Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS): An International Multidisciplinary Consensus

Abstract

There has been tremendous interest in developing eosinophilic esophagitis (EoE)–specific pharmacotherapies,1de Rooij W.E. Dellon E.S. Parker C.E. et al.Pharmacotherapies for the treatment of eosinophilic esophagitis: state of the art review.Drugs. 2019; 79: 1419-1434Crossref PubMed Scopus (24) Google Scholar and more than 50 active or enrolling interventional studies are currently registered on ClinicalTrials.gov. Recent positive results from phase 3 trials of dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha, budesonide orodispersible tablets as both induction and maintenance therapy, and budesonide oral suspension, have inspired even greater enthusiasm for drug development in this field.2Lucendo A.J. Miehlke S. Schlag C. et al.Efficacy of budesonide orodispersible tablets as induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial.Gastroenterology. 2019; 157: 74-86.e15Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 3Straumann A. Lucendo A.J. Miehlke S. et al.Budesonide orodispersible tablets maintain remission in a randomized, placebo-controlled trial of patients with eosinophilic esophagitis.Gastroenterology. 2020; 159: 1672-1685.e5Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 4Hirano I. Collins M.H. Katzka D.A. et al.Efficacy of budesonide oral suspension for eosinophilic esophagitis in adolescents and adults: results from a phase 3, randomized, placebo-controlled trial.Am J Gastroenterol. 2019; 114: S205-S206Crossref Google Scholar, 5Hirano I. Dellon E.S. Hamilton J.D. et al.Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.Gastroenterology. 2020; 158: 111-122.e10Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar Despite these breakthroughs, efficient drug development in EoE has been hampered by the lack of standardized outcome measures that can be used in both registrational trials to support labeling claims, and in observational studies to answer practice-based questions. Agreement on the most appropriate end points for use in clinical studies has not been reached, and significant heterogeneity exists in the outcome measures that are reported.6Ma C. van Rhijn B.D. Jairath V. et al.Heterogeneity in clinical, endoscopic, and histologic outcome measures and placebo response rates in clinical trials of eosinophilic esophagitis: a systematic review.Clin Gastroenterol Hepatol. 2018; 16: 1714-1729.e3Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Given the lack of consensus and the increasing scrutiny of outcome measures in clinical trials of EoE, developing a core outcome set (COS) is a research priority. A COS is a consensus-derived minimum set of outcomes that should be measured and reported in all trials in a given therapeutic area.7Williamson P.R. Altman D.G. Bagley H. et al.The COMET Handbook: version 1.0.Trials. 2017; 18: 280Crossref PubMed Scopus (847) Google Scholar Using a COS to inform study design and choose end points can improve the efficiency of clinical studies by ensuring appropriate outcomes are measured, minimize heterogeneity in reporting, reduce the risk of publication bias, and improve the quality of evidence synthesis by facilitating fair comparisons across different therapies. Therefore, in collaboration with the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR); the European Eosinophilic Esophagitis Research Network (EUREOS); and with several individuals recruited from the Eosinophil Gastrointestinal Disorders Committee of The American Academy of Allergy, Asthma, and Immunology, we developed an international consensus COS for use in studies of pharmacologic and dietary interventions for adult and pediatric patients with EoE (COREOS). Detailed methods used to define the COS are summarized in the accompanying Meeting Summary. We used a multiple-phase approach, conducted in accordance with recommendations from the Core Outcome Measures in Effectiveness Trials (COMET) initiative7Williamson P.R. Altman D.G. Bagley H. et al.The COMET Handbook: version 1.0.Trials. 2017; 18: 280Crossref PubMed Scopus (847) Google Scholar,8Kirkham J.J. Davis K. Altman D.G. et al.Core Outcome Set-STAndards for Development: The COS-STAD recommendations.PLoS Med. 2017; 14e1002447Crossref PubMed Scopus (302) Google Scholar to identify relevant outcome domains and end-point definitions for randomized controlled trials (RCTs) and observational studies in adult and pediatric patients with EoE. First, a series of systematic reviews6Ma C. van Rhijn B.D. Jairath V. et al.Heterogeneity in clinical, endoscopic, and histologic outcome measures and placebo response rates in clinical trials of eosinophilic esophagitis: a systematic review.Clin Gastroenterol Hepatol. 