Endoscopic Diagnosis of Eosinophilic Esophagitis Using a Multi-Task U-Net: A Pilot Study

A Summary of the Meetings of the Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS) International Multidisciplinary Consensus

The aim of the present study was to analyze the diagnostic accuracy of serum eosinophilic cationic protein (ECP) for eosinophilic esophagitis (EoE) and the correlation of ECP with clinical, histopathological, laboratory, and endoscopic features of EoE. Fifteen patients with EoE and 14 healthy controls were included in the study. Demographic parameters were recorded. EoE Endoscopic Reference Score (EREFS) was calculated according to endoscopic features, and esophageal biopsies were obtained by a single experienced endoscopist in a patient group. Serum ECP levels (μg/mL), absolute eosinophil count (U/mm3), and maximum peak of eosinophils/high-power field in esophageal biopsies were analyzed. The median age of all participants was 33.0 (min-max: 18-46) years. There were 27 (93.1%) male patients. Serum ECP level was significantly higher in patients with EoE than in healthy volunteers (20.4 vs. 8.8, p<0.0001). According to the receiver operating characteristic (ROC) curve analysis, ECP had 80% sensitivity and 92.8% specificity to diagnose EoE with a cut-off value of 13.9 µg/mL (area under the ROC curve 0.895; p<0.0001; 95% CI: 0.725-0.978). EREFS (p<0.0001) and the presence of food impaction (p=0.04) were significantly correlated with ECP. Serum ECP is an accurate non-invasive biomarker for EoE with high specificity and sensitivity. In addition, ECP is strongly correlated with EREFS and the symptom of food impaction.

INTRODUCTION: The validated Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) quantifies five key endoscopic features associated with eosinophilic esophagitis (EoE). We aimed to determine the post-treatment EREFS threshold that corresponds best with histologic response in patients with EoE after 12 weeks of therapy with budesonide oral suspension (BOS). METHODS: This post hoc analysis used data from a phase 3, 12-week, placebo-controlled trial in patients 11–55 years old with EoE and dysphagia (NCT02605837). Patients were randomized (2:1) to receive BOS 2.0 mg twice daily or placebo. Changes in EREFS from baseline to week 12 were measured as a secondary efficacy endpoint; total scores ranged from 0 to 20 (proximal and distal esophagus). We used a receiver operating characteristic (ROC) curve analysis to assess the accuracy of EREFS to distinguish between histologic responders (≤ 6 eosinophils/high-power field [eos/hpf]) and non-responders (>6 eos/hpf) after 12 weeks of BOS therapy, for patients who received ≥ 1 dose. The ROC curve was generated using the true-positive rate (sensitivity) versus the false-positive rate (1−specificity) for different cut-off thresholds of EREFS. The optimal threshold for EREFS was determined using the Youden Index (sensitivity+[specificity−1]). RESULTS: Overall, 318 patients received ≥ 1 dose of study drug. Only BOS-treated patients were included in this analysis (n = 213); of these, 113 (53.1%) were histologic responders. Greater improvements in least-squares mean EREFS were observed for BOS- versus placebo-treated patients (−4.0 vs −2.2, respectively; P < 0.001) from baseline to week 12. Histologic responders had significantly lower post-treatment EREFS and greater improvements in EREFS from baseline to week 12 of therapy than non-responders (Table 1). The area under the ROC curve was 0.705 for EREFS and histologic response (Figure 1). An EREFS of 4 was the optimal threshold for distinguishing histologic response to BOS therapy. Specifically, there was a 68% probability that a patient with a post-treatment EREFS of ≤ 4 was a true positive (responder). CONCLUSION: Endoscopic scoring of EoE with EREFS is responsive to BOS therapy and represents a parameter which has moderate accuracy for determining histologic response (≤ 6 eos/hpf). Analyses that evaluate EREFS compared with additional disease parameters will further support its use as an independent assessment of disease activity in patients with EoE.Table 1.: EREFS at baseline and after 12 weeks of therapy with BOS 2.0 mg b.i.d., stratified by histologic response statusFigure 1.: ROC curve analysis of EREFS to predict histologic response (≤ 6 eos/hpf) to 12 weeks of therapy with BOS 2.0 mg b.i.d. in patients with EoE.

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. 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. 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. 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.

