Impedance and Histologic Characteristics of the Sub-Laryngeal Esophagus Distinguish Eosinophilic Esophagitis From Other Esophageal Disorders.

BACKGROUND & AIMS: The region of the esophagus 15-17 cm below the incisors, called the sub-upper esophageal sphincter (sub-UES), has not been characterized in adults with eosinophilic esophagitis (EoE) but appears different during endoscopy. We investigated how the sub-UES differs from the remaining esophagus in patients with EoE and aimed to determine whether these differences be used to distinguish patients with EoE from those with lichen planus. METHODS: We performed a prospective study of 14 patients with EoE, 7 patients with lichen planus (based on presence of Civatte bodies, dysphagia, and/or narrow esophagus with thin esophageal mucosa without signs of EoE), and 20 patients undergoing upper endoscopy for upper gastrointestinal or with dysphagia but without features of EoE (controls) at a single medical center from 2015 through 2018. Biopsies from the distal, middle, and sub-UES regions of the esophagus were analyzed by histology, quantitative PCR, and immunohistochemistry. We measured mucosal impedance (MI) in all subjects at the sub-UES and 2 cm, 5 cm, and 10 cm from the gastro-esophageal junction. RESULTS: Patients with EoE had significantly fewer eosinophils (median, 2 eosinophils/high-powered field [HPF]; range, 0-8 eosinophils/HPF) in sub-UES tissues compared with distal esophagus (median, 50 eosinophils/HPF; range, 22.5-60.8 eosinophils/HPF; P < .0001) or middle esophagus (median, 32 eosinophils/HPF; range, 19.3-60; P < .0001). Sub-UES tissues from patients with EoE had significantly less basal cell hyperplasia (P < .01), papillary elongation (P < .01), and dilated intercellular spaces (P < .01) than middle or and distal esophagus. MI in the sub-UES did not differ significantly between patients with EoE vs controls (P = .24), but was significantly lower in patients with lichen planus (median, 1344 ohms; range, 1046-1488) than patients with EoE (median, 2880 ohms; range, 2149-4858) (P < .001). mRNA and protein expression patterns did not differ significantly in the sub-UES of patients with EoE vs controls, except for expression of desmoglein-1, which was increased in sub-UES tissues from patients with EoE. CONCLUSIONS: Sub-UES tissues from patients with EoE differ in numbers of eosinophils, histologic features, and MI compared to controls or patients with lichen planus. These features might help to distinguish these 2 diseases.

Model to Select On-Therapy vs Off-Therapy Tests for Patients With Refractory Esophageal or Extraesophageal Symptoms.

BACKGROUND & AIMS: It is not clear whether we should test for reflux in patients with refractory heartburn or extraesophageal reflux (EER) symptoms, such as cough, hoarseness, or asthma. Guidelines recommend testing patients by pH monitoring when they are on or off acid-suppressive therapies based on pretest probability of reflux, determined by expert consensus. However, it is not clear what constitutes a low or high pretest probability of reflux in these patients. We aimed to develop a model that clinicians can use at bedside to estimate pretest probability of abnormal reflux. METHODS: We performed a prospective study of 471 adult patients with refractory heartburn (n = 214) or suspected EER symptoms (n = 257) who underwent endoscopy with wireless pH monitoring while they were off acid-suppressive treatment and assigned them to groups based on symptoms at presentation (discovery cohort). Using data from the discovery cohort, we performed proportional odds ordinal logistic regression to select factors (easy to obtain demographic criteria and clinical symptoms such as heartburn, regurgitation, asthma, cough, and hoarseness) associated with esophageal exposure to acid. We validated our findings in a cohort of 118 patients with the same features from 2 separate tertiary care centers (62% women; median age 59 years; 62% with cough as presenting symptom). RESULTS: Abnormal pH (>5.5% of time spent at pH <4) was found in 56% of patients with heartburn and 63% of patients with EER (P = .15). Within EER groups, abnormal pH was detected in a significantly larger proportion (80%) of patients with asthma compared with patients with cough (60%) or hoarseness (51%; P < .01). Factors significantly associated with abnormal pH in patients with heartburn were presence of hiatal hernia and body mass index >25 kg/m2. In patients with EER, the risk of reflux was independently associated with the presence of concomitant heartburn (odds ratio [OR] 2.0; 95% confidence interval [CI] 1.3-3.1), body mass index >25 kg/m2 (OR 2.1; 95% CI 1.5-3.1), asthma (OR 2.0; 95% CI 1.2-3.5), and presence of hiatal hernia (OR 1.9; 95% CI 1.2-3.1). When we used these factors to create a scoring system, we found that a score of ≤2 excluded patients with moderate to severe reflux, with a negative predictive value of 80% in the discovery cohort and a negative predictive value of 85% in the validation cohort. CONCLUSION: We developed a clinical model to estimate pretest probability of abnormal pH in patients who were failed by proton pump inhibitor therapy. This system can help guide clinicians at bedside in determining the most appropriate diagnostic test in this challenging group of patients.

