Optimal Histologic Cutpoints for Treatment Response in Patients With Eosinophilic Esophagitis: Analysis of Data From a Prospective Cohort Study

  • Craig C. Reed
    Affiliations
    Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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  • W. Asher Wolf
    Affiliations
    Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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  • Cary C. Cotton
    Affiliations
    Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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  • Spencer Rusin
    Affiliations
    Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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  • Irina Perjar
    Affiliations
    Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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  • Johnathan Hollyfield
    Affiliations
    Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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  • John T. Woosley
    Affiliations
    Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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  • Nicholas J. Shaheen
    Affiliations
    Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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  • Evan S. Dellon
    Correspondence
    Reprint requests Address requests for reprints to: Evan S. Dellon, MD, MPH, CB#7080 Bioinformatics Building, 130 Mason Farm Road, UNC-CH, Chapel Hill, North Carolina 27599-7080. fax: (919) 843-2508.
    Affiliations
    Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, North Carolina

    Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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Published:October 05, 2017DOI:https://doi.org/10.1016/j.cgh.2017.09.046

      Background and Aims

      No prospective studies substantiate 15 eos/hpf as an appropriate endpoint for treatment of eosinophilic esophagitis (EoE). We aimed to determine a histologic cutpoint that identifies successful treatment of EoE by assessing symptomatic and endoscopic improvement.

      Methods

      We performed a prospective cohort study of 62 consecutive adult patients undergoing outpatient esophagogastroduodenoscopy at the University of North Carolina from 2009 through 2014. At diagnosis of EoE and after 8 weeks of standard treatment, symptom and endoscopic responses were measured using a visual analogue scale and an endoscopic severity score (ESS), and eosinophil counts were assessed. Receiver operator curves and logistic regression models evaluated the histologic threshold that best predicted symptomatic and endoscopic response. For symptoms, analysis was limited to patients without baseline esophageal dilation.

      Results

      The mean eosinophil count at diagnosis was 124 eos/hpf, falling to 35 eos/hpf after treatment. The mean visual analogue scale decreased from 3.4 at baseline to 1.7 after treatment, and the mean ESS decreased from 3 to 1.6. Twenty-nine patients had symptom responses (47%) and 34 had endoscopic responses (55%). Post-treatment eosinophil count thresholds of 8, 15, and 5 eos/hpf best predicted symptom, endoscopic and combined responses, respectively. On logistic regression, decreasing eosinophil count was significantly associated with the probability of symptomatic (P = .01) and endoscopic response (P < .001).

      Conclusions

      In a prospective study of patients with EoE, we found that a cutpoint of <15 eos/hpf identifies most patients with symptom and endoscopic improvements, providing support for the current diagnostic threshold. A lower threshold (<5 eos/hpf) identifies most patients with a combination of symptom and endoscopic responses; this cutpoint might be used in situations that require a stringent histologic threshold.

      Keywords

      Abbreviations used in this paper:

