluded.

In their wrap-up, the authors noted the following 5 clinical care points:

• "Endoscopic features of EoE are edema, rings, exudates, furrows, and strictures (EREFS)."
• "Endoscopic activity of EoE should be graded using EREFS at every endoscopy."
• "Endoscopic response to therapy should be graded using the EREFS score (total score range: 0–8 points)."
• "The EREFS applied to the highest scoring area should be used to assess the entire esophagus."
• "Endoscopic activity should be assessed in conjunction with histologic activity to gain insights into biologic activity of EoE."

Schoepfer received consulting fees and/or speaker fees and/or research grants from Avir Pharma, Inc., Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS Corp., Dr Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestle´ S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals, Inc. E. Safroneeva reports (i) consulting fees from Avir Pharma, Inc., Aptalis Pharma, Inc., Celgene Corp., Novartis, AG, and Regeneron Pharmaceuticals Inc; (ii) being an employee of Tillotts Pharma AG. Work supported by a grant from the Swiss National Science Foundation (32003B_204751/1 to A.M. Schoepfer) and the Swiss EoE foundation (to A.M. Schoepfer). All authors contributed equally to this article.

Dellon was the guarantor of the ACG guidelines and received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda; was a consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/ Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/ Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; and received educational grants from Allakos, Aqilion, Holoclara, and Invea.

Schoeper AM, et al "Endoscopic features of EoE" Immunol Allergy Clin North Am 2024;44(2):197-204. DOI: 10.1016/j.iac.2023.12.007.

Dellon ES, et al "ACG clinical guideline: diagnosis and management of EoE" Am J Gastroenterol 2025;120:31-59. DOI: 10.14309/ajg.0000000000003194.