Mepolizumab for treatment of adolescents and adults with eosinophilic oesophagitis: a multicentre, randomised, double-blind, placebo-controlled clinical trial.

OBJECTIVE: We aimed to determine whether mepolizumab, an anti-IL-5 antibody, was more effective than placebo for improving dysphagia symptoms and decreasing oesophageal eosinophil counts in eosinophilic oesophagitis (EoE). METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled, trial. In the first part, patients aged 16-75 with EoE and dysphagia symptoms (per EoE Symptom Activity Index (EEsAI)) were randomised 1:1 to 3 months of mepolizumab 300 mg monthly or placebo. Primary outcome was change in EEsAI from baseline to month 3 (M3). Secondary outcomes included histological, endoscopic and safety metrics. In part 2, patients initially randomised to mepolizumab continued 300 mg monthly for 3 additional months (mepo/mepo), placebo patients started mepolizumab 100 mg monthly (pbo/mepo), and outcomes were reassessed at month 6 (M6). RESULTS: Of 66 patients randomised, 64 completed M3, and 56 completed M6. At M3, EEsAI decreased 15.4±18.1 with mepolizumab and 8.3±18.0 with placebo (p=0.14). Peak eosinophil counts decreased more with mepolizumab (113±77 to 36±43) than placebo (146±94 to 160±133) (p<0.001). With mepolizumab, 42% and 34% achieved histological responses of <15 and ≤6 eos/hpf compared with 3% and 3% with placebo (p<0.001 and 0.02). The change in EoE Endoscopic Reference Score at M3 was also larger with mepolizumab. At M6, EEsAI decreased 18.3±18.1 points for mepo/mepo and 18.6±19.2 for pbo/mepo (p=0.85). The most common adverse events were injection-site reactions. CONCLUSIONS: Mepolizumab did not achieve the primary endpoint of improving dysphagia symptoms compared with placebo. While eosinophil counts and endoscopic severity improved with mepolizumab at 3 months, longer treatment did not yield additional improvement. TRIAL REGISTRATION NUMBER: NCT03656380.

Determination of a treatment response threshold for the Eosinophilic Esophagitis Endoscopic Reference Score.

BACKGROUND: Endoscopic features of eosinophilic esophagitis (EoE) are measured using the validated EoE Endoscopic Reference Score (EREFS); however, a threshold for treatment response has not been defined. We aimed to determine a cut-point for endoscopic response as measured by EREFS. METHODS: We performed a secondary analysis of a randomized clinical trial comparing budesonide slurry with swallowed fluticasone multidose inhaler for initial treatment of EoE. In the parent trial, EREFS was determined before and after treatment (score range 0-9), as were histologic findings and dysphagia symptoms. We performed tabular, flexible trend, and dependent mixture analyses of measures of treatment response to select the best clinical EREFS threshold. RESULTS: In the 111 included patients (mean age 39 years; 67 % male; 96 % white), an EREFS threshold of ≤ 2 was 80 % sensitive (95 % confidence interval [CI] 69 % to 88 %) and 83 % specific (95 %CI 67 % to 94 %) for histologic response (peak of < 15 eosinophils per high-power field). Flexible trend analysis and dependent mixture modeling similarly suggested that a threshold of ≤ 2 best captured the correlation of EREFS with histologic and symptomatic measures. Dependent mixture modeling found near-total membership in the response class at EREFS of 0 or 1 and > 75 % at EREFS of 2 or 3. CONCLUSIONS: An EREFS of ≤ 2 was the best clinical threshold for endoscopic response to topical steroid treatment, and was consistent with clinical and histologic response. Therefore, future studies can report a binary outcome of endoscopic response when EREFS is 2 or less.

A Model Using Clinical and Endoscopic Characteristics Identifies Patients at Risk for Eosinophilic Esophagitis According to Updated Diagnostic Guidelines.