Introduction: Eosinophilic esophagitis (EoE) has become an increasingly well-described disease entity characterized by symptoms of esophageal dysfunction and eosinophil-predominant inflammation of esophageal mucosa. EoE has been associated with atopic and autoimmune diseases. This study compares clinical and endoscopically identified esophageal manifestations of patients with EoE and inflammatory bowel disease (IBD) concomitantly to patients with EoE alone. Methods: Data from 22 patients with concomitant EoE and IBD (64% with Crohn's disease) and 50 control patients with EoE alone between 1993 and 2014 was retrospectively evaluated. Clinical charts of patients between ages 18-80 years old were identified using ICD-9 codes (EoE: 530.13; CD: 555.9, 555.1, 555.2, 555.0; UC: ICD-9 556.9, 557.0, 556.5, 556.3, 556.6) by our Enterprise Data Warehouse (EDW). EoE controls were tested to not be statistifically significantly different from patients with concomitant EoE and IBD in gender, race, or age. Demographic and disease-specific characteristics, endoscopic findings using a validated instrument (EoE Endoscopic Reference Score), histopathology, and treatment in patients with concomitant IBD and EoE were examined. Bivariate analysis with the chi-square test was used to look for statistical significance between the two groups.Table 1: Demographics and Disease-specific Characteristics of Concomitant EoE and IBD Compared to EoE AloneResults: Patients with concomitant EoE and IBD compared to EoE alone were found to have significantly less strictures (9% vs 58%, p=0.0001), furrows (64% vs 92%, p-0.003) and exudates (18% vs 56%, p=0.003) on endoscopy (Table and Figure 1). Of the 22 patients with concomitant EoE and IBD, 11 patients (50%) were treated with immunomodulators including anti-TNF agents, 6-MP, azathioprine and methotrexate for IBD, and 0/11 of these patients had strictures. Patients with EoE and IBD compared to EoE alone were also found to present less frequently with dysphagia as an initial symptom (68% vs 88%, p=0.04).Figure 1Conclusion: Patients with concomitant EoE and IBD demonstrated significantly lower prevalence of endoscopically identified inflammatory (furrows, exudate) and remodeling (stricture) features compared to EoE patients alone. The decreased activity of EoE in patients with concomitant EoE and IBD may be related to immunomodulator therapy used to treat IBD or earlier diagnosis of EoE owing to healthcare utilization amongst IBD patients.

Outcome of liver disease in children is mainly determined by severity and progression of liver fibrosis. Liver biopsy is the accepted standard for evaluating fibrosis but is limited by the need for sedation in children, sampling error, and risks including bleeding. The aim of the present study was to compare tools for noninvasive assessment of liver fibrosis in a paediatric cohort. Children undergoing liver biopsy for chronic liver disease were recruited and underwent transient elastography (TE). Liver biopsies were scored by a hepatohistopathologist from F0 (no fibrosis) to F4 (cirrhosis). TE was compared with biopsy score. During the study period, 104 children (62 boys) were enrolled (median age 13.6 years). Diagnosis was autoimmune liver disease in 27; nonalcoholic fatty liver disease in 37; posttransplant in 16; hepatitis B/C in 8; Wilson disease in 5; and the remainder, miscellaneous. TE was successful in all but 7 patients and was a good discriminator of significant fibrosis (≥ F2) (P < 0.001), severe fibrosis (≥ F3) (P < 0.001), and cirrhosis (F4) (P = 0.003). The area under the receiver operating characteristic curve for the prediction of ≥ F2, ≥ F3, and F4 using TE was 0.78, 0.79, and 0.96, respectively. TE performed best in children with autoimmune liver disease and in those posttransplant. The present study demonstrates that TE is a reliable tool in distinguishing different stages of liver fibrosis in paediatric patients. Thus, TE may serve as a useful adjunct to liver biopsy for diagnostic purposes providing a reliable method of noninvasively monitoring liver disease progression in children.