      AUC (area under the curve), EGD (esophagogastroduodenoscopy), EoE (eosinophilic esophagitis), eos/hpf (eosinophils per high-power field), EREFS (eosinophilic esophagitis endoscopic reference score system), ESS (endoscopic severity score), ROC (receiver operator curve), tCS (topical corticosteroid), VAS (visual analog scale)
      Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated disorder characterized histologically by esophageal inflammation with intraepithelial eosinophils and clinically by symptoms of esophageal dysfunction.
      • Dellon E.S.
      • Liacouras C.A.
      Advances in clinical management of eosinophilic esophagitis.
      The current criteria for diagnosis require the presence of at least 15 eosinophils per high-power field (eos/hpf) in esophageal biopsies and the exclusion of alternative etiologies of esophageal eosinophilia in the correct clinical context.
      • Furuta 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.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      • Dellon 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).
      Since its original description 2 decades ago, EoE emerged as an important and increasingly recognized etiology of gastrointestinal morbidity.
      • Safroneeva E.
      • Coslovsky M.
      • Kuehni C.E.
      • et al.
      Eosinophilic oesophagitis: relationship of quality of life with clinical, endoscopic and histological activity.
      Treatment options for EoE include medications, dietary elimination, and esophageal dilation.
      • Dellon E.S.
      • Liacouras C.A.
      Advances in clinical management of eosinophilic esophagitis.
      However, what constitutes a response to these treatment modalities remains unclear. Possible outcome measures include symptoms, quality of life, endoscopic findings, biomarkers, and histologic findings.
      • Hirano I.
      Editorial: should patients with suspected eosinophilic esophagitis undergo a therapeutic trial of proton pump inhibition?.
      From a clinical standpoint, the goal is to decrease or eliminate symptoms, improve or normalize the endoscopic appearance, and decrease or resolve esophageal eosinophilia.
      • Dellon E.S.
      • Liacouras C.A.
      Advances in clinical management of eosinophilic esophagitis.
      However, no guidelines set firm response thresholds for any outcome measure.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      • Dellon 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).
      Most studies set histology as the primary outcome measure, because this may be assessed objectively, but used a range of values (from 0 to <15 eos/hpf).
      • Dellon 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).
      • Hirano I.
      Editorial: should patients with suspected eosinophilic esophagitis undergo a therapeutic trial of proton pump inhibition?.
      • Wolf W.A.
      • Cotton C.C.
      • Green D.J.
      • et al.
      Evaluation of histologic cutpoints for treatment response in eosinophilic esophagitis.
      There are only a limited number of studies assessing the utility of different histologic end points for response in treated EoE patients.
      • Hirano I.
      Therapeutic end points in eosinophilic esophagitis: is elimination of esophageal eosinophils enough?.
      Although 15 eos/hpf provides conceptual symmetry with the diagnostic threshold, no prospective data substantiate that this threshold constitutes an appropriate treatment end point. Furthermore, it remains unknown which degrees of esophageal eosinophilia represent the most clinically relevant outcome measure. The degree of concordance between symptomatic, endoscopic, and histologic outcomes also remains unclear.
      • Schoepfer A.M.
      • Straumann A.
      • Panczak R.
      • et al.
      Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis.
      • Hirano 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.
      • Dellon 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.
      This knowledge gap impedes patient care as well as the synthesis of the medical literature.
      • Dellon E.S.
      • Aderoju A.
      • Woosley J.T.
      • et al.
      Variability in diagnostic criteria for eosinophilic esophagitis: a systematic review.
      • Sperry S.L.W.
      • Shaheen N.J.
      • Dellon E.S.
      Toward uniformity in the diagnosis of eosinophilic esophagitis (EoE): the effect of guidelines on variability of diagnostic criteria for EoE.
      The aim of this study was to determine an optimal histologic cutpoint after EoE treatment that maximizes symptomatic and endoscopic improvement.

      Methods

       Study Design, Patients, and Measures

      We analyzed data collected during a prospective cohort study at the University of North Carolina at Chapel Hill from 2009 to 2014 that enrolled consecutive adult patients undergoing outpatient esophagogastroduodenoscopy (EGD).
      • Dellon E.S.
      • Gibbs W.B.
      • Fritchie K.J.
      • et al.
      Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease.
      • Dellon E.S.
      • Chen X.
      • Miller C.R.
      • et al.
      Diagnostic utility of major basic protein, eotaxin-3, and leukotriene enzyme staining in eosinophilic esophagitis.
      The University of North Carolina institutional review board approved this study. Incident EoE cases were diagnosed per consensus guidelines. Cases had symptoms of esophageal dysfunction and at least 15 eos/hpf (hpf area = 0.24 mm2) on esophageal biopsy after 8-week high-dose proton pump inhibitor trial to exclude proton pump inhibitor–responsive esophageal eosinophilia; competing causes of eosinophilia were excluded.
      • Furuta 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.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      • Dellon 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).
      After incident diagnosis, treatment of cases was at the discretion of their primary gastroenterologist with either a topical corticosteroid (tCS) (budesonide viscous slurry dosed at 1 mg twice daily
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      • Dellon E.S.
      Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial.
      or fluticasone 880 μg twice daily
      • Konikoff M.R.
      • Noel R.J.
      • Blanchard C.
      • et al.
      A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.
      • Alexander J.A.
      • Jung K.W.
      • Arora A.S.
      • et al.
      Swallowed fluticasone improves histologic but not symptomatic response of adults with eosinophilic esophagitis.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      ) or dietary elimination therapy (6 food elimination diets or targeted elimination diets).
      • Wolf W.A.
      • Jerath M.R.
      • Sperry S.L.W.
      • et al.
      Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis.
      • Gonsalves N.
      • Yang G.Y.
      • Doerfler B.
      • et al.
      Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.
      • Spergel J.M.
      • Brown-Whitehorn T.F.
      • Cianferoni A.
      • et al.
      Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet.
      Patients were treated for 8 weeks and then reassessed with EGD. During the baseline and post-treatment endoscopies, a total of 5 research protocol biopsies obtained from the distal, mid, and proximal esophagus (2 biopsies at 3, one biopsy at 8, and 2 biopsies at 13 cm, respectively, above the gastroesophageal junction) determined eosinophil counts. Quantification of eosinophils for the maximum number per hpf (eos/hpf) used our previously validated protocol.
      • Dellon E.S.
      • Fritchie K.J.
      • Rubinas T.C.
      • et al.
      Inter- and intraobserver reliability and validation of a new method for determination of eosinophil counts in patients with esophageal eosinophilia.
      At baseline and follow-up, a visual analogue scale (VAS) recorded dysphagia severity, which we previously showed to represent a reliable and responsive measure.
      • Reed C.
      • Wolf W.
      • Cotton C.
      • et al.
      A visual analogue scale and a Likert scale are simple and responsive tools for assessing dysphagia in eosinophilic oesophagitis.
      For the VAS, patients placed a mark on a 10-cm line to answer the question, “How bad, on average, has your swallowing difficulty been over the past 30 days?” The VAS was anchored at 0 with “no trouble swallowing” and at 10 with “unable to even swallow saliva”. The mark was measured in millimeters to provide a 0–100 VAS score, with higher scores indicating more severe dysphagia.
      Endoscopic findings of EoE were prospectively recorded at baseline and post-treatment. Because data gathering pre-dated the EoE endoscopic reference score system (EREFS),
      • Dellon E.S.
      • Cotton C.C.
      • Gebhart J.H.
      • et al.
      Accuracy of the eosinophilic esophagitis endoscopic reference score in diagnosis and determining response to treatment.
      we used a simplified endoscopic severity score (ESS) where each EREFS finding (exudates, rings, edema, furrows, stricture) was rated as absent or present. Scores ranged from 0 to 5, with higher scores representing a larger number of findings.
      We also recorded patient demographics and comorbidities by using standardized data collection tools.