BACKGROUND AND AIMS: Updated diagnostic guidelines for eosinophilic esophagitis (EoE) have eliminated the requirement for a proton pump inhibitor (PPI) trial, but there are no models to identify patients with EoE based on these new criteria. We aimed to develop a predictive model for diagnosis of EoE based on the updated EoE diagnostic guidelines. METHODS: We performed a secondary analysis of a prospective study of adult patients referred for outpatient esophagogastroduodenoscopy at University of North Carolina who had symptoms of esophageal dysfunction; patients with prevalent EoE were excluded. We analyzed data from 206 EoE cases (mean age 40.1, 62.6% male, 93.2% white) and 306 controls (mean age 52.3, 37.9% male, 79.7% white). We built predictive models for case-control status, using clinical, endoscopic, and histologic features, and defining EoE by either the new or historical definition of PPI non-response. Model discrimination was assessed by the area under the receiver-operator characteristic curve (AUC). RESULTS: Before endoscopy, younger age, male sex, history of atopic condition or food allergy, and dysphagia identified patients with EoE with an AUC of 0.83. When we included endoscopy findings suggestive of EoE, the model identified patients with EoE with an AUC of 0.92; this increased to 0.99 when histology was included. CONCLUSION: We developed a model to identify patients with EoE, without a trial of PPIs, based on updated diagnostic guidelines. Clinical features and endoscopic findings identified patients with EoE with an AUC of 0.92-even without histologic data and in the absence of dysphagia. This model can be used to select patients with upper gastrointestinal symptoms but without dysphagia for early diagnostic endoscopy. The model can also be used to identify cases of EoE when eosinophil counts are greater than 15 in biopsies but other causes of esophageal eosinophilia cannot necessarily be excluded.

Generic Measures of Quality of Life Are Not Correlated with Disease Activity in Eosinophilic Esophagitis.

BACKGROUND: The relationship between histologic disease activity in eosinophilic esophagitis (EoE) and generic measures of quality of life (QoL) is unclear. AIMS: To determine differences in QoL in adults with EoE based on histologic activity and assess changes in QoL over time. METHODS: We performed an analysis of prospectively collected data from patients in the University of North Carolina EoE Registry. Patients were categorized with histologically active (≥ 15 eosinophils per high-power field [eos/hpf]) or inactive (< 15 eos/hpf) disease. Dysphagia severity was measured with a Likert scale. QoL was measured with 36-Item Short Form (SF-36), compared between active and inactive groups, and assessed longitudinally. RESULTS: Of 147 EoE cases, those with inactive disease (n = 56) reported less dysphagia severity (3.2 vs. 1.9; p = 0.003) and had lower endoscopic severity (3.8 vs. 1.0; p < 0.001) than those with active disease (n = 91). While SF-36 scores did not differ between active and inactive status, lower mental component scores (MCS) were seen in patients treated with empiric dietary elimination (44.9 vs. 50.8; p = 0.005). Dysphagia severity was negatively correlated with both physical component score (PCS) (r = -0.33; p < 0.001) and MCS (r = -0.18; p = 0.03). Despite more cases achieving histologic response over time, SF-36 scores did not improve on either raw or adjusted analyses. CONCLUSION: QoL measured by SF-36 in EoE was similar regardless of histologic disease activity and was in the range of population averages. General QoL metrics like the SF-36 do not appear to have substantial utility in EoE.

Rapid Recurrence of Eosinophilic Esophagitis Activity After Successful Treatment in the Observation Phase of a Randomized, Double-Blind, Double-Dummy Trial.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is chronic and recurs if treatment is discontinued. We aimed to determine rates of recurrence, and whether initial treatment with oral viscous budesonide (OVB) resulted in less recurrence than fluticasone from a multidose inhaler (MDI). METHODS: This was the observation phase of a randomized, double-blind, double-dummy trial comparing OVB with MDI for initial EoE treatment. Subjects with a histologic response (<15 eosinophils/high-power field) in the trial entered an observation phase in which treatment was discontinued and symptoms were monitored. Patients underwent an endoscopy or a biopsy when symptoms recurred or at 1 year. We analyzed time to symptom recurrence and assessed endoscopic severity and histologic relapse (≥15 eosinophils/high-power field) at follow-up endoscopy. RESULTS: Thirty-three of the 58 subjects (57%) had symptom recurrence before 1 year. The overall median time to symptom recurrence was 244 days. There was no difference in the rate of symptom recurrence for subjects treated with OVB vs MDI (hazard ratio, 1.04; 95% CI, 0.52-2.08). At symptom recurrence, 78% of patients had histologic relapse. The patients had significant increases in mean Dysphagia Symptom Questionnaire score (3.8 vs 8.7; P < .001), and the EoE Endoscopic Reference Score (1.3 vs 4.6; P < .001) compared with end of treatment. CONCLUSIONS: EoE disease activity recurred rapidly after initial histologic response to topical steroids (either OVB or MDI). Because most subjects had recurrent endoscopic and histologic signs not reliably detected by symptoms, maintenance therapy should be recommended in EoE patients achieving histologic response to topical steroids. Clinicaltrials.gov no: NCT02019758.

