A synthesis and subgroup analysis of the eosinophilic esophagitis tissue transcriptome.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic immune mediated inflammatory disorder of the esophagus. It is still unknown why children and adults present differently, and there is little evidence about why it is more common in men than women. OBJECTIVE: Our aim was to synthesize published and unpublished esophageal bulk RNA-sequencing (RNA-seq) data to gain novel insights into the pathobiology of EoE and examine the differences in EoE transcriptome by sex and age group. METHODS: Esophageal bulk RNA-seq data from 5 published and 2 unpublished studies resulting in 137 subjects (EoE: N = 76; controls: N = 61) were analyzed. For overall analysis, combined RNA-seq data of patients with EoE were compared with those of controls and subgroup analysis was conducted in patients with EoE by age of the patient (children [<18 years] vs adults [≥18 years]) and sex (female vs male). Gene-set enrichment analysis, ingenuity pathway analysis (IPA), cell-type analysis, immunohistochemistry, and T-cell or B-cell receptor analysis were performed. RESULTS: Overall analysis identified dysregulation of new genes in EoE compared with controls. IPA revealed that EoE is characterized by a mixed inflammatory response compared with controls. Cell-type analysis showed that cell composition varied with age: children had more mast cells, whereas adults had more macrophages. Finally, gene-set enrichment analysis and IPA revealed pathways that were differentially regulated in adults versus children and male versus female patients with EoE. CONCLUSIONS: Using a unique approach to analyze bulk RNA-seq data, we found that EoE is characterized by a mixed inflammatory response, and the EoE transcriptome may be influenced by age and sex. These findings enhance insights into the molecular mechanisms of EoE.

Opioid Exposure Differentially Impacts Esophageal Body Contraction Over the Lower Esophageal Sphincter.

BACKGROUND & AIMS: Studies with limited sample sizes have investigated association of chronic opioid use with motility disorders of esophagogastric junction and esophageal body peristalsis. Our aims were to use a large cohort of patients to assess (1) the impact of opioid exposure on clinical and manometric characteristics, and (2) the association of opioid exposure with higher long-term symptom burden. METHODS: Patients recruited from a tertiary medical center who underwent high-resolution manometry (HRM) between 2007 and 2018 were included. Demographics, opiate exposure, clinical symptoms, and HRM parameters were compared. Patient-Reported Outcomes Measurement Information System-Gastrointestinal swallowing domain (PROMIS-GI swallowing domain) and Eckardt score were administered via phone interviews in patients with hypercontractile esophagus (HE) or distal esophageal spasm (DES) to determine long-term symptom burden between opioid and nonopioid users. RESULTS: Our cohort included 4075 patients (869 with opiate exposure with median morphine milligram equivalent [interquartile range] of 30 [10-45]). Patients in the opioid group were significantly more likely to have dysphagia (65% vs 51%, P < .01) and diagnosis of DES (11% vs 5%, P < .01) and HE (9% vs 3%, P < .01). Partial opioid agonists were not associated with motility abnormalities. Patients on opioids had significantly higher symptom burden on median (interquartile range) follow-up of 8.9 years (5.8-10.4) post manometric diagnosis with median PROMIS-GI swallowing domain score of 21.5 (17-25) compared with the nonopioid group at 15 (9.8-21, P = .03). CONCLUSIONS: Nearly 2 of 3 patients with opioid exposure undergoing HRM have dysphagia and more than 25% of them with dysphagia as the primary symptom have a diagnosis of either DES or HE. Opioid users with spastic disorders have higher symptom burden long-term compared with nonopioid users.

Mucosal Integrity Testing Can Detect Differences in the Rectums of Patients with Inflammatory Bowel Disease Compared to Controls: A Pilot Study.

