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.

Lack of Knowledge and Low Readiness for Health Care Transition in Eosinophilic Esophagitis and Eosinophilic Gastroenteritis.

OBJECTIVES: A growing population of adolescents/young adults with eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE) will need to transition from pediatric to adult health providers. Measuring health care transition (HCT) readiness is critical, but no studies have evaluated this process in EoE/EGE. We determined the scope and predictors of HCT knowledge in patients and parents with EoE/EGE and measured HCT readiness in adolescents/young adults. METHODS: We conducted an online survey of patients 13 years or older and parents of patients with EoE/EGE who were diagnosed when 25 years or younger. Parents answered questions regarding their children and their own knowledge of HCT. HCT readiness was assessed in adolescents/young adults aged 13 to 25 years with the Self-Management and Transition to Adulthood with Rx Questionnaire (a 6-domain self-report tool) with a score range of 0 to 90. RESULTS: Four hundred fifty participants completed the survey: 205 patients and 245 parents. Included in the analysis (those diagnosed with EoE/EGE at age 25 years or younger) were 75 of 205 patients and children of 245 parent respondents. Overall, 78% (n = 52) of the patients and 76% (n = 187) of parents had no HCT knowledge. Mean HCT readiness score in adolescents/young adults (n = 50) was 30.4 ±â€Š11.3 with higher scores in domains of provider communication and engagement during appointments. Mean parent-reported (n = 123) score was 35.6 ±â€Š9.7 with higher scores in medication management and disease knowledge. CONCLUSIONS: There was a significant deficit in HCT knowledge, and HCT readiness scores were lower than other chronic health conditions. HCT preparation and readiness assessments should become a priority for adolescents/young adults with EoE/EGE and their parents.

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.

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.

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.

A Clinical Prediction Tool Identifies Cases of Eosinophilic Esophagitis Without Endoscopic Biopsy: A Prospective Study.

OBJECTIVES: Eosinophilic esophagitis (EoE) is difficult to distinguish from gastroesophageal reflux (GERD) and other causes of dysphagia. We assessed the utility of a set of clinical and endoscopic features for predicting EoE without obtaining esophageal biopsies. METHODS: We prospectively enrolled consecutive adults undergoing outpatient upper endoscopy at the University of North Carolina from July 2011 through December 2013. Incident cases of EoE were diagnosed per consensus guidelines. Non-EoE controls had either GERD- or dysphagia-predominant symptoms. A predictive model containing clinical and endoscopic, but no histological, data was assessed. Receiver operator characteristic curves were constructed and the area under the curve (AUC) was calculated. RESULTS: A total of 81 EoE cases (mean age 38 years; 60% male; 93% white; 141 eosinophils per high-power field (eos/hpf)) and 144 controls (mean age 52, 38% male; 82% white; 3 eos/hpf) were enrolled. A combination of clinical (age, sex, dysphagia, food allergy) and endoscopic (rings, furrows, plaques, hiatal hernia) features was highly predictive of EoE. The AUC was 0.944, with sensitivity, specificity, and accuracy of 84, 97, and 92%. Similar values were seen after limiting controls to those with only reflux or dysphagia or to those with esophageal eosinophilia not due to EoE. CONCLUSIONS: We validated a set of clinical and endoscopic features to predict EoE with a high degree of accuracy and allow identification of those at very low risk of disease. Use of these predictors at the point-of-care will avoid the effort and expense of low-yield histological examinations for EoE.

Utility of a Noninvasive Serum Biomarker Panel for Diagnosis and Monitoring of Eosinophilic Esophagitis: A Prospective Study.

OBJECTIVES: Noninvasive biomarkers would be valuable for diagnosis and monitoring of eosinophilic esophagitis (EoE). The aim of this study was to determine the utility of a panel of serum biomarkers for the diagnosis and management of EoE. METHODS: We conducted a prospective cohort study of consecutive adults undergoing outpatient esophagogastroduodenoscopy. Incident cases of EoE were diagnosed per consensus guidelines; controls had gastroesophageal reflux disease (GERD) or dysphagia and did not meet the EoE criteria. EoE cases were treated with topical steroids and had repeat endoscopy. Pre- and post-treatment serum samples were analyzed in a blinded manner for interleukin (IL)-4, IL-5, IL-6, IL-9, IL-13, transforming growth factor (TGF)-α, TGF-ß, tumor necrosis factor-α, eotaxin-1, -2, and -3, thymic stromal lymphopoietin (TSLP), major basic protein, and eosinophil-derived neurotoxin. Cases and controls were compared at baseline, and pre- and post-treatment assays were compared in cases. RESULTS: A total of 61 incident EoE cases and 87 controls were enrolled; 51 EoE cases had post-treatment serum analyzed. There were no significant differences in any of the biomarkers between EoE cases and controls at baseline. IL-13 and eotaxin-3 for cases and controls were 85 ± 160 vs. 43 ± 161 pg/ml (P=0.12) and 41 ± 159 vs. 21 ± 73 (P=0.30). There were no significant differences in assay values among cases before and after treatment. There were also no differences after stratification by atopic status or treatment response. CONCLUSIONS: A panel of inflammatory factors known to be associated with EoE pathogenesis were not increased in the serum, nor were they responsive to therapy. None of these biomarkers are likely candidates for a serum test for EoE. Histologic analysis for diagnosis and management of EoE continues to be necessary, and novel, less invasive, biomarkers are needed.