Efficacy of Budesonide vs Fluticasone for Initial Treatment of Eosinophilic Esophagitis in a Randomized Controlled Trial.

BACKGROUND AND AIMS: Topical steroid treatments for eosinophilic esophagitis (EoE) include swallowed fluticasone from a multi-dose inhaler (MDI) or oral viscous budesonide (OVB) slurry, but the 2 have never been compared. We assessed whether OVB was more effective than MDI for initial treatment of patients with EoE. METHODS: In a double-blind, double-dummy trial, patients with a new diagnosis of EoE were randomly assigned to groups given 8 weeks of either OVB (1 mg/4 mL) twice daily plus a placebo inhaler (n = 56) or fluticasone MDI (880 µg) twice daily plus a placebo slurry (n = 55). Primary outcomes were post-treatment maximum eosinophil counts per high-power field (eos/hpf) and a validated dysphagia score (dysphagia symptom questionnaire [DSQ]) at week 8. Secondary outcomes included endoscopic severity (validated EoE endoscopic reference score), histologic response (<15 eos/hpf), and safety. RESULTS: In a modified intention-to-treat analysis, the subjects had baseline peak eosinophil counts of 73 and 77 eos/hpf in the OVB and MDI groups, respectively, and DSQ scores of 11 and 8. Post-treatment eosinophil counts were 15 and 21 in the OVB and MDI groups, respectively (P = .31), with 71% and 64% achieving histologic response (P = .38). DSQ scores were 5 and 4 in the OVB and MDI groups (P = .70). Similar trends were noted for post-treatment total EoE endoscopic reference scores (2 vs 3; P = .06). Esophageal candidiasis developed in 12% of patients receiving OVB and 16% receiving MDI; oral thrush was observed in 3% and 2%, respectively. CONCLUSIONS: In a randomized clinical trial, initial treatment of EoE with either OVB or fluticasone MDI produced a significant decrease in esophageal eosinophil counts and improved dysphagia and endoscopic features. However, OVB was not superior to MDI, so either is an acceptable treatment for EoE. ClinicalTrials.gov ID NCT02019758.

Dilation Modifies Association Between Symptoms and Esophageal Eosinophilia in Adult Patients With Eosinophilic Esophagitis.

INTRODUCTION: We investigated whether dilation modifies the association between symptoms and esophageal eosinophilia (peak esophageal eosinophils/high-power field [eos/hpf]) in patients with eosinophilic esophagitis enrolled into a randomized trial comparing the efficacy of budesonide and fluticasone. METHODS: Baseline Dysphagia Symptom Questionnaire and Eosinophilic Esophagitis Activity Index were available in 102 and 73 patients, respectively, of whom 56 and 39 underwent dilation at screening endoscopy before symptom assessment. The pair-wise relationship between Dysphagia Symptom Questionnaire, Eosinophilic Esophagitis Activity Index, and eos/hpf was analyzed with nonparametric correlations. RESULTS: In nondilated patients, the association between baseline eos/hpf and symptoms was moderate and significant, although it was abolished in dilated patients. DISCUSSION: Dilation modifies association between symptoms and eos/hpf (clinicaltrials.gov NCT02019758).

Utility of major basic protein, eotaxin-3, and mast cell tryptase staining for prediction of response to topical steroid treatment in eosinophilic esophagitis: analysis of a randomized, double-blind, double dummy clinical trial.