BACKGROUND: While the pathogenesis of inflammatory bowel disease (IBD) is incompletely understood, disruption of epithelial integrity is suspected to play a prominent role in disease initiation and progression. Currently, there is no convenient way to measure this in vivo. AIMS: Our aim is to determine whether a mucosal integrity (MI) testing device that has been used to measure MI in the esophagus can also be used to measure barrier function in the colon during colonoscopy. METHODS: Mucosal integrity testing was measured in patients with IBD (n = 17) and controls (n = 7) during colonoscopy. During the procedure, an MI catheter was passed down the working channel of the colonoscope and placed along the mucosal wall to measure MI in the rectum, left, transverse, and right colon. In patients with IBD, MI measurements and biopsies were taken in areas which appeared inflamed when present. We then determined if there was a significant difference in MI between patients with IBD and controls. RESULTS: MI was significantly higher in the rectum of patients with IBD (CD and UC combined) versus control colons [767 (618-991) vs. 531 (418-604) ohms, P < 0.01]. There were no significant differences in MI among patients with IBD versus controls in the right, transverse, or left colon. Within the IBD group, there were no significant differences in MI between inflamed versus non-inflamed rectums. There was no correlation between quality of life scores or endoscopic severity with MI, though this study was likely underpowered to detect these differences. CONCLUSION: Rectal MI is significantly higher in patients with IBD versus controls. Future studies are needed to determine how this information can be used clinically.

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.

Measurements of Duodenal Mucosal Integrity Are Altered in Celiac Disease.

Altered barrier function is a part of celiac disease (CeD) pathophysiology that we currently cannot reliably measure. Catheter-based mucosal integrity (MI) is an endoscopic technology that has identified altered esophageal barrier function in esophageal disease.1 The aim of this study was to evaluate feasibility, safety, and clinical utility of measuring duodenal integrity with an MI catheter in patients with and without CeD.

Development and Validation of a Mucosal Impedance Contour Analysis System to Distinguish Esophageal Disorders.

BACKGROUND & AIMS: Diagnostic testing for chronic esophageal disorders relies on histopathology analysis of biopsies or uncomfortable transnasal catheters or wireless pH monitoring, which capture abnormal intraluminal refluxate. We therefore developed a balloon mucosal impedance (MI) catheter system that instantly detects changes in esophageal mucosal integrity during endoscopy over a long segment of the esophagus. We performed a prospective study to evaluate the ability of a balloon-incorporated MI catheter to detect and evaluate esophageal disorders, including gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE). METHODS: We performed a prospective study of 69 patients undergoing esophagogastroduodenoscopy with or without wireless pH monitoring. Patients were classified as having GERD (erosive esophagitis or abnormal pH; n = 24), EoE (confirmed with pathology analysis of tissues from both distal and proximal esophagus; n = 21), or non-GERD (normal results from esophagogastroduodenoscopy and pH tests; n = 24). Receiver operating characteristic curves and area under the operating characteristic curve (AUC) were used to compare the accuracy of balloon MI in diagnosis. Probabilities of assignment to each group (GERD, non-GERD, or EoE) were estimated using multinomial logistic regression. Association between MI patterns and diagnoses were validated using data from patients seen at 3 separate institutions. RESULTS: MI pattern along the esophageal axis differed significantly (P < .01) among patients with GERD, EoE, and non-GERD. Patients with non-GERD had higher MI values along all measured segments. The MI pattern for GERD was easily distinguished from that of EoE: in patients with GERD, MI values were low in the distal esophagus and normalized along the proximal esophagus, whereas in patients with EoE, measurements were low in all segments of the esophagus. Intercept and rate of rise of MI value (slope) as distance increased from the squamocolumnar junction identified patients with GERD with an AUC = 0.67, patients with EoE with an AUC = 0.84, and patients with non-GERD with an AUC = 0.83 in the development cohort. One patient had an adverse event (reported mild chest pain after the procedure) and was discharged from the hospital without further events. CONCLUSIONS: We developed a balloon MI catheter system that instantly detects changes in esophageal mucosal integrity during endoscopy and found it to be safe and able to identify patients with GERD, EoE, or non-GERD. We validated our findings in a separate cohort for patients. ClinicalTrials.gov ID NCT03103789.

Comparison of mucosal impedance measurements throughout the esophagus and mucosal eosinophil counts in endoscopic biopsy specimens in eosinophilic esophagitis.