       Statistical Analysis

      We examined the characteristics of the sample to determine the distribution of the variables and to assess any impact of missing data or extreme values. For continuous variables, the mean, standard deviation, and the shape of the distribution were determined. Frequencies were tabulated for categorical variables. Non-parametric testing did not alter the interpretation of the data. Bivariable analysis was described for the entire patient cohort. To explore the relationship between baseline and follow-up VAS, ESS, and eosinophil counts, paired t tests compared continuous variables (VAS and ESS), and McNemar χ2 test compared categorical variables (endoscopic findings).
      Because we aimed to evaluate histologic cutpoints optimizing symptomatic and endoscopic responses to treatment, we assessed whether esophageal dilation explained discordance between post-treatment histologic and symptom response. Because baseline dilation did impact results, analyses of symptom and combined symptomatic and endoscopic responses were restricted to patients who were not undergoing baseline esophageal dilation. Assessment of post-treatment endoscopic response alone included dilated and non-dilated patients. We empirically defined symptomatic and endoscopic responses as ≥50% decrease in the VAS or ESS, respectively.
      We used logistic regression to estimate the probability of symptomatic, endoscopic, and combined symptomatic and endoscopic response after treatment. Models were constructed by using post-treatment eosinophil count or percentage change in the eosinophil count as a continuous variable. Adjustment for confounding was limited because of the available sample size and the number of outcomes. When appropriate, models were adjusted for baseline VAS and/or ESS measurement. These baseline covariates were included to help control for regression to the mean. In addition, baseline scores negatively correlated with change, because low baseline scores generally improved more than higher scores.
      • Vickers A.J.
      • Altman D.G.
      Statistics notes: analysing controlled trials with baseline and follow up measurements.
      We constructed receiver operator curves (ROCs) to assess the impact of a range of cutoff values for both post-treatment eosinophil counts and percentage change in eosinophil counts on VAS and ESS scores. To determine the optimal histologic threshold that best predicted symptomatic, endoscopic, and combined responses, we found the maximum sensitivity and specificity and the associated probability defining response from each ROC. We also performed a sensitivity analysis to determine whether 100% change in the VAS, ESS, or both (ie, complete response as measured by no symptoms and/or normalization of the esophagus) would change our conclusions. Methods for sensitivity analyses related to endoscopic phenotypes and histology by esophageal level are in the Supplementary Materials. All data analysis was performed by using Stata 14.1 (StataCorp, College Station, TX).