Eosinophilic esophagitis (EoE) is associated with atopy; however, recent studies have identified an association with food-specific immunoglobulin G 4 (FS-IgG 4 ) rather than immunoglobulin E antibodies. This study aimed to evaluate the role of serum FS-IgG 4 in guiding an elimination diet and its outcomes. Patients with and without EoE were enrolled in a prospective, controlled, single tertiary center trial. Serum FS-IgG 4 titers, esophageal eosinophil counts, and dysphagia symptom questionnaire scores were assessed, and participants with elevated FS-IgG 4 (ImmunoCAP, cutoff of 10 mgA/L) commenced 6-week targeted elimination diet. Repeat serum FS-IgG 4 and endoscopic and histologic examination were performed at 6-week follow-up. Twenty-two patients with active EoE and 13 controls were recruited. Serum FS-IgG 4 to milk, wheat, soy, eggs, and nuts was significantly higher in EoE ( P = 0.0002, P = 0.002, P = 0.003, P = 0.012, and P < 0.001, respectively). Elevated serum FS-IgG 4 to 1 or more food groups (median 2) was identified in 21/22 (95.4%) patients with EoE; 20/21 underwent 6-week dietary elimination. Median reductions in dysphagia symptom questionnaire score and EoE endoscopic reference score after elimination were 8 ( P = 0.0007) and 1 ( P = 0.002), respectively. Nine (45%) patients had histological remission (<15 eosinophils per high-power field). Fall in median esophageal eosinophil count was not statistically significant (50 vs 23; P = 0.068). Serum FS-IgG 4 did not decline by 6-week follow-up. Serum FS-IgG 4 to milk, wheat, soy, egg, and nuts was present at higher levels in EoE, with targeted elimination resulting in 45% histologic remission rate. Serum FS-IgG 4 has potential as a noninvasive biomarker in EoE. When successful, FS-IgG 4 -led elimination diet can negate need for medications and be viewed more favorably by patients because of its smaller endoscopic burden compared with empirical elimination diets.

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

Fluticasone Propionate Orally Disintegrating Tablet (APT-1011) for Eosinophilic Esophagitis: Randomized Controlled Trial

To extra validate and evaluate the reproducibility of a commercial deep convolutional neural network (DCNN) algorithm for pulmonary nodules on chest radiographs (CRs) and to compare its performance with radiologists. This retrospective study enrolled 434 CRs (normal to abnormal ratio, 246:188) from 378 patients that visited a tertiary hospital. DCNN performance was compared with two radiology residents and two thoracic radiologists. Abnormality assessment (using the area under the receiver operating characteristics (AUROC)) and nodule detection (using jackknife alternative free-response ROC (JAFROC)) were compared among three groups (DCNN only, radiologist without DCNN and radiologist with DCNN). A subset of 56 paired cases, having two CRs taken within a 7-day period, were assessed for intraobserver reproducibility using the intraclass correlation coefficient. Independent characteristics of pulmonary nodules detected by DCNN were assessed by multiple logistic regression analysis. The AUROC for abnormality detection for the three groups were 0.87, 0.93 and 0.96, respectively (P<0.05), whereas the JAFROC analysis of nodule detection was 0.926, 0.929 and 0.964. Reproducibility for the three groups was 0.80, 0.67 and 0.80, which shows an increase in radiologists using DCNN (P<0.05). Nodules detected by DCNN were more solid, round-shaped and well marginated, not masked and laterally located (P<0.05). Extra validation results of DCNN showed high ROC results and there was a significant improvement in the performance when radiologists used DCNN. Reproducibility by DCNN alone showed good agreement, and there was an improvement from moderate to good agreement for radiologists using DCNN.

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF ANTI-INTERLEUKIN-13 MONOCLONAL ANTIBODY RPC4046 IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS

