Development and Validation of a Symptom-Based Activity Index for Adults With Eosinophilic Esophagitis

doi:10.1053/j.gastro.2014.08.028

Gastroenterology

Volume 147, Issue 6, December 2014, Pages 1255-1266.e21

https://doi.org/10.1053/j.gastro.2014.08.028 Get rights and content

Background & Aims

Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE) and to provide end points for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patient assessments of disease severity. We also evaluated relationships between patient assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings.

Methods

We collected information from 186 patients with EoE in Switzerland and the United States (69.4% male; median age, 43 y) via surveys (n = 135), focus groups (n = 27), and semistructured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patient assessment of EoE severity. The PRO instrument was used prospectively in 153 adult patients with EoE (72.5% male; median age, 38 y), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 y).

Results

Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patient assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity (range, 0–10) and PRO score (range, 0–8.52) was 0.15.

Conclusions

We developed and validated an EoE scoring system based on 7 PRO items that assess symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263.

Section snippets

Study Overview

The adult Eosinophilic Esophagitis Activity Index (EEsAI) study was performed in 3 phases, which are illustrated in Supplementary Figure 1. During the first phase, a comprehensive list of relevant items to be potentially incorporated into the PRO, endoscopy, histology, and blood biomarker instruments was generated. During the second phase, the prototypes of standardized instruments were evaluated in one patient group (evaluation group). Data derived from the PRO instrument were used to derive a

Patient Characteristics

A total of 153 and 120 adult EoE patients were recruited for the evaluation and validation phases, respectively. The characteristics of these patients are shown in Table 1. Age at inclusion, sex, ethnicity, and education level were comparable between the 2 groups. When compared with the patients in the evaluation group, the patients in the validation group were more likely to have EoE symptom onset more than 5 years before inclusion in the study (67.2% vs 52.9%), to experience self-reported

Discussion

Eosinophilic esophagitis is a young disease, and, to date, no validated PRO instruments reliably assessing disease activity have been approved by the regulatory authorities in the United States and Europe.

In this article, we describe the process of the development and validation of the adult EEsAI PRO instrument that assesses EoE symptom severity. We developed the EEsAI PRO instrument according to FDA guidelines.¹⁶ Patient surveys, focus groups, and semistructured interviews were used to gain

Acknowledgments

The authors would like to thank the following members of the FDA, Maryland, for their guidance to develop the PRO instrument: Office of New Drugs, including the Division of Gastroenterology and Inborn Errors Products: Andrew E. Mulberg, MD, and Robert Fiorentino, MD; Office of New Drugs, Rare Diseases: Anne R. Pariser, MD, MPH; and the Study Endpoints and Labeling Division: Elektra J. Papadopoulos MD, MPH, and Laurie B. Burke, RPh, MPH. The authors also would like to acknowledge the following

References (33)

G.A. Prasad et al.
Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota
Clin Gastroenterol Hepatol
(2009)
A. Straumann et al.
Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years
Gastroenterology
(2003)
A. Straumann et al.
Fragility of the esophageal mucosa: a pathognomonic endoscopic sign of primary eosinophilic esophagitis?
Gastrointest Endosc
(2003)
R. Fiorentino et al.
Cross-sector sponsorship of research in eosinophilic esophagitis: a collaborative model for rational drug development in rare diseases
J Allergy Clin Immunol
(2012)
P. Erickson et al.
A concept taxonomy and an instrument hierarchy: tools for establishing and evaluating the conceptual framework of a patient-reported outcome (PRO) instrument as applied to product labeling claims
Value Health
(2009)
D.L. Patrick et al.
Patient-reported outcomes to support medical product labeling claims: FDA perspective
Value Health
(2007)
A. Bottomley et al.
Patient-reported outcomes: assessment and current perspectives of the guidelines of the Food and Drug Administration and the reflection paper of the European Medicines Agency
Eur J Cancer
(2009)
A. Straumann et al.
Eosinophilic esophagitis: analysis of food impaction and perforation in 251 adolescent and adult patients
Clin Gastroenterol Hepatol
(2008)
M.A. Kwiatek et al.
Mechanical properties of the esophagus in eosinophilic esophagitis
Gastroenterology
(2011)
S.E. Attwood et al.
Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome
Dig Dis Sci
(1993)

A. Straumann et al.

Idiopathic eosinophilic esophagitis: a frequently overlooked disease with typical clinical aspects and discrete endoscopic findings

Schweiz Med Wochenschr

(1994)

C.A. Liacouras et al.