BACKGROUND AND AIMS: Assessing eosinophilic esophagitis (EoE) activity from limited esophageal mucosal biopsy samples has been questioned. Here our aim was to compare mucosal impedance (MI) throughout the esophagus and eosinophil counts in endoscopic biopsy samples in EoE. METHODS: We compared 20-site MI using a balloon catheter in the esophagus and eosinophils per high-power field (eos/HPF) in esophageal mucosal biopsy samples. Data are summarized as median (interquartile range) comparing control subjects and EoE using Mann-Whitney rank sum test and between endoscopic reference score and MI (minimal and average) using rank Spearman correlation. RESULTS: Ten adult control patients (ages 38-70) and 23 EoE patients (ages 21-80, 18 active) were studied. The mean (range) pan-esophageal MI in control subjects was significantly higher (6435 ohms [4546-7301]) compared with EoE patients (2004 ohms [1437-2546], P < .001). In control patients 172 of 180 (95.6%) individual impedance measurements (18 per patient) were normal when compared with 126 of 432 (29.2%) measurements in EoE. No EoE patient had uniformly normal MI. MI varied widely, with 19 of 23 patients having values above and below 2300 ohms (normal) regardless of EoE activity. Correlation of maximim eos/HPF with minimum and average MI per patient was r = -.243, P = .072 and r = -.358, P = .086, respectively. Of 5 patients with inactive EoE, 3 had >50% abnormal MI segments. Correlation coefficients of the endoscopic reference score with minimum and average MI were r = -.154, P = .47 and r = -.27, P = .20, respectively. The procedure was <5 minutes without adverse events. CONCLUSIONS: MI is lower in the esophagus of EoE patients compared with control subjects with poor correlation between peak esophageal eosinophil counts, EoE activity, and MI. Segmental esophageal MI provides a unique marker of esophageal dysfunction in EoE. (Clinical trial registration number: NCT02995395.).

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.

Mucosal Impedance Measurements Differentiate Pediatric Patients With Active Versus Inactive Eosinophilic Esophagitis.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EoE) is a chronic disorder in children that requires continued assessment of disease activity, involving repeated sedation, endoscopy, and biopsy analysis. We investigated whether mucosal impedance measurements can be used to monitor disease activity in pediatric patients with EoE. METHODS: We measured mucosal impedance at 3 locations in the esophagus in pediatric patients (1-18 years old; 32 with active EoE, 10 with inactive EoE, 32 with nonerosive reflux disease [NERD]) and 53 children with symptoms but normal findings from histologic analyses (controls) undergoing routine esophagogastroduodenoscopy at the Vanderbilt Pediatric Gastroenterology Clinic. Pathologists reviewed biopsies per routine protocol, determined eosinophilic density, and graded spongiosis on an ordinal visual scale. Mucosal impedance measurements were compared within patient groups. The primary outcome was correlation of mucosal impedance measurements with disease activity, based on severity of spongiosis and eosinophil counts. RESULTS: Mucosal impedance measurements were significantly lower in patients with active EoE at 2, 5, and 10 cm above the squamo-columnar junction (median values of 1069, 1368, and 1707, respectively) compared to patients with inactive EoE (median values of 3663, 3657, and 4494, respectively), NERD (median values of 2754, 3243, and 4387), and controls (median values of 3091, 3760, and 4509) (P < 0.001 for all comparisons to patients with active EoE). We found inverse correlations between mucosal impedance measurements and eosinophil count (P < 0.001), and spongiosis severity (P < 0.001). CONCLUSIONS: Mucosal impedance measurements may provide immediate information about mucosal inflammation in children. Patients with active EoE have significantly lower mucosal impedance values than patients with inactive EoE, NERD, or controls; mucosal impedance measurements correlate inversely with eosinophil counts and spongiosis severity. Mucosal impedance is a promising rapid and less-invasive method to monitor EoE activity in pediatric patients with EoE; it could reduce costs and risks of disease monitoring.

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.

Association Between Response to Acid-Suppression Therapy and Efficacy of Antireflux Surgery in Patients With Extraesophageal Reflux.