Background/AimsThe epidemiology and pathogenesis of eosinophilic esophagitis (EoE) remain unclear in Asian countries. We investigated clinicopathological characteristics and diagnostic trends of EoE, and evaluated 3 tissue biomarkers for correlation with disease activity and treatment response in Korean patients with EoE.MethodsWe retrospectively reviewed 25 271 esophageal biopsies performed during upper endoscopies between 2006 and 2017. We diagnosed EoE based on ≥ 15 eosinophils/high-power field (HPF) and, symptoms of esophageal dysfunction. We performed immunohistochemical analysis for tryptase, eosinophilic derived neurotoxin (EDN), and eotaxin-3.ResultsWe diagnosed EoE in 72 patients (53 men and 19 women; mean age, 46.2 years) with presenting symptoms of, dysphagia (15.3%), epigastric pain (31.9%), and heartburn (30.6%). The diagnostic rate of EoE considerably increased between 2006 and 2017, from 0.29 diagnoses to 7.99 diagnoses per 1000 esophageal biopsies (P < 0.001). The mean peak eosinophil count (PEC) was 56.0 (± 77.8)/HPF. Whereas the EDN (rho = 0.667, P < 0.001) and eotaxin-3 levels (rho = 0.465, P < 0.001) correlated with PEC, tryptase and PEC were weakly correlated (rho = 0.291, P = 0.013). EDN (rho = 0.279, P = 0.017), and tryptase (rho = 0.279, P = 0.033) correlated with the inflammatory score of Eosinophilic Esophagitis Endoscopic Reference Score. Immunohistochemical analysis and changes in tryptase, EDN, and eotaxin-3 levels were associated with histologic and endoscopic improvements.ConclusionsEoE incidence considerably increased during the 12-year period, regardless of endoscopic esophageal biopsy rate. Tryptase, EDN, and eotaxin-3 levels in esophageal biopsy specimens could be promising biomarkers for disease activity, symptom, and endoscopic response in Korea.

Topical steroids are the primary medical therapy for eosinophilic esophagitis (EoE). Current steroid formulations are used off-label and designed for airway delivery. It is known that the efficacy of topical steroids depends on drug-mucosal contact time, which is related to its formulation. The purpose of this study is to examine the effectiveness of fluticasone administered by means of an orally administered powder formulation. We conducted a retrospective analysis of patients diagnosed with EoE based on current guidelines and who were treated with orally administered fluticasone powder. The primary outcome was histologic response (peak eosinophil density (eos/hpf)). Secondary outcomes included patient-reported symptoms (EoEQ) and endoscopic features measured by a validated instrument (EoE endoscopic reference score, EREFS). Forty patients were treated with fluticasone powder with doses of 500 to 1000 mcg b.i.d. A significant difference was found between pre- and posttreatment levels of eosinophilia (P<0.0001). Seventy-five percent of patients achieved peak densities of<15 eos/hpf. Improvement was also demonstrated in dysphagia symptoms (P=0.031) and endoscopic findings of furrows (P=0.0001) and exudates (P=0.0001). Oral fluticasone powder induced significant improvement in histopathology, symptoms, and endoscopic features of inflammation in adults with EoE. It offers an easy-to-administer formulation of a topical steroid that circumvents concerns with esophageal delivery of commonly used, aerosolized inhaler preparations.

Ovarian reserve index outperforms AMH, Inhibin B, and FSH in predicting poor egg supply

To compare the circumpapillary and macular vessel density (cpVD/mVD) of eyes with temporal visual field (VF) defect and band atrophy (BA) of the optic nerve and normal controls using OCTA and to verify the association of VD parameters with circumpapillary retinal nerve fibre layer (cpRNFL) thickness, macular ganglion cell complex (mGCC) thickness and VF loss. Thirty-three eyes of 26 patients with BA and 42 eyes of 22 age-matched normal controls underwent OCT + OCTA scanning. cpVD and cpRNFL were expressed as average and sector measurements. mVD and mGCC were calculated as averages and in quadrants and hemiretinas. VF loss was estimated using the 24-2 and the 10-2 protocols. Generalized estimated equation models were used for comparisons and area under the receiver operating characteristics (AROC) were calculated. Compared with controls, BA eyes displayed smaller average cpVD and mVD values (p < 0.001 and AROC = 0.91 for both). Sectorial measurements were also reduced, especially the nasotemporal sector average cpVD (p < 0.001 and AROC = 0.96) and the nasal retina mVD measurements (p < 0.001 and AROC = 0.93). cpVD and mVD correlated strongly with corresponding cpRNFL and mGCC thickness measurements in affected regions (r range: 0.67-0.78 and 0.56-0.76, respectively). Similarly, cpVD and mVD parameters correlated significantly with corresponding VF loss (r range: 0.45-0.68). cpVD and mVD are significantly reduced in BA eyes compared with controls and are strongly correlated with retinal neural and VF loss. cpVD and mVD reduction on OCTA could serve as a surrogate for retinal neural loss in compressive optic neuropathy and might be useful in its management.