2018; 16: 1714-1729.e3Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,9Warners M.J. Hindryckx P. Levesque B.G. et al.Systematic review: disease activity indices in eosinophilic esophagitis.Am J Gastroenterol. 2017; 112: 1658-1669Crossref PubMed Scopus (38) Google Scholar,10Schoepfer A.M. Schürmann C. Trelle S. et al.Systematic review of outcome measures used in observational studies of adults with eosinophilic esophagitis.Int Arch Allergy Immunol. 2021; (E-pub ahead of print)Google Scholar and patient engagement surveys11Safroneeva E. Balsiger L. Hafner D. et al.Adults with eosinophilic oesophagitis identify symptoms and quality of life as the most important outcomes.Aliment Pharmacol Ther. 2018; 48: 1082-1090Crossref PubMed Scopus (21) Google Scholar was conducted to identify candidate outcomes of importance. Input was gathered from a diverse range of patients with EoE to determine their values on the importance of different outcomes and recruited using purposive sampling from multiple clinics to capture a range of disease duration, disease activity, and treatment experiences. A total of 36 patients with EoE participated in semi-structured interviews and 109 patients with EoE completed a paper-based survey. Outcomes identified in the patient engagement surveys and through systematic literature reviewer were organized into 11 domains, and a series of working group meetings were held to review the pertinent end points. These domains were then discussed in a moderated face-to-face meeting at Digestive Disease Week 2019 in San Diego, CA, and a Delphi panel of multidisciplinary experts voted to categorize these into core, important, and research agenda domains based on the Outcome Measures in Rheumatology model.12Tugwell P. Boers M. Brooks P. et al.OMERACT: an international initiative to improve outcome measurement in rheumatology.Trials. 2007; 8: 38Crossref PubMed Scopus (377) Google Scholar In phase 3, a comprehensive list of outcome measures within each core domain was evaluated in a 2-round Delphi survey to establish consensus. Finally, a virtual ratification meeting was held to vote on the final outcomes included in the COS. The COS panel included diverse stakeholders, reflecting a broad range of clinical knowledge and geographical diversity, including patients with EoE, gastroenterologists, pathologists, allergists, dietitians, psychologists, researchers, and methodologists. Several rounds of Delphi surveys were completed to first rank each domain and subsequently individual outcomes on a 9-point Likert scale.13Guyatt G.H. Oxman A.D. Kunz R. et al.GRADE guidelines: 2. Framing the question and deciding on important outcomes.J Clin Epidemiol. 2011; 64: 395-400Abstract Full Text Full Text PDF PubMed Scopus (1152) Google Scholar Scores of 1–3 indicate an outcome domain that was not considered important for inclusion, scores of 4–6 indicate an outcome domain that was considered important but not critical for inclusion, and scores of 7–9 indicate an outcome domain considered critical for inclusion in the COS. Outcome domains and outcome definitions scored in the 7–9 range by ≥70% of panelists and in the 1–3 range by <15% of panelists were considered to have met consensus. A moderated video conference to ratify the final COS was conducted December 8, 2020. Although this was initially planned as a face-to-face meeting, this was amended to a virtual conference due to COVID-19 public health restrictions. After discussion, panelists anonymously voted on the final items as “include in the COS,” “do not include in the COS,” or “unsure.” Items receiving ≥70% of votes in the “include in the COS” category and <15% of votes in the “do not include in the COS” category were ratified for final inclusion. The following 4 outcome domains were voted as critical for inclusion in an EoE COS: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life (QoL) (Figure 1). Although genetic profiling, biomarkers, esophageal distensibility, patient perceptions of health, and immunologic end points were important, they were not deemed critical for assessment in every study at this time. Patients with EoE identified improvement in EoE-related symptoms and QoL as the most important outcome domains: >90% of patients identified improvements in these domains as important in both the short- and long-term. From the 4 core domains, a total of 122 outcome definitions were identified. During 2 rounds of Delphi survey voting by 69 (round 1) and 62 (round 2) panelists, a total of 59 outcomes were considered for inclusion (18 for histology, 12 for endoscopy, 19 for patient-reported symptoms, and 10 for EoE-specific QoL). At the ratification meeting, 42 items were discussed and voted on with 33 items included in the final COS. These are summarized in Table 1.Table 1Core Outcome Set for Eosinophilic EsophagitisOutcome domainRCTsObservational studiesHistopathologyPeak esophageal eosinophilia (and appropriate