BACKGROUND & AIMS: The effectiveness of antireflux surgery (ARS) varies among patients with extraesophageal manifestations of gastroesophageal reflux disease (GERD). By studying a cohort of patients with primary extraesophageal symptoms and abnormal physiologic markers for GERD, we aimed to identify factors associated with positive outcomes from surgery, and compare outcomes to those with typical esophageal manifestations of GERD. METHODS: We performed a retrospective cohort study to compare adult patients with extraesophageal and typical reflux symptoms who underwent de novo ARS from 2004 through 2012 at a tertiary care center. All 115 patients (79 with typical GERD and 36 with extraesophageal manifestations of GERD) had evidence of abnormal distal esophageal acid exposure based on pH testing or endoscopy. The principle outcome was time to primary symptom recurrence after surgery, based on patient reports of partial or total recurrence of symptoms at follow-up visits. Patients were followed up for a median duration of 66 months (interquartile range, 52-77 mo). RESULTS: The median time to recurrence of symptoms in the overall cohort was 68 months (11.5 months in the extraesophageal cohort vs >132 months in the typical cohort). Symptom recurrence after ARS was associated with having primarily extraesophageal symptoms (adjusted hazard ratio, 2.34; 95% confidence interval, 1.31-4.17) and poor preoperative symptom response to acid-suppression therapy (AST) (hazard ratio, 3.85; 95% confidence interval, 2.05-7.22). Patients with primary extraesophageal symptoms who had a full or partial preoperative AST response experienced lower rates of symptom recurrence compared to patients with poor AST response (P < .01). The rate of symptom recurrence was lowest among patients with primary typical reflux symptoms who had a partial or full symptom response to AST (P < .01). The severity of acid reflux on pH testing, symptom indices, severity of esophagitis, and hiatal hernia size were not associated with symptom response. CONCLUSIONS: In a retrospective study, we found the effectiveness of ARS to be less predictable in patients with extraesophageal symptoms of GERD than in patients with typical GERD. Response to AST before surgery was associated with ARS effectiveness in patients with extraesophageal reflux symptoms. Caution should be exercised when advocating ARS for patients with extraesophageal symptoms that do not respond to AST.

Esophageal Mucosal Impedance Pattern is Distinct in Patients With Extraesophageal Reflux Symptoms and Pathologic Acid Reflux.

OBJECTIVES/STUDY DESIGN: Current diagnostic tests for gastroesophageal reflux disease (GERD) do not consistently measure chronicity of reflux. Mucosal impedance (MI) is a minimally invasive measurement to assess esophageal conductivity changes due to GERD. We aimed to investigate MI pattern in patients with symptoms of extraesophageal reflux (EER) in a prospective longitudinal cohort study. METHODS: Patients with potential symptoms of EER undergoing esophagogastroduodenoscopy (EGD) with wireless pH monitoring were studied. Participants included those with erosive esophagitis (E+), normal EGD/abnormal pH (E-/pH+), and normal EGD/normal pH (E-/pH-). MI was measured from the site of injury in patients with E+, as well as at 2, 5, and 10 cm above the squamocolumnar junction (SCJ) in all participants. RESULTS: Forty-one patients with symptoms of EER were studied. MI measurements at 2 cm above the SCJ were significantly (P = 0.04) different among the three groups, with MI lowest for E+ and greatest for E-/pH- patients. Although not statistically significant, there is a graded increase in median (interquartile range) MI axially along the esophagus at 5 cm (P = 0.20) and at 10 cm (P = 0.27) above the SCJ, with those with reflux (E+ and E-/pH+) having a lower MI than those without. CONCLUSIONS: Patients with symptoms of EER and evidence of acid reflux have an MI lower than those without at 2 cm above the SCJ, with a trend at 5 cm and 10 cm as well. MI may be a tool to assess presence of GERD in patients presenting with EER symptoms.

Video on Diet Before Outpatient Colonoscopy Does Not Improve Quality of Bowel Preparation: A Prospective, Randomized, Controlled Trial.