Eosinophilic esophagitis: updated consensus recommendations for children and adults

J Allergy Clin Immunol

(2011)

J.M. Spergel et al.

Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States

J Pediatr Gastroenterol Nutr

(2011)

P. Hruz et al.

Escalating incidence of eosinophilic esophagitis: a 20-year prospective, population-based study in Olten County, Switzerland

J Allergy Clin Immunol

(2011)

E.S. Dellon et al.

Prevalence of eosinophilic esophagitis in the United States

Clin Gastroenterol Hepatol

(2014)

R.J. Noel et al.

Eosinophilic esophagitis

N Engl J Med

(2004)

Cited by (211)

Clinical Evaluation of the Adult with Eosinophilic Esophagitis
2024, Immunology and Allergy Clinics of North America
Eosinophilic Esophagitis: Clinical Pearls for Primary Care Providers and Gastroenterologists
2024, Mayo Clinic Proceedings
Eosinophilic esophagitis (EoE) is a chronic and progressive immune-mediated esophageal disorder. Given its increasing incidence, it is now a leading cause of dysphagia and food impaction in the United States. Eosinophilic esophagitis is most common in adult White men and has a high concurrence rate with other atopic conditions like allergic rhinitis, bronchial asthma, and eczema. The initial presentation includes symptoms of esophageal dysfunction, classically solid-food dysphagia. Without treatment, inflammation can progress to fibrosis with the formation of strictures, leading to complications such as food impaction. It is a clinicopathologic disease requiring compatible clinical symptoms and histologic evidence of eosinophil-predominant inflammation of the esophageal epithelium with more than 15 eosinophils per high-power field. The mainstay of management includes the 3 d’s (diet, drugs, dilation): dietary modifications to eliminate trigger food groups; medications including proton pump inhibitors, swallowed topical glucocorticoids, and dupilumab; and esophageal dilation to manage strictures. Various elimination diets have been found to be effective, including 1-food, 2-food, 4-food, and 6-food elimination diets. Dupilumab, a humanized monoclonal antibody that regulates interleukin 4 and 13 signaling pathways, has shown promising results in clinical trials and was approved by the Food and Drug Administration in 2022 for use in EoE. Symptom alleviation, although important, is not the sole end point of treatment in EoE as persistent inflammation, even in the absence of symptoms, can lead to esophageal fibrosis and stricture formation over time. The chronic nature and high recurrence rates of EoE warrant maintenance therapy in patients with EoE after initial remission is achieved.
Composite score of physiomechanical esophageal function using functional lumen imaging probe panometry in eosinophilic esophagitis
2024, Gastrointestinal Endoscopy
The evaluation provided by functional lumen imaging probe (FLIP) panometry includes esophageal distensibility/compliance (mechanics) of the esophageal body and esophagogastric junction (EGJ) and esophageal motility (secondary peristalsis). We developed a composite score using these parameters to characterize physiomechanical function in patients with eosinophilic esophagitis (EoE).
Two hundred fifteen adult patients with EoE who completed FLIP panometry during sedated endoscopy with esophageal biopsy sampling were included. FLIP metrics of esophageal body Compliance, Contractile response, Distensibility plateau, and maximum EGJ Diameter (C2D2) were scored as 0 for normal versus 1 or 2 for increasing degree of abnormality. Scores were summed to calculate the composite C2D2 score.