      Results

       Patient Characteristics and Overall Treatment Responses

      A total of 62 adult patients newly diagnosed with EoE met inclusion criteria for this study. The mean age was 38 years, and cases were predominately white (94%) and male (55%) (Table 1). The mean peak eosinophil count at diagnosis was 123.7 ± 120.5, and this decreased to 34.6 ± 69.5 after treatment (Table 2). The baseline mean VAS score was 3.4, which decreased to 1.7 after treatment (P < .001). The mean ESS decreased from 3.0 to 1.6 (P < .001). For all patients, symptomatic response occurred in 29 (47%), endoscopic response in 34 (55%), and both symptomatic and endoscopic response in 16 (26%).
      Table 1Baseline Characteristics (n = 62)
      Demographics
       Age, y (mean ± SD)38 ± 12
       Male (n, %)34 (55)
       White (n, %)58 (94)
      Any atopic disease (n, %)50 (86)
       Asthma23 (37)
       Rhinitis/sinusitis48 (77)
       Dermatitis7 (11)
       Food allergies12 (29)
      Symptoms (n, %)
       Dysphagia61 (98)
       Heartburn7 (11)
       Abdominal pain7 (11)
      Treatment type (n, %)
       Topical steroids59 (95)
      Oral viscous budesonide51 (86)
      Mean dose (μg) (± SD)2140 ± 700
      Fluticasone inhaler8 (14)
      Mean dose (μg) (± SD)1790 ± 85
       Dietary elimination3 (5)
      Targeted2 (67)
      Six food elimination diet1 (33)
      SD, standard deviation.
      Table 2Symptom, Endoscopic, and Histologic Findings Before and After Treatment
      Baseline (n = 62)Follow-up (n = 62)P value
      Dysphagia severity (mean VAS ± SD)3.4 ± 3.01.7 ± 2.0<.001
       Mean % change in VAS–26.7 ± 104.0
       50% improvement in VAS (n, %)29 (47)
      Endoscopic severity (mean ESS ± SD)3.0 ± 1.31.6 ± 1.3<.001
       Mean % change in ESS–38.1 ± 51.9
       50% improvement in ESS (n, %)34 (55)
      Endoscopic findings (n, %)
       Normal2 (3)11 (18).007
       Rings54 (87)39 (67)<.001
       Stricture15 (24)11 (17).21
       Narrowing20 (32)18 (29).53
       Furrows54 (87)23 (27)<.001
       Crêpe-paper mucosa5 (8)1 (2).05
       White plaques/exudates29 (47)12 (19)<.001
       Edema/decreased vascularity31 (50)13 (21)<.001
       Dilation performed18 (29)17 (27).48
      Eosinophil count (mean eos/hpf) (± SD)123.7 ± 120.534.6 ± 69.5<.001
      Histologic responses (n, %)
       <15 eos/hpf44 (71)
       <5 eos/hpf35 (57)
       <1 eos/hpf27 (44)
       50% decrease50 (81)
       90% decrease41 (66)
      eos/hpf, eosinophils per high-power field; ESS, endoscopic severity score; SD, standard deviation; VAS, visual analog scale.
      Considering several histologic outcome values, 44 patients (71%) had post-treatment eosinophil counts <15 eos/hpf, whereas only 27 (44%) had 0 eos/hpf. In 50 patients (81%), eosinophil counts decreased from baseline by ≥50%, whereas 41 (66%) had a decrease in counts of ≥90%.

       Symptomatic and Endoscopic Responses by Histologic Response and Baseline Dilation