Inflammatory factors in eosinophilic esophagitis (EoE), including major basic protein (MBP), eotaxin-3 (EOT3) and mast cell tryptase (TRP), may predict treatment response to topical corticosteroids (tCS). We aimed to determine whether baseline levels of these markers predict response to tCS for EoE. To do this, we analyzed data from a randomized trial comparing two topical steroids for treatment of newly diagnosed EoE (NCT02019758). A pretreatment esophageal biopsy was stained for MBP, EOT3, and TRP to quantify tissue biomarker levels (cells/mm2). Levels were compared between histologic responders (<15 eos/hpf) and nonresponders (the primary outcome), and endoscopic responders (EREFS<2) and nonresponders. Complete histologic response (<1 eos/hpf) was also assessed, and area under the receiver operator characteristic curve (AUC) was calculated. We also evaluated whether baseline staining predicted symptom relapse in the trial's off-treatment observation phase. Baseline samples were evaluable in 110/111 subjects who completed the randomized trial. MBP levels were higher in nonresponders (n = 36) than responders (704 vs. 373 cells/mm2; P = 0.007), but EOT3 and TRP levels were not statistically different. The combination of all three stains had an AUC of 0.66 to predict response. For complete histologic response, baseline TRP levels were higher in nonresponders (n = 69) than responders (370 vs. 268 mast cells/mm2; P = 0.01), with an AUC of 0.65. The AUC for endoscopic response was 0.68. Baseline staining did not predict symptom recurrence after remission. Pretreatment MBP, EOT3, and TRP levels were not strongly or consistently associated with histologic or endoscopic response to topical steroids. While elevated TRP levels may be associated with nonresponse compared with complete response, the magnitude and predictive utilities were modest. Novel methods for predicting steroid response are still required.

Clinical and Molecular Factors Associated With Histologic Response to Topical Steroid Treatment in Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Few factors have been identified that can be used to predict response of patients with eosinophilic esophagitis (EoE) to topical steroid treatment. We aimed to determine whether baseline clinical, endoscopic, histologic, and molecular features of EoE can be used to predict histologic response. METHODS: We collected data from 97 patients with EoE, from 2009 through 2015, treated with a topical steroid for 8 weeks; 59 patients had a histologic response to treatment. Baseline clinicopathologic features and gene expression patterns were compared between patients with a histologic response to treatment (<15 eos/hpf) and non-responders (≥15 eos/hpf). We performed sensitivity analyses for alternative histologic response definitions. Multivariate logistic regression was performed to identify predictive factors associated with response to therapy, which were assessed with area under the receiver operator characteristic (AUROC) curves. RESULTS: Baseline dilation was the only independent predictor of non-response (odds ratio [OR], 0.30; 95% CI, 0.10-0.89). When an alternate response (<1 eos/hpf) and non-response (<50% decrease in baseline eos/hpf) definition was used, independent predictors of response status were age (OR, 1.08; 95% CI, 1.02-1.14), food allergies (OR, 12.95; 95% CI, 2.20-76.15), baseline dilation (OR, 0.17; 95% CI, 0.03-0.88), edema or decreased vascularity (OR, 0.20; 95% CI, 0.04-1.03), and hiatal hernia (OR, 0.07; 95% CI, 0.01-0.66). Using these 5 factors, we developed a predictive model that discriminated complete responders from non-responders with an AUROC of 0.88. Baseline gene expression patterns were not associated with treatment response and did not change with different histologic response thresholds. CONCLUSIONS: In an analysis of 97 patients with EoE, we found dilation to be the only baseline factor associated with non-response to steroid treatment (<15 eos/hpf). However, a model comprising 5 clinical, endoscopic, and histologic factors identified patients with a complete response (<1 eos/hpf). A baseline gene expression panel was not predictive of treatment response at any threshold.