Esophageal Mucosal Impedance Patterns Discriminate Patients With Eosinophilic Esophagitis From Patients With GERD.

BACKGROUND & AIMS: It is a challenge to make a diagnosis of eosinophilic esophagitis (EoE) because its symptoms and histologic features overlap with those of gastroesophageal reflux disease (GERD). A minimally invasive device was recently developed to detect mucosal impedance (MI) that measures epithelial integrity during upper endoscopy. We aimed to quantify MI along the esophagus and identify patterns that differentiated patients with and without GERD from those with EoE, and determine whether MI values and patterns are sufficient to identify patients with EoE using histologic findings as a reference. METHODS: We performed a retrospective analysis of 91 patients with upper gastrointestinal symptoms referred for diagnostic testing for GERD and EoE from 2012 through 2014 (discovery set). During the first endoscopy, MI measurements were obtained at 2, 5, and 10 cm from the squamocolumnar junction. GERD was confirmed by ambulatory pH tests, and histologic analyses of biopsies were used to confirm EoE. We then used statistical modeling to identify MI patterns along the esophagus (at 10 cm, 5 cm, and 2 cm) that associated with GERD vs EoE. We validated our findings in a prospective cohort of 49 patients undergoing elective upper endoscopy for dysphagia, from 2015 through 2016, testing the ability of MI patterns to identify patients with vs. without EoE. RESULTS: We found patients with EoE to have a unique MI pattern, with low values along the esophageal axis. MI measurements at 5 cm could discern patients with normal vs abnormal mucosa with 83% sensitivity and 79% specificity, and patients with EoE vs GERD with 84% sensitivity and 70% specificity; these measurements differentiated the patient populations with the highest level of accuracy of any of the 6 measurements tested. In the validation study, a rater using the esophageal MI pattern identified patients with EoE with 100% sensitivity and 96% specificity. CONCLUSION: We identified and validated a pattern of MI along the esophagus that can identify patients with EoE vs normal mucosa or GERD with high levels of sensitivity.

Semiautomated Glasgow-Blatchford Bleeding Score helps direct bed placement for patients with upper gastrointestinal bleeding.

OBJECTIVE: The Glasgow-Blatchford Bleeding Score (GBS) was designed to identify patients with upper gastrointestinal bleeding (UGIB) who do not require hospitalisation. It may also help stratify patients unlikely to benefit from intensive care. DESIGN: We reviewed patients assigned a GBS in the emergency room (ER) via a semiautomated calculator. Patients with a score ≤7 (low risk) were directed to an unmonitored bed (UMB), while those with a score of ≥8 (high risk) were considered for MB placement. Conformity with guidelines and subsequent transfers to MB were reviewed, along with transfusion requirement, rebleeding, length of stay, need for intervention and death. RESULTS: Over 34 months, 1037 patients received a GBS in the ER. 745 had an UGIB. 235 (32%) of these patients had a GBS ≤7. 29 (12%) low-risk patients were admitted to MBs. Four low-risk patients admitted to UMB required transfer to MB within the first 48 hours. Low-risk patients admitted to UMBs were no more likely to die, rebleed, need transfusion or require more endoscopic, radiographic or surgical procedures than those admitted to MBs. No low-risk patient died from GIB. Patients with GBS ≥8 were more likely to rebleed, require transfusion and interventions to control bleeding but not to die. CONCLUSION: A semiautomated GBS calculator can be incorporated into an ER workflow. Patients with a GBS ≤7 are unlikely to need MB care for UGIB. Further studies are warranted to determine an ideal scoring system for MB admission.