measures of spread, such as error terms or confidence intervals) should be measured and reported in all RCTs, expressed as:No. of eosinophils per hpf (400× magnification)No. of cells adjusted per mm2 (400× magnification)Histologic remission should be measured in all RCTsIn RCTs, histologic remission should be defined based on a peak eosinophil count of <15 esophageal eosinophil/hpf in any locationaRemission cutoff of <15 eos/hpf corresponding to <60 eos/mm2.The grade (severity) and stage (extent) of all components in the EoEHSS should be measured and reported in all RCTsThe EoEHSS remission score should be measured and reported in all RCTs: for each item, proximal and distal esophagus: remission score of ≤3 for grade and ≤3 for stage and peak eosinophil count of <15 eos/hpfPeak esophageal eosinophilia (and appropriate measures of spread, such as error terms or confidence intervals) should be measured and reported in all observational studies, expressed as:No. of eosinophils per hpf (400× magnification)No. of cells adjusted per mm2 (400× magnification)Histologic remission should be measured in all observational studiesIn observational studies, histologic remission should be defined based on a peak eosinophil count of <15 esophageal eosinophils/hpf in any locationEndoscopyEREFS should be measured and reported in all RCTsThe major features of the EREFS should be scored from 0 to 8, scoring the most severe grade of esophageal EoE-associated features present in the proximal and distal esophagus (with furrows scored as absent or present)bSee section on Core Outcomes Set: Endoscopy Outcomes in text for full details; if the EREFS is scored from 0 to 9 with furrows graded as grade 0 (absent), grade 1 (mild, vertical lines without visible depth), and grade 2 (severe, vertical lines with mucosal depth), recommended to report component scores to calculate post-hoc an EREFS score on a 0–8 scale.EREFS should be measured and reported in all observational studiesThe major features of the EREFS should be scored from 0 to 8, scoring the most severe grade of esophageal EoE-associated features present in the proximal and distal esophagus (with furrows scored as absent or present)bSee section on Core Outcomes Set: Endoscopy Outcomes in text for full details; if the EREFS is scored from 0 to 9 with furrows graded as grade 0 (absent), grade 1 (mild, vertical lines without visible depth), and grade 2 (severe, vertical lines with mucosal depth), recommended to report component scores to calculate post-hoc an EREFS score on a 0–8 scale.Endoscopic remission based on EREFS should be measured and reported in all RCTs and observational studies In RCTs or observational studies, the endoscopic EREFS-based remission should be defined as an EREFS score ≤2 (based on EREFS scoring from 0 to 8cEndoscopic remission recommended to be defined by EREFS ≤2 if scored on 0 to 8 or 0 to 9 scale.In RCTs or observational studies, endoscopic inflammatory EREFS-based remission should be defined as the inflammation-associated components (exudate, edema, furrows) score ≤2 (based on EREFS scoring from 0 to 8)In RCTs or observational studies, the endoscopic fibrotic EREFS-based remission should be defined as categorical definition as absence of strictures, moderate and severe ringsPatient-reported symptomsIn all RCTs, symptom severity in adults with EoE should be assessed using a generic instrument with a daily recall perioddSee section on Core Outcomes Set: Patient-Reported Symptoms in text for full details; considered appropriate to use a generic instrument with a daily recall period in accordance with regulatory recommendations.In all RCTs, symptom severity in adults with EoE should be assessed using the following instruments: DSQ and EEsAI (7-d recall period)In all RCTs, the following language should be used to query dysphagia in adults with EoE:Dysphagia defined as trouble swallowingDysphagia defined as delayed or slow passage of foodsIn all RCTs, symptom severity in pediatric EoE patients should be measured using Pediatric Eosinophilic Esophagitis Symptom Score, version 2.0No patient-reported symptom instruments met consensus thresholds for use in all observational studiesIn all observational studies, the following language should be used to query dysphagia in adults with EoE:Dysphagia defined as trouble swallowingDysphagia defined as delayed or slow passage of foodQoLIn all RCTs, EoE-specific QoL in adults should be measured using EoE-QoL-A questionnaireIn all RCTs, pediatric EoE-specific QoL should be measured using the PedsQL EoE moduleWhen using PedsQL EoE module for children, for whom both parent-proxy report and child self-report are available, both should be reported in all RCTsNo patient-reported QoL instruments met consensus thresholds for use in all observational studiesEoE-QoL-A, EoE Quality of Life for adults.a