      Symptomatic, endoscopic, and combined treatment responses were assessed for all patients after their initial treatment course. Among patients achieving <15 eos/hpf, 70% had an endoscopic response, 46% had a symptomatic response, and 34% had both a symptomatic and endoscopic response (Figure 1A). Among patients with 0 eos/hpf post-treatment, 74% had an endoscopic response, 43% had symptomatic response, and 38% had both. Results were similar by using a percent change in the post-treatment eosinophil count; a decrease of 50% from the baseline eosinophil count was associated with an endoscopic and a symptom response rate of 64% and 46%, respectively, and both a symptomatic and endoscopic response in 33%. With a 90% decrease from the baseline eosinophil count, 76% had an endoscopic response, 44% had symptomatic response, and 38% had both a symptomatic and endoscopic response (Figure 1B; Supplementary Figure 1A–C).
      Figure thumbnail gr1
      Figure 1(A) Endoscopic, symptomatic, and combined response depending on post-treatment eosinophil count thresholds. (B) Endoscopic, symptomatic, and combined response depending on percent change in post-treatment eosinophil counts.
      Because we hypothesized that esophageal dilation produces symptom response despite the tissue effect of anti-inflammatory therapy, we explored the relationship between post-treatment eosinophil counts and dilation among symptomatic responders. When examining the entire patient cohort, 18 patients did not have a histologic response (as defined by a post-treatment eosinophil count <15 eos/hpf). There were 9 of 18 (50%) histologic non-responders who reported a symptom response. Of these 9 non-responders with a symptom response, 7 (78%) were dilated at baseline. In contrast, just 4 of 20 (20%) of those with both a histologic and symptomatic response had baseline dilation (P = .01). Esophageal dilation likely explains why many histologic non-responders reported symptom responses (Figure 2). We thus restricted further statistical analysis of symptoms, as well as combined symptom and endoscopic responses, to patients who did not undergo esophageal dilation during the endoscopy when EoE was diagnosed.
      Figure thumbnail gr2
      Figure 2Frequency of baseline esophageal dilation in symptom responders (defined by 50% decrease in VAS), as stratified by histologic response (defined as <15 eos/hpf). rx, treatment.

       Assessment of Histologic Response Thresholds

      For every post-treatment decrease of 10 eos/hpf, the probability of symptomatic response increased by approximately 6% (P = .01) (Figure 3A), endoscopic response by approximately 7% (P < .001) (Figure 3B), and both symptomatic and endoscopic response by approximately 5% (P < .001) (Figure 3C). Percentage change in the post-treatment eosinophil counts produced similar results. For every 10% decrease in eosinophil count, symptom response increased by approximately 7% (P = .04) (Figure 3D), endoscopic response by 6% (P < .001) (Figure 3E), and combined symptomatic and endoscopic responses by 10% (P = .01) (Figure 3F). Because post-treatment eosinophil counts clustered toward lower values, the limited number of patients with high post-treatment counts inflated variance and the width of associated predicted 95% confidence intervals.
      Figure thumbnail gr3
      Figure 3(A) Predicted probability of symptom response per post-treatment eosinophil count. (B) Predicted probability of endoscopic treatment response per post-treatment eosinophil count. (C) Predicted probability of combined treatment response per post-treatment eosinophil count. (D) Predicted probability of symptom response per percent change in post-treatment eosinophil count. (E) Predicted probability of endoscopic treatment response per percent change in post-treatment eosinophil count. (F) Predicted probability of combined treatment response per percent change in post-treatment eosinophil count. CI, confidence interval.
      The areas under the ROCs (AUCs) for symptomatic, endoscopic, and combined symptomatic and endoscopic responses, by using post-treatment eosinophil counts as cutpoints, were 0.67, 0.85, and 0.83, respectively (Supplementary Figure 1D). When considering all patients including those dilated at baseline, the AUC for symptomatic response decreased to 0.56. When using a 50% change in eosinophil counts as the cutpoint, the AUCs for symptomatic, endoscopic, and both symptomatic and endoscopic responses were 0.61, 0.74, and 0.80, respectively (Supplementary Figure 1E). The ROC AUCs for 90% change in the eosinophil count were 0.60, 0.86, and 0.81 for symptom, endoscopic, and combined responses (Supplementary Figure 1F).
      The post-treatment eosinophil count best predicting a symptomatic response was 8 eos/hpf (Figure 3). This corresponded to 63% of patients being correctly classified, with sensitivity of 61% and specificity of 64%. The post-treatment eosinophil count best predicting an endoscopic response was 15 eos/hpf. This corresponded to 76% of patients being correctly classified and sensitivity and specificity of 79% and 71%, respectively. Last, the post-treatment eosinophil count found best predicting a combined response was 5 eos/hpf. Here, 79% of patients were correctly classified, and the sensitivity was 88% and specificity was 76%.
      We analyzed the impact of using 100% improvement in VAS and ESS as the definition of outcome responses. A 100% improvement in the VAS score produced an AUC of 0.59, which was similar to using a 50% definition. A 100% improvement in the ESS resulted in an AUC of 0.66, which was less discriminative than the 50% definition. Only 1 patient achieved 100% improvement in his/her VAS and ESS, which precluded a model examining this combined outcome.
      Results from the sensitivity analyses related to endoscopic phenotypes and histology by esophageal level are presented in the Supplementary Materials and Supplementary Table 1.