OBJECTIVES: Successful outpatient colonoscopy (CLS) depends on many factors including the quality of a patient's bowel preparation. Although education on consumption of the pre-CLS purgative can improve bowel preparation quality, no study has evaluated dietary education alone. We have created an educational video on pre-CLS dietary instructions to determine whether dietary education would improve outpatient bowel preparation quality. METHODS: A prospective randomized, blinded, controlled study of patients undergoing outpatient CLS was performed. All patients received a 4 l polyethylene glycol-based split-dose bowel preparation and standard institutional pre-procedure instructions. Patients were then randomly assigned to an intervention arm or to a no intervention arm. A 4-min educational video detailing clear liquid diet restriction was made available to patients in the intervention arm, whereas those randomized to no intervention did not have access to the video. Patients randomized to the video were provided with the YouTube video link 48-72 h before CLS. An attending endoscopist blinded to randomization performed the CLS. Bowel preparation quality was scored using the Boston Bowel Preparation Scale (BBPS). Adequate preparation was defined as a BBPS total score of ≥6 with all segment scores ≥2. Wilcoxon rank-sum and Pearson's χ2-tests were performed to assess differences between groups. RESULTS: Ninety-two patients were randomized (video: n=42; control: n=50) with 47 total video views being tallied. There were no demographic differences between groups. There was no statistically significant difference in adequate preparation between groups (video=74%; control=68%; P=0.54). CONCLUSIONS: The availability of a supplementary patient educational video on clear liquid diet alone was insufficient to improve bowel preparation quality when compared with standard pre-procedure instruction at our institution.

Providing Hospitalized Patients With an Educational Booklet Increases the Quality of Colonoscopy Bowel Preparation.

BACKGROUND & AIMS: Inadequate bowel preparation is a problem frequently encountered by gastroenterologists who perform colonoscopies on hospitalized patients. A method is needed to increase the quality of bowel preparation in inpatients. An educational booklet has been shown to increase the overall quality of bowel preparation for outpatients. We performed a prospective study to evaluate the effects of an educational booklet on the quality of bowel preparation in a group of hospitalized patients. METHODS: We performed a randomized, single-blind, controlled trial of all inpatients at a tertiary care medical center scheduled for inpatient colonoscopy from October 2013 through March 2014. They were randomly assigned to groups that were (n = 45) or were not (controls, n = 40) given the booklet before bowel preparation the evening before their colonoscopy. All patients received a standard bowel preparation (clear liquid diet the day before the procedure, followed by split-dose GoLYTELY). At the colonoscopy, the Boston Bowel preparation scale (BBPS) was used to assess bowel preparation. The primary outcome measure was adequate bowel preparation (a total BBPS score ≥6 with all segment scores ≥2). Secondary outcomes assessed included total BBPS score, BBPS segment score, and a total BBPS score of 0. RESULTS: There were no differences between the groups in age, race, sex, body mass index, history of colonoscopy, history of polyps, or time of colonoscopy. Twenty-eight patients who received the booklet (62%) and 14 who did not (35%) had an adequate bowel preparation (P = .012). The number needed to treat to attain adequate bowel preparation was 4. After adjusting for age and history of prior colonoscopies, the odds of achieving an adequate bowel preparation and a higher total BBPS score after receipt of the booklet were 3.14 (95% confidence interval, 1.29-7.83) and 2.27 (95% confidence interval, 1.05-4.88), respectively. Three patients in the booklet group and 9 in the no-booklet group had a BBPS score of 0 (P = .036). The mean BBPS segment score was greater for the booklet group than the no-booklet group (right colon, P = .097; transverse colon, P = .023; left colon, P = .045). CONCLUSIONS: In a randomized controlled trial, we found that providing hospitalized patients with an educational booklet on colonoscopy preparation increases the odds of a quality bowel preparation more than 2-fold.

Airway Hypersensitivity, Reflux, and Phonation Contribute to Chronic Cough.