Remission cutoff of <15 eos/hpf corresponding to <60 eos/mm2.b See section on Core Outcomes Set: Endoscopy Outcomes in text for full details; if the EREFS is scored from 0 to 9 with furrows graded as grade 0 (absent), grade 1 (mild, vertical lines without visible depth), and grade 2 (severe, vertical lines with mucosal depth), recommended to report component scores to calculate post-hoc an EREFS score on a 0–8 scale.c Endoscopic remission recommended to be defined by EREFS ≤2 if scored on 0 to 8 or 0 to 9 scale.d See section on Core Outcomes Set: Patient-Reported Symptoms in text for full details; considered appropriate to use a generic instrument with a daily recall period in accordance with regulatory recommendations. Open table in a new tab EoE-QoL-A, EoE Quality of Life for adults. There was consensus that the peak eosinophil count (PEC) should be reported in all RCTs and observational studies, expressed either as eosinophils per high-power field (eos/hpf; including exact area used and the hpf size, reported in mm2) or as eos/mm2, viewed at 400× magnification. Several panelists identified that both measures should be reported, as eos/hpf has been used historically, whereas eos/mm2 adjusts for differences in microscope ocular field size. In RCTs, the EoE Histology Scoring System (EoEHSS)14Collins M.H. Martin L.J. Alexander E.S. et al.Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.Dis Esophagus. 2017; 30: 1-8PubMed Google Scholar should be used, and both the grade and stage of each component item reported. There was consensus that histologic remission should be reported in all studies, although the precise threshold for histologic remission was debated. The proportion of patients with <15 eos/hpf in all esophageal locations should be reported, but there was disagreement on reporting a more stringent threshold of ≤6 eos/hpf. Given the importance of eosinophilic inflammation in defining EoE, histopathology was almost universally agreed upon as a core domain. However, 3 areas of controversy garnered discussion. First, although using eos/mm2 was thought to be advantageous for standardizing density measurements across different microscopes and field sizes,15Dellon E.S. Eosinophilic esophagitis: diagnostic tests and criteria.Curr Opin Gastroenterol. 2012; 28: 382-388Crossref PubMed Scopus (45) Google Scholar most of the literature to date has expressed PEC/hpf. There was consensus that this should continue to be reported to facilitate historical treatment comparisons, although we advocate for a greater emphasis on reporting eos/mm2 (using remission definitions of PEC ≤25 eos/mm2 and <60 eos/mm2, corresponding to PEC of ≤6 eos/hpf and <15 eos/hpf, respectively). Second, there was consensus that a PEC of <15 eos/hpf should be used as the threshold to define histologic remission, although this is discordant from recent recommendations from the US Food and Drug Administration.16Lyons E. Donohue K. Lee J.J. Developing pharmacologic treatments for eosinophilic esophagitis: draft guidance from the United States Food and Drug Administration.Gastroenterology. 2019; 157: 275-277Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Multiple guidelines have established ≥15 eos/hpf as the cutoff for diagnostic purposes, and the panel voted that the proportion of patients achieving a PEC lower than this threshold should continue to be reported.17Furuta G.T. Liacouras C.A. Collins M.H. et al.Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.Gastroenterology. 2007; 133: 1342-1363Abstract Full Text Full Text PDF PubMed Scopus (1380) Google Scholar, 18Dellon E.S. Liacouras C.A. Molina-Infante J. et al.Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference.Gastroenterology. 2018; 155: 1022-1033.e10Abstract Full Text Full Text PDF PubMed Scopus (504) Google Scholar, 19Dellon E.S. Gonsalves N. Hirano I. et al.ACG clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE).Am J Gastroenterol. 2013; 108 (quiz 693): 679-692Crossref PubMed Scopus (808) Google Scholar A threshold of ≤6 eos/hpf may be too stringent to achieve and may not necessarily be appropriate for potential future drug targets with mechanisms of action that do not directly inhibit eosinophils. Nevertheless, we anticipate that in future trials designed for regulatory approval of medications, the proportion of patients with post-treatment PEC <15 eos/hpf and ≤6 eos/hpf will both be reported. Finally, the EoEHSS has been demonstrated previously to be valid, reliable, responsive, applicable in adult and pediatric populations, and measures histologic items that are prevalent in patients with EoE beyond the PEC alone.14Collins M.H. Martin L.J. Alexander E.S. et al.Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.Dis Esophagus. 2017; 30: 1-8PubMed Google Scholar,20Hiremath G. Correa H. Acra S. et al.Correlation of endoscopic signs and mucosal alterations in children with eosinophilic esophagitis.Gastrointest Endosc. 