      Discussion

      Few data describe the association of symptomatic, endoscopic, and histologic outcomes in EoE, and at this time, no consensus exists on the definition of an optimal post-treatment histologic cutpoint. One complication is that studies have also documented discordance in these outcomes.
      • Pentiuk S.
      • Putnam P.E.
      • Collins M.H.
      • et al.
      Dissociation between symptoms and histological severity in pediatric eosinophilic esophagitis.
      • Debrosse C.W.
      • Franciosi J.P.
      • King E.C.
      • et al.
      Long-term outcomes in pediatric-onset esophageal eosinophilia.
      • Safroneeva E.
      • Straumann A.
      • Coslovsky M.
      • et al.
      Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis.
      Our article further suggests a nebulous relationship between EoE-related symptoms and histologic activity. The variable histologic end points selected in clinical trials of EoE treatment add to this confusion. However, concordant symptomatic and endoscopic response was common in studies reaching a post-treatment eosinophil count <15 eos/hpf (despite started histologic outcome).
      • Konikoff M.R.
      • Noel R.J.
      • Blanchard C.
      • et al.
      A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.
      • Gupta S.K.
      • Vitanza J.M.
      • Collins M.H.
      Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis.
      • Assa’ad A.H.
      • Gupta S.K.
      • Collins M.H.
      • et al.
      An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis.
      • Wolf W.A.
      • Cotton C.C.
      • Green D.J.
      • et al.
      Predictors of response to steroid therapy for eosinophilic esophagitis and treatment of steroid-refractory patients.
      • Dellon E.S.
      • Kim H.P.
      • Sperry S.L.W.
      • et al.
      A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease.
      • Dellon 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.
      Only 1 trial achieved <1eos/hpf without improvement in symptoms or endoscopy.
      • Alexander J.A.
      • Jung K.W.
      • Arora A.S.
      • et al.
      Swallowed fluticasone improves histologic but not symptomatic response of adults with eosinophilic esophagitis.
      In contrast, trials failing to lower eosinophil counts to <15 had inconsistent symptomatic and endoscopic outcomes.
      • Dellon E.S.
      • Sheikh A.
      • Speck O.
      • et al.
      Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis.
      • Debrosse C.W.
      • Franciosi J.P.
      • King E.C.
      • et al.
      Long-term outcomes in pediatric-onset esophageal eosinophilia.
      In our study, the post-treatment eosinophil counts best predicting symptom, endoscopic, and combined responses were 8, 15, and 5 eos/hpf. Making the count thresholds more restrictive did not result in substantial gains in symptomatic or endoscopic response. If a histologic response outcome were used as a measure of treatment efficacy, we favor using the absolute eosinophil count over the percentage change. The ongoing presence of eosinophils, which would occur in patients with high baseline counts treated to an end point of 50 or 90% reduction, may produce ongoing risk for fibrotic remodeling of the esophagus.
      • Dellon E.S.
      • Kim H.P.
      • Sperry S.L.W.
      • et al.
      A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease.
      • Schoepfer A.M.
      • Safroneeva E.
      • Bussmann C.
      • et al.
      Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner.
      Considering the sum of our results, a threshold <15 eos/hpf appears a reasonable end point, particularly in clinical settings. However, our analysis demonstrates that the rate of endoscopic and symptomatic response increases with decreasing eosinophil counts. Although pushing the response threshold lower than <15 eos/hpf may not result in large gains of response, settings exist (eg, clinical trials) where a stringent histologic threshold is desired. In these cases, we found a threshold <5 eos/hpf maximized a combined symptomatic and endoscopic response. The feasibility of achieving these response thresholds must be considered. In our data, 71% of patients obtained a post-treatment eosinophil count of <15 eos/hpf, whereas only 44% achieved <1 eos/hpf. This suggests that a sizable percentage of EoE patients would require intensified (or alternative) therapy to reach a more stringent threshold; this subjects patients to additional risks of treatment with marginal improvement in their disease process. We also determined the post-treatment eosinophil counts best predicting the resolution of phenotypic features of EoE. The resolution of fibrostenotic features required near normalization of biopsies, whereas resolution of inflammatory findings occurred with a less stringent reduction in eosinophil counts. Our models also better predicted symptomatic, endoscopic, and combined responses in patients, with involvement of all esophageal segments (proximal, middle, and distal) at baseline, although this was most pronounced for symptom improvement.