Variation in Endoscopic Activity Assessment and Endoscopy Score Validation in Adults With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is assessed endoscopically (endoscopic activity), based on grades of edema, rings, exudates, furrows, and strictures (EREFS). We examined variations in endoscopic assessments of severity, developed and validated 3 EREFS-based scoring systems, and assessed responsiveness of these systems using data from a randomized placebo-controlled trial of patients with EoE. METHODS: For the development set, 5 gastroenterologists reviewed EREFS findings from 266 adults with EoE and provided endoscopist global assessment scores (EndoGA, scale of 0 to 10); variation (ΔEndoGA) was assessed using linear regression. We evaluated simple scores (features given arbitrary values from 0 to 3) and developed 2 scoring systems (adjusted score range, 0-100). We then fitted our linear regression model with mean EndoGA to data from 146 adults recruited in centers in Switzerland and the United States between April 2011 and December 2012. For the validation set, we collected data from 120 separate adults (recruited in centers in Switzerland and the United States between May 2013 and July 2014), assessing regression coefficient-based scores using Bland-Altman method. We assessed the responsiveness of our scoring systems using data from a randomized trial of patients with EoE given fluticasone (n=16) or placebo (n=8). RESULTS: The distribution of EndoGA values differed among endoscopists (mean ΔEndoGA, 2.6±1.8; range 0-6.6). We developed 2 regression-based scoring systems to assess overall and proximal and distal esophageal findings; variation in endoscopic features accounted for more than 90% of the mean EndoGA variation. In the validation group, differences between mean EndoGA and regression-based scores were small (ranging from -4.70 to 2.03), indicating good agreement. In analyses of data from the randomized trial, the baseline to end of study change in patients given fluticasone was a reduction of 24.3 in simple score (reduction of 4.6 in patients given placebo, P=.052); a reduction of 23.5 in regression-based overall score (reduction of 6.56 in patients given placebo, P=.12), and a reduction of 23.8 (reduction of 8.44 in patients given placebo, P=.11). CONCLUSION: Assessments of endoscopic activity in patients with EoE vary among endoscopists. In an analysis of data from a randomized controlled trial, we found that newly developed scoring systems are no better than simple scoring system in detecting changes in endoscopic activity. These results support the use of a simple scoring system in evaluation of endoscopic activity in patients with EoE. clinicaltrials.gov no: NCT00939263 and NCT01386112.

T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that affects the function and development of immune cells. Here, we show that recipient mice receiving AhR-/- T cells have improved survival and decreased acute graft-versus-host disease (aGVHD) in 2 different murine allogeneic bone marrow transplant (BMT) models. We also show that CD4+ T cells lacking AhR demonstrate reduced accumulation in secondary lymphoid tissue because of low levels of proliferation 4 days after BMT. Additionally, we found a significant increase in the quantity of peripherally induced regulatory donor T (pTreg) cells in the colon of recipients transplanted with AhR-/- T cells 14 days after transplant. Blockade of AhR using a clinically available AhR antagonist greatly enhanced the in vitro generation of inducible Treg (iTreg) cells from naïve CD4+ human T cells. We have identified AhR as a novel target on donor T cells that is critical to the pathogenesis of aGVHD.

Heartburn and dyspepsia symptom severity improves after treatment and correlates with histology in adults with eosinophilic esophagitis.

Non-dysphagia symptoms, such as heartburn and dyspepsia, are poorly characterized in adults with eosinophilic esophagitis (EoE). It is unclear if treatment improves these symptoms. The aim of this paper was to assess (i) heartburn and dyspepsia symptom severity in adult EoE patients using validated symptom measures; (ii) change in symptoms after treatment; and (iii) symptom association with endoscopic and histologic features. In a prospective cohort of adult EoE patients who were not responsive to proton pump inhibitor therapy, non-dysphagia symptoms were assessed with heartburn items from the validated GERD-HRQL (gastroesophageal reflux disease health-related quality of life) and SODA (severity of dyspepsia assessment) instruments. Subjects completed the questionnaires at baseline and after treatment. Association of baseline symptoms with endoscopic and histologic features, and before and after treatment with diet or topical steroids, was assessed. Eighty-six EoE patients (mean age 39 years, 57% male, 95% white) completed a baseline questionnaire and 62 completed the follow-up questionnaire. The mean baseline GERD-HRQL score was 4.5 ± 6.5 and the mean total SODA score was 41.0 ± 12.6. At baseline, there was a weak but significant correlation between peak eosinophils and the SODA score (r = 0.28; p = 0.03) and no association between heartburn and SODA scores and endoscopic or other histologic findings. After treatment, there was a decrease in GERD-HRQL heartburn (4.3 vs. 2.6; p = 0.04) and SODA (49.5 vs. 35.5; p = 0.04) scores in histologic responders, but not in nonresponders. In a prospective cohort of EoE patients, baseline eosinophils positively correlated with dyspepsia severity. Heartburn and dyspepsia symptoms improved after treatment in histologic responders.