Markers of eosinophilic inflammation for diagnosis of eosinophilic esophagitis and proton pump inhibitor-responsive esophageal eosinophilia: a prospective study.

BACKGROUND & AIMS: Distinguishing between eosinophilic esophagitis (EoE), gastroesophageal reflux disease, and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is challenging. We assessed whether immunohistochemical analysis of esophageal tissues for major basic protein (MBP), eotaxin-3, and tryptase can be used for diagnosis of EoE and to differentiate EoE from PPI-REE. METHODS: We conducted a prospective study of 196 consecutive adults who underwent outpatient endoscopy at the University of North Carolina from 2009 through 2012. Incident cases of EoE were diagnosed per consensus guidelines. Patients with gastroesophageal reflux disease or dysphagia served as controls. PPI-REE was defined as a symptomatic and histologic response to a PPI. Immunohistochemistry was performed to quantify MBP, eotaxin-3, and tryptase. The maximum density of epithelial staining was determined for each assay; levels were compared between EoE and control groups and then EoE and PPI-REE groups, and receiver operating characteristic curves were constructed. RESULTS: Esophageal tissues from patients with EoE (n = 50) had a median 951 MBP-positive cells/mm(2), whereas those from controls (n = 123) had a median 2 MBP-positive cells/mm(2) (P < .001). Samples from patients with EoE had a median 155 eotaxin-3-positive cells/mm(2), and those from controls (n = 123) had 18 eotaxin-3-positive cells/mm(2) (P < .001). Samples from patients with EoE had a median 249 tryptase-positive cells/mm(2), and those from controls (n = 123) had 11 tryptase-positive cells/mm(2) (P < .001). Levels of MBP, eotaxin-3, tryptase, and the combination of all 3 identified patients with EoE with area under the receiver operating characteristic curve values of 0.99, 0.94, 0.99, and 1.00. Analyses of only samples with eosinophil counts of 10-100 eosinophils per high-power field produced similar results. No marker distinguished EoE from PPI-REE. Esophageal tissues from patients with PPI-REE (n = 23) had 987 MBP-positive cells/mm(2) (P = .18, compared with EoE), 160 eotaxin-3-positive cells/mm(2) (P = .33), and 243 tryptase-positive cells/mm(2) (P = .28). CONCLUSIONS: Esophageal tissues from patients with EoE have substantially higher levels of MBP, eotaxin-3, and tryptase than controls on the basis of immunohistochemical analysis. Assays for the 3 markers identify patients with EoE with 100% accuracy but cannot distinguish EoE from PPI-REE.

Clinical and endoscopic characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study.

OBJECTIVES: Proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is a newly recognized entity that must be differentiated from eosinophilic esophagitis (EoE). Little is known about this condition. We aimed to determine the prevalence of PPI-REE and EoE in patients undergoing upper endoscopy and determine features that distinguish the two groups. METHODS: This prospective study conducted at the University of North Carolina from 2009 to 2011 enrolled consecutive adult patients undergoing outpatient upper endoscopy. Subjects had esophageal biopsies to quantify the maximum eosinophil count per high-power field (eos/hpf; hpf=0.24 mm(2)). If biopsies revealed ≥15 eos/hpf, subjects were treated with twice daily PPI for 8 weeks and endoscopy was repeated. If ≥15 eos/hpf persisted despite PPI therapy, EoE was diagnosed. If there were <15 eos/hpf, PPI-REE was diagnosed. The proportion of patients in each group was calculated, and patients with EoE and PPI-REE were compared. RESULTS: Of the 223 subjects enrolled, 173 had dysphagia and 50 did not. Of those with dysphagia, 66 (38%) had ≥15 eos/hpf. After the PPI trial, 40 (23%) were confirmed to have EoE, and 24 (14%) had PPI-REE. Of those without dysphagia, 2 (4%) had ≥15 eos/hpf, and after the PPI trial, 1 (2%) had EoE. Compared with EoE, PPI-REE patients were more likely to be older and male and less likely to have typical endoscopic findings of EoE. However, none of the individual factors was independently predictive of PPI-REE status on multivariable analysis. Similarly, although some endoscopic findings were differentially distributed between PPI-REE and EoE, none were significantly associated with disease status on multivariable analysis. CONCLUSIONS: Esophageal eosinophilia is common among patients undergoing esophagogastroduodenoscopy for dysphagia. Although EoE was seen in nearly a quarter of patients with dysphagia, PPI-REE was almost as common, and accounted for over one-third of those with ≥15 eos/hpf. No clinical or endoscopic features independently distinguished PPI-REE from EoE before the PPI trial.