      As demonstrated by the actual rather than predicted outcome responses, improvements in outcomes at higher post-treatment eosinophil counts occur. However, because a limited number of patients exhibited high post-treatment eosinophil counts, cautious conclusions should be drawn for responses at these levels.
      This study has several limitations. We relied on non-validated measures of symptom and endoscopic response. This was required because no validated measures existed when the study was designed and initiated. However, the VAS provided an objective measure of dysphagia severity, and we demonstrated that this is a simple and accurate measure that is treatment responsive.
      • Reed C.
      • Wolf W.
      • Cotton C.
      • et al.
      A visual analogue scale and a Likert scale are simple and responsive tools for assessing dysphagia in eosinophilic oesophagitis.
      Similarly, the ESS can be thought of as closely related to the EREFS, but with the categories collapsed. We do acknowledge that validated symptom and endoscopic assessments for evaluating EoE have now been published,
      • Schoepfer A.M.
      • Straumann A.
      • Panczak R.
      • et al.
      Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis.
      • Hirano 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.
      • Dellon 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.
      • Franciosi J.P.
      • Hommel K.
      • DeBrosse C.W.
      • et al.
      Development of a validated patient-reported symptom metric for pediatric eosinophilic esophagitis: qualitative methods.
      and these should be applied in future prospective studies. In addition, we used a 30-day recall period for the VAS. This period is relatively long and may have produced inaccuracies not seen with a shorter recall period. Furthermore, because we limited our final analyses to non-dilated patients, the sample size analyzing symptomatic and combined symptomatic and endoscopic outcomes was smaller than the entire cohort. This may have limited power to detect meaningful changes but not the validity of the findings. Outcomes were also assessed after an initial 8-week treatment course. Therefore, we are unable to comment on what histologic threshold might decrease long-term complications such as strictures of the esophagus or intermittent outcomes such as food bolus impactions. Last, most patients received tCS, so the results may not be fully applicable to dietary elimination.
      This study also has multiple strengths. This is one of the largest prospective cohorts with post-treatment data. In addition, because these results were found outside of a clinical trial, we believe they represent “real-world” response rates that could be typical of clinical practice, giving them broad applicability. The analyses linking specific histologic treatment outcomes to symptomatic and endoscopic responses are also relatively unique in the EoE literature, particularly when considering prospectively collected data. We used a VAS for symptomatic outcomes, which we previously documented to represent a reliable and responsive measure.
      • Reed C.
      • Wolf W.
      • Cotton C.
      • et al.
      A visual analogue scale and a Likert scale are simple and responsive tools for assessing dysphagia in eosinophilic oesophagitis.
      This allowed us to capture patient symptom experience along a continuum, rather than relying on physician impression of symptom improvement. In addition, endoscopic outcomes were captured prospectively with an ESS that is conceptually similar to the EREFS scoring system.
      • Hirano 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.
      We also excluded patients with baseline esophageal dilation to obviate confounding. Last, the post-treatment eosinophil cutpoints were similar to those that we previously reported in a retrospective study, which strengthens the validity of our current conclusions.
      • Wolf W.A.
      • Cotton C.C.
      • Green D.J.
      • et al.
      Evaluation of histologic cutpoints for treatment response in eosinophilic esophagitis.
      In conclusion, we identified post-treatment eosinophil counts that best predicted symptom, endoscopic, and combined responses of 8, 15, and 5 eos/hpf, respectively. After exploring potential histologic outcome thresholds, we favor an eosinophil cutpoint of <15 eos/hpf because this optimizes the probability of symptomatic and endoscopic improvement while also being readily attainable in most patients. It also provides conceptual symmetry, mirroring the current diagnostic threshold of ≥15 eos/hpf, which has been supported by empiric data.
      • Dellon S.
      • Speck O.
      • Woodward K.
      • et al.
      Distribution and variability of esophageal eosinophilia in patients undergoing upper endoscopy.
      Although difficult to obtain in routine clinical practice, a threshold of 5 eos/hpf maximizes symptomatic and endoscopic responses. This cutpoint may be more appropriate in settings such as clinical trials if a stringent histologic threshold is desired. These cutpoints provide a starting point for future investigations where the merits of this response threshold in additional prospective cohorts of EoE can be assessed.