BACKGROUND & AIMS: Although chronic cough is common, its etiology is often elusive, making patient management a challenge. Gastroesophageal reflux and airway hypersensitivity can cause chronic cough. We explored the relationship between reflux, phonation, and cough in patients with idiopathic chronic cough. METHODS: We performed a blinded, cross-sectional study of nonsmoking patients with chronic cough (duration, >8 weeks) refractory to reflux treatment referred to the Digestive Disease Center at Vanderbilt University. All underwent 24-hour acoustic recording concurrently and temporally synchronized with ambulatory pH-impedance monitoring. Cough, phonation, and pH-impedance events were recorded. We evaluated the temporal relationship between cough and phonation or reflux events using Poisson and logistic regression. RESULTS: Seventeen patients met the inclusion criteria (88% female; 100% white; median age, 63 years [interquartile age range, 52-66 years]; mean body mass index, 30.6 [interquartile range, 27.9-34.0]); there were 2048 analyzable coughing events. The probability of subsequent coughing increased with higher burdens of preceding cough, reflux, or phonation. Within the first 15 minutes after a cough event, the cough event itself was the main trigger of subsequent cough events. After this period, de novo coughing occurred with increases of 1.46-fold in association with reflux alone (95% confidence interval, 1.17-1.82; P < .001) and 1.71-fold in association with the combination of phonation and reflux events. CONCLUSIONS: Antecedent phonation and reflux increased the rate of cough events in patients with idiopathic chronic cough. Reflux events were more strongly associated with increased rate of coughing. Our findings support the concept that airway hypersensitivity is a cause of chronic cough, and that the vocal folds may be an effector in chronic cough ClinicalTrials.gov number: NCT01263626.

Mucosal impedance discriminates GERD from non-GERD conditions.

BACKGROUND & AIMS: Current diagnostic tests for gastroesophageal reflux disease (GERD) are suboptimal and do not accurately and reliably measure chronicity of reflux. A minimally invasive device has been developed to assess esophageal mucosal impedance (MI) as a marker of chronic reflux. We performed a prospective longitudinal study to investigate MI patterns in patients with GERD and common nonreflux conditions, to assess MI patterns before and after treatment with proton pump inhibitors and to compare the performance of MI and wireless pH tests. METHODS: We evaluated MI in 61 patients with erosive esophagitis, 81 with nonerosive but pH-abnormal GERD, 93 without GERD, 18 with achalasia, and 15 with eosinophilic esophagitis. MI was measured at the site of esophagitis and at 2, 5, and 10 cm above the squamocolumnar junction in all participants. MI was measured before and after acid suppressive therapy, and findings were compared with those from wireless pH monitoring. RESULTS: MI values were significantly lower in patients with GERD (erosive esophagitis or nonerosive but pH-abnormal GERD) or eosinophilic esophagitis than in patients without GERD or patients with achalasia (P < .001). The pattern of MI in patients with GERD differed from that in patients without GERD or patients with eosinophilic esophagitis; patients with GERD had low MI closer to the squamocolumnar junction, and values increased axially along the esophagus. These patterns normalized with acid suppressive therapy. MI patterns identified patients with esophagitis with higher levels of specificity (95%) and positive predictive values (96%) than wireless pH monitoring (64% and 40%, respectively). CONCLUSIONS: Based on a prospective study using a prototype device, measurements of MI detect GERD with higher levels of specificity and positive predictive values than wireless pH monitoring. Clinical Trials.gov, Number: NCT01556919.

Preference of endoscopic ablation over medical prevention of esophageal adenocarcinoma by patients with Barrett's esophagus.