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

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.

Symptoms Have Modest Accuracy in Detecting Endoscopic and Histologic Remission in Adults With Eosinophilic Esophagitis.

BACKGROUND & AIMS: It is not clear whether symptoms alone can be used to estimate the biologic activity of eosinophilic esophagitis (EoE). We aimed to evaluate whether symptoms can be used to identify patients with endoscopic and histologic features of remission. METHODS: Between April 2011 and June 2014, we performed a prospective, observational study and recruited 269 consecutive adults with EoE (67% male; median age, 39 years old) in Switzerland and the United States. Patients first completed the validated symptom-based EoE activity index patient-reported outcome instrument and then underwent esophagogastroduodenoscopy with esophageal biopsy collection. Endoscopic and histologic findings were evaluated with a validated grading system and standardized instrument, respectively. Clinical remission was defined as symptom score <20 (range, 0-100); histologic remission was defined as a peak count of <20 eosinophils/mm(2) in a high-power field (corresponds to approximately <5 eosinophils/median high-power field); and endoscopic remission as absence of white exudates, moderate or severe rings, strictures, or combination of furrows and edema. We used receiver operating characteristic analysis to determine the best symptom score cutoff values for detection of remission. RESULTS: Of the study subjects, 111 were in clinical remission (41.3%), 79 were in endoscopic remission (29.7%), and 75 were in histologic remission (27.9%). When the symptom score was used as a continuous variable, patients in endoscopic, histologic, and combined (endoscopic and histologic remission) remission were detected with area under the curve values of 0.67, 0.60, and 0.67, respectively. A symptom score of 20 identified patients in endoscopic remission with 65.1% accuracy and histologic remission with 62.1% accuracy; a symptom score of 15 identified patients with both types of remission with 67.7% accuracy. CONCLUSIONS: In patients with EoE, endoscopic or histologic remission can be identified with only modest accuracy based on symptoms alone. At any given time, physicians cannot rely on lack of symptoms to make assumptions about lack of biologic disease activity in adults with EoE. ClinicalTrials.gov, Number: NCT00939263.

Causes and Outcomes of Esophageal Perforation in Eosinophilic Esophagitis.

GOALS: To characterize patients who suffer perforation in the context of eosinophilic esophagitis (EoE) and to identify predictors of perforation. BACKGROUND: Esophageal perforation is a serious complication of EoE. MATERIALS AND METHODS: We conducted a retrospective cohort study of the University of North Carolina EoE clinicopathologic database from 2001 to 2014. Subjects were included if they had an incident diagnosis of EoE and met consensus guidelines, including nonresponse to a PPI trial. Patients with EoE who had suffered perforation at any point during their course were identified, and compared with EoE cases without perforation. Multiple logistic regression was performed to determine predictors of perforation. RESULTS: Out of 511 subjects with EoE, 10 (2.0%) had experienced an esophageal perforation. Although those who perforated tended to have a longer duration of symptoms before diagnosis (11.4 vs. 7.0 y, P=0.13), a history of food impaction (odds ratio, 14.9; 95% confidence interval, 1.7-129.2) and the presence of a focal stricture (odds ratio, 4.6; 95% confidence interval, 1.1-19.7) were the only factors independently associated with perforation. Most perforations (80%) occurred after a prolonged food bolus impaction, and only half of individuals (5/10) carried a diagnosis of EoE at the time of perforation; none occurred after dilation. Six patients (60%) were treated with nonoperative management, and 4 (40%) required surgical repair. CONCLUSIONS: Esophageal perforation is a rare but serious complication of eosinophilic esophagitis, occurring in ∼2% of cases. Most episodes are due to food bolus impaction or strictures, suggesting that patients with fibrostenotic disease due to longer duration of symptoms are at increased risk.

Association Between Body Mass Index and Clinical and Endoscopic Features of Eosinophilic Esophagitis.