      Supplementary Materials

       Methods

      We identified all patients with inflammatory (ie, exudates, furrows, and/or edema) and fibrotic (ie, rings and/or strictures) on endoscopy. Logistic regression models and ROC curves determined the post-treatment eosinophil counts and percentage change in eosinophil counts best predicting complete resolution of both phenotypes. We also examined patients by the location (ie, proximal, middle, and distal esophagus) of esophageal eosinophilic infiltration >15 eos/hpf at baseline. Patients were stratified into those with all segments involved, 2 of 3 segments involved, 1 of 3 segments involved, and 1 and/or 2 segments involved. Logistic regression models and ROC curves determined the histologic cutpoint and associated AUC best predicting symptom, endoscopic, and combined responses in these subsets.

       Results

      We found 56 patients (90%) with inflammatory features before treatment, 55 patients (89%) with fibrotic features, and 53 patients (85%) with evidence of both. A cutpoint of 14 eos/hpf with AUC of 0.73 best predicted the complete resolution of inflammatory features. A 90% decrease in eosinophil counts best predicted the same outcome and was associated with AUC of 0.74. Similarly, for the complete resolution of fibrotic features of EoE, a cutpoint of 0 eos/hpf with associated AUC of 0.68 best predicted this outcome. The percentage change best predicting fibrotic feature resolution was 100%, and AUC was also 0.68.
      After stratifying the cohort by level of esophageal eosinophilic involvement, the post-treatment eosinophil counts and AUCs for symptomatic, endoscopic, and combined responses were 11 eos/hpf and 0.80, 27 eos/hpf and 0.87, and 11 eos/hpf and 0.81, respectively, in patients with all 3 segments involved at baseline. The same values when examining the percentage change in post-treatment eosinophil counts were 93% and 0.80, 85% and 0.90, and 92% and 0.85, respectively. For patients with 1 and/or 2 involved segments, the post-treatment eosinophil count and AUC for endoscopic response were 24 eos/hpf and 0.85, respectively. Additional analyses examining patients with only 1 segment and examining patients with 2 involved segments were not statistically significant (Supplementary Table 1).
      Figure thumbnail fx1
      Supplementary Figure 1(A) Symptomatic responses per post-treatment eosinophil category. (B) Endoscopic responses per post-treatment eosinophil category. (C) Combined symptomatic and endoscopic responses per post-treatment eosinophil category. (D) AUC values per treatment response using post-treatment eosinophil counts. (E) AUC values per treatment response using 50% change in post-treatment eosinophil count. (F) AUC values per treatment response using 90% change in post-treatment eosinophil count.
      Supplementary Table 1Post-treatment Histologic Cutpoints and AUCs for Symptom, Endoscopic, and Combined Responses per Pre-treatment Esophageal Levels of Involvement
      Logistic regression models were significant for all predictions with 3 levels of involvement and endoscopic response with 1 and/or 2 levels of involvement using post-treatment counts.
      Esophageal segments (proximal, middle, distal) with >15 eos/hpf at baselineHistologic cutpoint
      Peak post-treatment eosinophil count per high-power field/% change from baseline in post-treatment eosinophil count.
      AUC
      Peak post-treatment eosinophil count per high-power field/% change from baseline in post-treatment eosinophil count.
      All 3 esophageal levels (n = 31)
       Symptomatic response11/93%0.81/0.80
       Endoscopic response27/85%0.87/0.90
       Combined response11/92%0.81/0.85
      One and/or 2 esophageal levels (n = 28)
       Symptomatic response0/100%0.75/0.55
       Endoscopic response24/75%0.85/0.69
       Combined response10/60%0.71/0.73
      Two esophageal levels (n = 15)
       Symptomatic response1/5%0.73/0.67
       Endoscopic response25/75%0.88/0.85
       Combined response
      Too few observations to model response.
      /
      Too few observations to model response.
      Too few observations to model response.
      /
      Too few observations to model response.
      One esophageal level (n = 13)
       Symptomatic response0/100%0.56/0.44
       Endoscopic response28/100%0.81/0.81
       Combined response
      Too few observations to model response.
      /
      Too few observations to model response.
      Too few observations to model response.
      /
      Too few observations to model response.
      AUC, area under the curve; eos/hpf, eosinophils per high-power field.
      a Logistic regression models were significant for all predictions with 3 levels of involvement and endoscopic response with 1 and/or 2 levels of involvement using post-treatment counts.
      b Peak post-treatment eosinophil count per high-power field/% change from baseline in post-treatment eosinophil count.
      c Too few observations to model response.

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