2020; 91: 785-794.e1Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar,21Safroneeva E. Straumann A. Coslovsky M. et al.Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis.Gastroenterology. 2016; 150: 581-590.e4Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar For these reasons, panelists agreed that the EoEHSS should be evaluated routinely in RCTs. However, the EoEHSS was not included as a core outcome in observational studies due to concerns about the time required for interpretation and lack of an atlas to help pathologists not specialized in EoE to score some of the features, although uptake in clinical practice may increase as it is adopted in RCTs. The panel voted that the EoE Endoscopic Reference Score (EREFS) should be used in both RCTs and observational studies to standardize endoscopic assessment of EoE disease activity, scoring the most severe grade of EoE-associated features. In addition, both inflammatory and fibrotic components of the EREFS should be reported. Different versions of the EREFS were explored (scoring from 0–8, 0–9, 0–16, and 0–18 with alternative definitions or weighting of the EREFS components). There was consensus to score the major features of the EREFS from 0–8 with furrows assessed as absent/present; however, there was extensive discussion that scoring from 0 to 8 may result in a narrower dynamic range of the EREFS score and decrease responsiveness measured by endoscopy compared with scoring the furrows ordinally using grade 0 (absent), grade 1 (mild, vertical lines without visible depth), and grade 2 (severe, vertical lines with mucosal depth/indentation). In addition, if scoring is performed on a 0–9 scale, post-hoc analysis collapsing the categories for moderate-to-severe furrows can generate an EREFS score on a 0–8 scale, but not vice versa. For both RCTs and observational studies, there was consensus that endoscopic remission should be defined using an EREFS ≤2. The EREFS score has been shown to accurately identify disease activity in both adult and pediatric populations, can be reliably scored by experts and quickly learned by nonexperts, and is responsive to treatment.22Hirano I. Moy N. Heckman M.G. et al.Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system.Gut. 2013; 62: 489-495Crossref PubMed Scopus (491) Google Scholar, 23Wechsler J.B. Bolton S.M. Amsden K. et al.Eosinophilic esophagitis reference score accurately identifies disease activity and treatment effects in children.Clin Gastroenterol Hepatol. 2018; 16: 1056-1063Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 24Dellon E.S. Katzka D.A. Collins M.H. et al.Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis.Gastroenterology. 2017; 152: 776-786.e5Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar From this consensus, we recommend scoring the EREFS in all EoE RCTs and observational studies, reporting individual component items, and using a cutoff of ≤2 for endoscopic remission. However, there was debate as to whether the EREFS should be scored on a 0 to 9 or 0 to 8 scale, recognizing that scoring on a broader range may improve the sensitivity of the instrument for detecting change in an RCT setting and can be converted to a 0 to 8 scale post-hoc if required. Functionally, reporting individual component subscores of the EREFS is also required to discern endoscopic inflammatory vs fibrostenotic disease activity. Investigators may choose to grade furrows on a 3-point rather than binary scale and collapse in post-hoc analyses if required. There was consensus that validated instruments for patient-reported symptoms, including the Dysphagia Symptoms Questionnaire (DSQ) and the symptom-based EoE Activity Index (EEsAI) with 7-day recall period should be assessed in EoE RCTs. There was discussion that guidance from the US Food and Drug Administration highlights the use of clinical outcome assessment instruments that use daily evaluations. The EEsAI was developed and has been used in previous RCTs with a 7-day recall period as secondary end point, and this outcome was voted to be included in the COS. The DSQ was the only 24-hour recall instrument selected out of a myriad of options and is the first such instrument to be validated for use in RCTs, allowing assessment of end points such as dysphagia-free days. Other instruments, including both conceptually similar and dissimilar tools, such as the Dysphagia Symptom Diary and Numeric Rating Scales for Dysphagia and Pain, respectively, have been used in other drug development programs, as historically licensing DSQ to all interested parties has not been possible. Given the multitude of instruments with daily recall currently used in RCTs, EEsAI’s 7-day recall period may be used as secondary end point to allow for cross-comparisons