BACKGROUND & AIMS: Endoscopic intervention or pharmacologic inhibition of cyclooxygenase might be used to prevent progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC). We investigated whether patients with BE prefer endoscopic therapy or chemoprevention of EAC. METHODS: Eighty-one subjects with nondysplastic BE were given a survey that described 2 scenarios. The survey explained that treatment A (ablation), endoscopy, reduced lifetime risk of EAC by 50%, with 5% risk for esophageal stricture, whereas treatment B (aspirin) reduced lifetime risk of EAC by 50% and the risk of heart attack by 30%, yet increased the risk for ulcer by 75%. Subjects indicated their willingness to undergo either treatment A and/or treatment B if endoscopic surveillance were required every 3-5 years, every 10 years, or were not required. Visual aids were included to represent risk and benefit percentages. RESULTS: When surveillance was required every 3-5 years, more subjects were willing to undergo treatment A than treatment B (78%, 63 of 81 vs 53%, 43 of 81; P < .01). There were no differences in age, sex, education level, or history of cancer, heart disease, or ulcer between patients willing to undergo treatment A and those willing to undergo treatment B. Altering the frequency of surveillance did not affect patients' willingness to undergo either treatment. CONCLUSIONS: In a simulated scenario, patients with BE preferred endoscopic intervention over chemoprevention for EAC. Further investigation of the shared decision-making process regarding preventive strategies for patients with BE may be warranted.

The role of impedance monitoring in patients with extraesophageal symptoms.

OBJECTIVES/HYPOTHESIS: Ambulatory esophageal impedance monitoring is commonly employed to assess for nonacid reflux in patients with extraesophageal reflux. We aimed to determine if on therapy impedance data can be predicted from off therapy upper endoscopy, manometry, or pH parameters. STUDY DESIGN: Prospective Cohort Study. METHODS: Patients with extraesophageal reflux symptoms and either partial- or nonresponders to twice-daily PPI underwent impedance monitoring on twice-daily PPI, as well as manometry, upper endoscopy, and 48-hour wireless pH monitoring off acid-suppressive medications for 1 week. Percent time pH < 4 and number of reflux episodes were obtained. Multivariable linear regression was used to determine association between the impedance data on therapy and upper endoscopy, manometry, and pH parameters measured off therapy. RESULTS: Seventy-five patients (77% female, median BMI 29, 38% with hiatal hernia, and 19% with esophagitis) were studied both on and off therapy. Thirty-five percent had abnormal impedance monitoring on therapy and 84% had abnormal pH testing off therapy. There was no significant (P = 0.184) overall correlation between total number of impedance events and the baseline physiologic parameters of hiatal hernia, degree of acid reflux, or manometric findings, with only weak correlation (r = 0.54, P = 0.045) with % time pH < 4 among patients with esophagitis. CONCLUSIONS: In patients with suspected extraesophageal reflux refractory to PPI therapy, impedance measures on therapy cannot be predicted from traditional baseline esophageal physiologic parameters. We recommend caution regarding over-interpretation of impedance data. LEVEL OF EVIDENCE: 2b.

Symptom reports are not reliable during ambulatory reflux monitoring.

OBJECTIVES: Patient reporting of symptom events during ambulatory reflux monitoring is commonly performed with little data regarding its accuracy. We employed a novel time-synchronized ambulatory audio recording of symptom events simultaneously with prolonged pH/impedance monitoring to assess temporal accuracy of patient-reported symptoms. METHODS: An acoustic monitoring system was employed to detect cough events via tracheal and chest wall sounds and it was temporally synchronized with an ambulatory impedance/pH monitoring system. Patients were instructed to record their symptoms in the usual manner. Six separate observers independently listened to the 24-h audio recordings and logged the exact timing of each cough event. Patients were blinded to study design and the audio reviewers were blinded to their own reports and those of patients and other reviewers. Concurrence of audio recordings and patient-reported symptoms were tested for three separate time thresholds: 1, 2, and 5 min. RESULTS: The median (interquartile range (IQR)) number of cough events by audio detection was significantly (P<0.001) higher than those reported by patients: 216 (90-275) and 34 (22-60), respectively. There was significantly (P<0.001) higher agreement among the audio recording listeners (substantial to almost perfect agreement; kappa=0.77-0.82) than between the audio recording and patient-reported symptoms (slight to fair agreement; kappa=0.13-0.27). Patients did not report 91, 82, and 71% of audible cough events based on 1-, 2-, and 5-min concordance time windows, respectively. CONCLUSIONS: We found that patients do not report the majority of their symptoms during ambulatory reflux monitoring even within a 5-min time window of the true event and advise caution in clinical decision-making based solely on symptom indices.