The C2D2 score had a significant positive correlation with mucosal eosinophil count (ρ = .241) and total Endoscopic EoE Reference Score (ρ = .467). Among 46 patients off treatment at the baseline evaluation, future proton pump inhibitor (PPI) responders (ie, achieved mucosal eosinophil count <15 per high-powered field after PPI treatment) had lower C2D2 scores than PPI nonresponders (median, 2 [interquartile range, 1-3] vs 4 [interquartile range, 2-6], respectively; P = .003). A regression model (that controlled for age, sex, and baseline eosinophil count) showed a C2D2 score ≤3 had an odds ratio of 14.5 (95% confidence interval, 2.6-85) to predict future PPI response. However, total Endoscopic EoE Reference Scores (P = .142) and baseline eosinophil count (P = .480) did not differ between PPI responders and PPI nonresponders.
This composite score of FLIP panometry metrics, the C2D2 score, may facilitate characterizing physiomechanical function in EoE and serve as an objective outcome measure.
Eosinophilic Esophagitis: What the Otolaryngologist Needs to Know
2024, Otolaryngologic Clinics of North America
The Index of Severity for Eosinophilic Esophagitis (I-SEE) Reflects Longitudinal Clinicopathologic Changes in Children
2024, Clinical Gastroenterology and Hepatology
The Index of Severity for Eosinophilic Esophagitis (I-SEE) was recently developed. We aimed to understand I-SEE scores in a longitudinal pediatric cohort and to determine the relationship between I-SEE and clinical features in children.
We performed a retrospective analysis on a prospectively enrolled cohort of children at a single center who were treated as part of routine clinical care. I-SEE was calculated at the diagnostic and follow-up endoscopies over a mean of 6.6 years. Scoring was 0 for inactive, 1–6 for mild, 7–14 for moderate, and ≥15 for severe eosinophilic esophagitis (EoE). We analyzed clinical, endoscopic, and histologic features at each instance. Symptoms were analyzed at the baseline, first follow-up, and last endoscopic instance.
Of 67 children who met study criteria of at least 3 endoscopies over at least 2 years of follow-up time, 43%, 36%, and 21% had mild, moderate, and severe I-SEE scores at baseline, respectively. Between the first and second endoscopic instances, there was a decrease in the group mean I-SEE from 9.7 ± 7.2 to 6.1 ± 5.9 (P < .001). By the last instance, the overall I-SEE score dropped to 3.9 (P < .001). Body mass index <5% and poor feeding were more common in the children with severe I-SEE scores at baseline, and both improved by the last instance. Fibrosis was improved by the last instance biopsy (P < .01).
I-SEE is a responsive severity metric in children treated long term during routine clinical care. Baseline low body mass index and poor feeding were more common in children with severe I-SEE scores.
The 1st EoETALY Consensus on the Diagnosis and Management of Eosinophilic Esophagitis–Current Treatment and Monitoring
2024, Digestive and Liver Disease
The present document constitutes Part 2 of the EoETALY Consensus Statements guideline on the diagnosis and management of eosinophilic esophagitis (EoE) developed by experts in the field of EoE across Italy (i.e., EoETALY Consensus Group). Part 1 was published as a different document, and included three chapters discussing 1) definition, epidemiology, and pathogenesis; 2) clinical presentation and natural history and 3) diagnosis of EoE. The present work provides guidelines on the management of EoE in two final chapters: 4) treatment and 5) monitoring and follow-up, and also includes considerations on knowledge gaps and a proposed research agenda for the coming years. The guideline was developed through a Delphi process, with grading of the strength and quality of the evidence of the recommendations performed according to accepted GRADE criteria.This document has received the endorsement of three Italian national societies including the Italian Society of Gastroenterology (SIGE), the Italian Society of Neurogastroenterology and Motility (SINGEM), and the Italian Society of Allergology, Asthma, and Clinical Immunology (SIAAIC). The guidelines also involved the contribution of members of ESEO Italia, the Italian Association of Families Against EoE.