between existing instruments. There was also consensus that the language used to query dysphagia in adults with EoE included trouble swallowing and delayed/slow passage of food. “Food being stuck” did not reach consensus thresholds in the ratification round. No instruments for measuring symptom severity reached consensus for use in observational studies. Separate instruments were considered for pediatric patients. In pediatric trials, there was consensus that symptoms should be measured using the Pediatric Eosinophilic Esophagitis Symptom Score, version 2.0, for RCTs, but not for observational studies. There was consensus that QoL should be measured in EoE RCTs using the EoE-specific QoL questionnaire for adults (EoE-QoL-A) and the Pediatric Quality of Life Inventory (PedsQL) EoE module for pediatrics. When using the PedsQL EoE module, it was considered appropriate for both parent-proxy report and child self-report to be reported in RCTs. The panel concluded that disease-specific QoL measures rather than generic QoL measures should be chosen for this domain. No instruments for use in all observational studies met the consensus threshold for inclusion in the COS. The development of a generic daily recall instrument was identified as a priority, as existing tools, such as DSQ and episode-based instruments, may be difficult or expensive to implement outside of industry-sponsored RCTs. Whether such instruments should use broad language to describe dysphagia is another relevant consideration, because most available instruments do not assess all possible symptoms relevant for adults with EoE or do not include the most common language used by patients to describe dysphagia.25Schoepfer A.M. Straumann A. Panczak R. et al.Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis.Gastroenterology. 2014; 147: 1255-1266.e21Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar,26Dellon E.S. Irani A.M. Hill M.R. et al.Development and field testing of a novel patient-reported outcome measure of dysphagia in patients with eosinophilic esophagitis.Aliment Pharmacol Ther. 2013; 38: 634-642Crossref PubMed Scopus (102) Google Scholar “Food being stuck” narrowly missed the consensus criteria during ratification round because there were concerns raised that this more accurately reflected food bolus impaction rather than dysphagia, although no clear distinction between language used to describe short- and long-lasting episodes of dysphagia has been noted in qualitative work. Lastly, data on cross comparisons of instruments are scarce, and it is not clear whether assessing symptoms more broadly by including all possible dysphagia language as well as all symptom domains relevant to patients might explain a greater extent of the variation in severity of biologic findings compared with assessing dysphagia frequency alone. The Pediatric Eosinophilic Esophagitis Symptom Score, version 2.0, is the only currently available instrument for assessing symptoms in pediatric patients with EoE. Although there are data to convincingly demonstrate the alignment between patient-reported and proxy-reported symptom severity, there are not enough data to understand the performance of this instrument in the context of treatment response, especially given that there is a 30-day recall period for this instrument; age influences symptom presentation in children; and a broad range of symptoms needs to be assessed. We have developed an internationally guided multidisciplinary COS for use in therapeutic trials in pediatric and adult patients with EoE. Groups assessing EoE therapies should be encouraged to adopt this COS to reduce heterogeneity in outcome reporting and improve comparability with future studies. We recognize that the end points used in EoE trials have evolved rapidly in the past 2 decades. Indeed, limitations of existing instruments for measuring histology, endoscopy, symptoms, and QoL were highlighted during the discussions that occurred in the consensus process and are reviewed in the accompanying Meeting Summary. Therefore, although this is the first iteration of a COS in EoE, we anticipate that ongoing work in the development of new instruments for measuring disease activity will shape the field moving forward. Importantly, the development of this COS represents only the minimum outcomes that should be measured currently, but should not discourage the development and validation of potentially more robust or appropriate instruments to measure disease activity in the future. In fact, we urge all investigators to measure other potential outcomes of interest, in addition to these benchmarked minimum end points. Areas of research priority, including comparisons of the performance characteristics of different tools for measuring disease activity in diverse patient populations, will help to inform the next version of this COS.