Unmet needs in treating laryngo-pharyngeal reflux disease: where do we go from here?

INTRODUCTION: Many patients experience ear, nose and throat symptoms associated with their gastroesophageal reflux disease. These symptoms are purportedly caused by reflux of gastroduodenal contents into the larynx, which leads to laryngopharyngeal reflux (LPR). Various modalities are used to diagnose LPR, including ambulatory pH monitoring, laryngoscopy, and esophagogastroduodenoscopy, as well as a few new emerging diagnostic tests. However, there are still no established diagnostic criteria or gold standard methodologies that can reliably distinguish LPR from other conditions. AREAS COVERED: In this review, we will evaluate currently available diagnostic tests and therapeutic options for patients with laryngeal signs and symptoms of reflux and briefly discuss the development and emergence of new treatments. Numerous studies have investigated the role of proton pump inhibitor therapy in this patient population, but have led to disparate and often inconsistent results. Expert commentary: While a subgroup of patients with LPR appears to respond to PPI therapy, many patients show no symptomatic improvement, particularly with respect to extraesophageal symptoms. As such, there is a vital need to explore alternative treatment options, including anti-reflux surgery, lifestyle changes, and other classes of medications to better address LPR.

Patient-Reported Outcome Measures Related to Laryngopharyngeal Reflux: A Systematic Review of Instrument Development and Validation.

OBJECTIVES: Patient-reported outcome (PRO) measures are often used to diagnose laryngopharyngeal reflux (LPR) and monitor treatment outcomes in clinical and research settings. The present systematic review was designed to identify currently available LPR-related PRO measures and to evaluate each measure's instrument development, validation, and applicability. DATA SOURCES: MEDLINE via PubMed interface, CINAHL, and Health and Psychosocial Instrument databases were searched with relevant vocabulary and key terms related to PRO measures and LPR. REVIEW METHODS: Three investigators independently performed abstract review and full text review, applying a previously developed checklist to critically assess measurement properties of each study meeting inclusion criteria. RESULTS: Of 4947 studies reviewed, 7 LPR-related PRO measures (publication years, 1991-2010) met criteria for extraction and analysis. Two focused on globus and throat symptoms. Remaining measures were designed to assess LPR symptoms and monitor treatment outcomes in patients. None met all checklist criteria. Only 2 of 7 used patient input to devise item content, and 2 of 7 assessed responsiveness to change. Thematic deficiencies in current LPR-related measures are inadequately demonstrated: content validity, construct validity, plan for interpretation, and literacy level assessment. CONCLUSION: Laryngopharyngeal reflux is often diagnosed according to symptoms. Currently available LPR-related PRO measures used to symptomatically identify suspected LPR patients have disparate developmental rigor and important methodological deficiencies. Care should be exercised to understand the measurement characteristics and contextual relevance before applying these PRO measures for clinical, research, or quality initiatives.

Thymidine analogs are transferred from prelabeled donor to host cells in the central nervous system after transplantation: a word of caution.

Thymidine analogs, including bromodeoxyuridine, chlorodeoxyuridine, iododeoxyuridine, and tritiated thymidine, label dividing cells by incorporating into DNA during S phase of cell division and are widely employed to identify cells transplanted into the central nervous system. However, the potential for transfer of thymidine analogs from grafted cells to dividing host cells has not been thoroughly tested. We here demonstrate that graft-derived thymidine analogs can become incorporated into host neural precursors and glia. Large numbers of labeled neurons and glia were found 3-12 weeks after transplantation of thymidine analog-labeled live stem cells, suggesting differentiation of grafted cells. Remarkably, however, similar results were obtained after transplantation of dead cells or labeled fibroblasts. Our findings reveal for the first time that thymidine analog labeling may not be a reliable means of identifying transplanted cells, particularly in highly proliferative environments such as the developing, neurogenic, or injured brain.