View all citing articles on Scopus

: Author names in bold designate shared co-first authors

: Conflicts of interest Alain Schoepfer has received research grants from AstraZeneca AG, Aptalis Pharma, Inc, Dr Falk Pharma GmbH, Glaxo Smith Kline, plc, Nestlé SA, and Novartis; he received consulting fees from Aptalis Pharma, Inc, and Dr Falk Pharma, GmbH. Alex Straumann has received research grants from AstraZeneca AG, Aptalis Pharma, Inc, Dr Falk Pharma GmbH, Glaxo Smith Kline, plc, Nestlé SA, Novartis and Regeneron Pharmaceuticals, Inc; he received consulting fees from Actelion Pharmaceuticals Ltd, Bühlmann Laboratories AG, Dr Falk Pharma GmbH, Genentech, Inc, Glaxo Smith Kline, plc, Meritage Pharma, Inc, Merck & Co, Inc, Nestle SA, Novartis AG, Oxagen, Ltd, Pfizer, Inc, Receptos, Inc, Regeneron Pharmaceuticals, Inc; he also received speaker fees from Takeda Pharmaceutical Company, Ltd; Radoslaw Panczak has received consulting fees from Aptalis Pharma, Inc; Claudia Kuehni has received research grants from AstraZeneca AG, Aptalis Pharma, Inc, Dr Falk Pharma GmbH, Glaxo Smith Kline, plc, and Nestlé SA; Yvonne Romero has collaborated on projects supported by Aptalis Pharma, Inc, and Meritage Pharma, Inc, and has received royalties for commercial use of the MDQ-30; Ikuo Hirano has received research grants from Meritage Pharma, Inc, and consulting fees from Aptalis Pharma, Inc, Meritage Pharma, Inc, and Receptos, Inc; Jeffrey Alexander has received consulting fees from Meritage Pharma, Inc, and Aptalis Pharma, Inc, and research grant from Merck & Co, Inc; he has received royalties for commercial use of the MDQ-30, and also has a financial interest in Meritage Pharma, Inc; Glenn Furuta has received consulting fees from Pfizer, Inc, Meritage Pharma, Inc, Knopp, and Biosciences, LLC, and has received royalties from UpToDate, Inc, and is also a founder of EnteroTrack, LLC; Evan Dellon has received research grants from AstraZeneca, AG, and Meritage Pharma, Inc, he has received consulting fees from Aptalis Pharma, Inc, Novartis, Receptos, Inc, and Regeneron Pharmaceuticals, Inc; John Leung has received research grants from Meritage Pharma, Inc; Margaret Collins has received consulting fees from Aptalis Pharma, Inc, Biogen Idec, Meritage Pharma, Inc, Novartis, and Receptos, Inc; Sandeep Gupta has received consulting fees from QOL, Receptos, Inc, and Meritage Pharma, Inc, and speaker fees from Abbott Laboratories and Nestlé SA. Seema Aceves is a co-inventor of oral viscous budesonide (patent held by University of California, San Diego), and also has received royalties for oral viscous budesonide from Meritage Pharma, Inc, owns stocks in Meritage Pharma, Inc, and has received consulting fees from Receptos, Inc, and Regeneron Pharmaceuticals, Inc; Felicity Enders receives royalties for commercial use of the MDQ-30; Marcel Zwahlen has received research grants from AstraZeneca AG, Aptalis Pharma, Inc, Dr Falk Pharma GmbH, Glaxo Smith Kline, plc, and Nestlé SA; and Ekaterina Safroneeva has received consulting fees from Aptalis Pharma, Inc, and Novartis. The remaining authors disclose no conflicts.

: Funding Supported by a grant from the Swiss National Science Foundation (32003B_135665/1), AstraZeneca AG, Aptalis, Dr Falk Pharma GmbH, Glaxo Smith Kline, plc (MEE114518), Nestlé SA, Receptos, Inc, and The International Gastrointestinal Eosinophil ResearcherS (A.M.S., A.S., C.E.K., and M.Z.). Also supported by a grant from the National Institute of Health (1K24DK100303 to G.T.F.).

^∗: Authors share co-first authorship.

View full text

Original ResearchFull Report: Clinical—Alimentary TractDevelopment and Validation of a Symptom-Based Activity Index for Adults With Eosinophilic Esophagitis

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Overview

Patient Characteristics

Discussion

Acknowledgments

Clin Gastroenterol Hepatol

Gastroenterology

Gastrointest Endosc

J Allergy Clin Immunol

Value Health

Value Health

Eur J Cancer

Clin Gastroenterol Hepatol

Gastroenterology

Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome

Dig Dis Sci

Idiopathic eosinophilic esophagitis: a frequently overlooked disease with typical clinical aspects and discrete endoscopic findings

Schweiz Med Wochenschr

Eosinophilic esophagitis: updated consensus recommendations for children and adults

J Allergy Clin Immunol

Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States

J Pediatr Gastroenterol Nutr

Escalating incidence of eosinophilic esophagitis: a 20-year prospective, population-based study in Olten County, Switzerland

J Allergy Clin Immunol

Prevalence of eosinophilic esophagitis in the United States

Clin Gastroenterol Hepatol

Eosinophilic esophagitis

N Engl J Med

Original Research
Full Report: Clinical—Alimentary Tract
Development and Validation of a Symptom-Based Activity Index for Adults With Eosinophilic Esophagitis