BACKGROUND: Because eosinophilic esophagitis (EoE) causes dysphagia, esophageal narrowing, and strictures, it could result in low body mass index (BMI), but there are few data assessing this. AIM: To determine whether EoE is associated with decreased BMI. METHODS: We conducted a prospective study at the University of North Carolina from 2009 to 2013 enrolling consecutive adults undergoing outpatient EGD. BMI and endoscopic findings were recorded. Incident cases of EoE were diagnosed per consensus guidelines. Controls had either reflux or dysphagia, but not EoE. BMI was compared between cases and controls and by endoscopic features. RESULTS: Of 120 EoE cases and 297 controls analyzed, the median BMI was lower in EoE cases (25 vs. 28 kg/m2, p = 0.002). BMI did not differ by stricture presence (26 vs. 26 kg/m2, p = 0.05) or by performance of dilation (26 vs. 27 kg/m2 for undilated; p = 0.16). However, BMI was lower in patients with narrow caliber esophagus (24 vs. 27 kg/m2, p < 0.001). EoE patients with narrow caliber esophagus also had decreased BMI compared to controls with narrow caliber esophagi (24 vs. 27 kg/m2, p = 0.001). On linear regression after adjustment for age, race, and gender, narrowing decreased BMI by 2.3 kg/m2 [95% CI -4.1, -0.6]. CONCLUSIONS: BMI is lower in EoE cases compared to controls, and esophageal narrowing, but not focal stricture, is associated with a lower BMI in patients with EoE. Weight loss or low BMI in a patient suspected of having EoE should raise concern for esophageal remodeling causing narrow caliber esophagus.

Accuracy of the Eosinophilic Esophagitis Endoscopic Reference Score in Diagnosis and Determining Response to Treatment.

BACKGROUND & AIMS: Little is known about the diagnostic utility of the Eosinophilic Esophagitis (EoE) Endoscopic Reference Score (EREFS), and how scores change in response to treatment. We investigated the operating characteristics of the EREFS in diagnosis of EoE, how the score changes with treatment, and ways to optimize scoring system. METHODS: We performed a prospective study of adults undergoing outpatient upper endoscopy from August 2011 through December 2013 at the North Carolina School of Medicine. Incident cases of EoE were diagnosed per consensus guidelines and were treated with topical steroids or dietary elimination (n = 67); 144 subjects without EoE were included as control subjects. EREFS scores were compared between cases and control subjects. For EoE cases, scores were compared before and after treatment. Area under the receiver operator characteristic curve analysis was used to determine diagnostic utility of the EREFS system. An iterative analysis was performed to determine optimal EREFS scoring weights. RESULTS: The mean total EREFS score was 3.88 for EoE cases and 0.42 for control subjects (P > .001); the score identified subjects with EoE with an area under the receiver operator characteristic curve of 0.934. After treatment of EoE cases, the mean score decreased from 3.88 to 2.01 (P > .001). This change was more prominent for patients with a histologic response (reduction to <15 eosinophils per high-power field) compared with nonresponders; posttreatment scores were 0.45 for responders versus 3.24 for nonresponders (P < .001). A weighted scoring system that doubled exudates, rings, and edema scores maximized the responsiveness of the total EREFS score. CONCLUSIONS: The EREFS classification system identifies patients with EoE an area under the receiver operator characteristic curve of 0.934; the score decreases with treatment, and histologic responders have significantly lower scores than nonresponders. This system can therefore be used to identify individuals with EoE and used as an endoscopic outcome measure to follow their response to treatment.

Outcomes of Esophageal Dilation in Eosinophilic Esophagitis: Safety, Efficacy, and Persistence of the Fibrostenotic Phenotype.

OBJECTIVES: Esophageal dilation is commonly performed in eosinophilic esophagitis (EoE), but there are few long-term data. The aims of this study were to assess the safety and long-term efficacy of esophageal dilation in a large cohort of EoE cases, and to determine the frequency and predictors of requiring multiple dilations. METHODS: We conducted a retrospective cohort study in the University of North Carolina EoE Clinicopathological Database from 2002 to 2014. Included subjects met consensus diagnostic criteria for EoE. Clinical, endoscopic, and histologic features were extracted, as were dilation characteristics (dilator type, change in esophageal caliber, and total number of dilations) and complications. Patients with EoE who had undergone dilation were compared with those who did not and also stratified by whether they required single or multiple dilations. RESULTS: Of 509 EoE patients, 164 were dilated a total of 486 times. Those who underwent dilation had a longer duration of symptoms before diagnosis (11.1 vs. 5.4 years, P<0.001). Ninety-five patients (58%) required >1 dilation (417 dilations total, mean of 4.4±4.3 per patient). The only predictor of requiring multiple dilations was a smaller baseline esophageal diameter. Dilation was tolerated well, with no major bleeds, perforations, or deaths. The overall complication rate was 5%, primarily due to post-procedural pain. Of 164 individuals dilated, a majority (58% or 95/164) required a second dilation. Of these individuals, 75% required repeat dilation within 1 year. CONCLUSIONS: Dilation in EoE is well-tolerated, with a very low risk of serious complications. Patients with long-standing symptoms before diagnosis are likely to require dilation. More than half of those dilated will require multiple dilations, often needing a second procedure within 1 year. These findings can be used to counsel patients with fibrostenotic complications of EoE.

The esophageal biopsy "pull" sign: a highly specific and treatment-responsive endoscopic finding in eosinophilic esophagitis (with video).

BACKGROUND AND AIMS: Esophageal biopsy specimens from patients with eosinophilic esophagitis (EoE) can feel firm, with resistance felt when pulling the forceps to obtain the tissue sample. We aimed to assess the diagnostic utility of the esophageal biopsy "pull" sign and determine its histologic associations and response to treatment. METHODS: This was a prospective cohort study of adults undergoing outpatient upper endoscopy. Cases of EoE were diagnosed per consensus guidelines, and patients were subsequently treated with either topical steroids or dietary elimination. Control subjects were individuals who did not have EoE. The frequency of the esophageal biopsy "pull" sign was assessed in EoE patients and controls, and diagnostic metrics were calculated. The "pull" sign was also reassessed in patients after therapy. RESULTS: A total of 83 EoE patients and 121 control subjects were included. Sixty-three EoE patients (76%) were "pull" sign positive compared with just 2 control subjects (2%; P < .001), corresponding to a sensitivity and specificity of 76% and 98%, positive and negative predictive values of 97% and 86%, and positive and negative likelihood ratios of 45.9 and 0.245, respectively. The "pull" sign was the strongest endoscopic predictor of EoE case status at baseline and was less frequent after successful treatment (20% vs 79%; P < .001). CONCLUSIONS: The "pull" sign is highly specific for EoE and is rarely seen in non-EoE control subjects. In patients with EoE who respond to treatment, the "pull" sign often resolves. The "pull" sign may be a simple and easily obtained measure of esophageal remodeling.

The extremely narrow-caliber esophagus is a treatment-resistant subphenotype of eosinophilic esophagitis.

BACKGROUND AND AIMS: Some patients with eosinophilic esophagitis (EoE) have an extremely narrow esophagus, but the characteristics of this group have not been extensively described. We aimed to characterize the narrow-caliber phenotype of EoE, determine associated risk factors, and identify differences in treatment response in this subgroup of patients. METHODS: This retrospective cohort study from 2001 to 2014 included subjects with a new diagnosis of EoE per consensus guidelines. Demographic, endoscopic, histologic, and treatment response data were extracted from medical records. An extremely narrow-caliber esophagus was defined when a neonatal endoscope was required to traverse the esophagus due to the inability to pass an adult endoscope. Patients with and without an extremely narrow-caliber esophagus were compared. Multivariable logistical regression was performed to assess treatment outcomes. RESULTS: Of 513 patients with EoE, 46 (9%) had an extremely narrow-caliber esophagus. These patients were older (33 vs 22 years; P < .01), had longer symptom duration (11 vs 3 years; P < .01), more dysphagia (98% vs 66%; P < .01), and food impactions (53% vs 31%; P < .01). Dilation was more common with extreme narrowing (69% vs 17%; P < .01). Patients with a narrow-caliber esophagus were more refractory to steroid treatment, with lower symptom (56% vs 85%), endoscopic (52% vs 76%), and histologic (33% vs 63%) responses (P < .01 for all), and these differences persisted after multivariate analysis. CONCLUSION: The extremely narrow-caliber esophagus is a more treatment-resistant subphenotype of EoE and is characterized by longer symptom duration and the need for multiple dilations. Recognition of an extremely narrow-caliber esophagus at diagnosis of EoE can provide important prognostic information.