Twice-Daily Proton Pump Inhibitor Induces Higher Remission Rate in Eosinophilic Esophagitis Than Once-Daily Regimen Regardless of Total Daily Dose.

INTRODUCTION: The optimal proton pump inhibitor (PPI) regimen for eosinophilic esophagitis (EoE) is unclear. We compared histologic response rates of different dosing combinations. METHODS: A total of 305 patients with newly diagnosed EoE received standard (omeprazole 20 mg daily), once-daily moderate (40 mg daily), twice-daily moderate (20 mg twice daily), or high (40 mg twice daily) dose PPI for ≥8 weeks. RESULTS: Approximately 42.3% achieved histologic response to PPI, with higher rates for twice-daily (moderate 52.8%/high 54.3%) than once-daily (standard 11.8%/moderate 10%) dosing ( P < 0.0001). On multivariable analysis, twice-daily moderate (adjusted odds ratio 6.75, confidence interval 2.53-18.0, P = 0.0008) and high (adjusted odds ratio 12.8, confidence interval 4.69-34.8, P < 0.0001) doses independently predicted histologic response. DISCUSSION: Twice-daily PPI is associated with higher EoE histologic response rates than once-daily regimen.

Baseline Peripheral Eosinophil Count Independently Predicts Proton Pump Inhibitor Response in Eosinophilic Esophagitis.

GOALS: To assess the predictive value of baseline peripheral absolute eosinophil counts (AECs) for proton pump inhibitor (PPI) response in eosinophilic esophagitis (EoE). BACKGROUND: PPI leads to histologic remission in ~50% of EoE patients, although there are few distinguishing clinical features between PPI-responsive (PPI-r-EoE) and nonresponsive (PPI-nr-EoE) diseases. Peripheral eosinophilia is present in ~50% of EoE cases and is associated with eosinophil density on esophageal biopsy and worse clinical outcomes. The association between peripheral eosinophilia and PPI-responsiveness in EoE remains unclear. STUDY: This is a retrospective cohort study of adult EoE patients at a tertiary center between 2012 and 2016. All patients underwent twice daily PPI trials for ≥8 weeks followed by repeat esophageal biopsies and were classified as PPI-r-EoE or PPI-nr-EoE based on histologic response (<15 eosinophils/high power field). Baseline peripheral AEC was obtained within 1 month before index endoscopy. Analyses were performed using Fisher exact/Student t test (univariate) and logistic regression (multivariable). RESULTS: One hundred eighty-three patients (91 PPI-nr-EoE and 92 PPI-r-EoE) were included. Mean peripheral AEC was higher among PPI-nr-EoE patients (0.41 vs 0.24 K/µL, P = 0.013). Baseline peripheral eosinophilia (>0.5 K/µL) was more prevalent among patients with PPI-nr-EoE (70.4% vs 45.5%, P = 0.023) and a history of food impaction (51.9% vs 23.7%, P = 0.0082). On multivariable analyses, peripheral eosinophilia remained an independent predictor for PPI response (adjacent odds ratio = 2.86, CI: 1.07-7.62, P = 0.036) and food impaction (adjacent odds ratio = 2.80, CI: 1.07-7.35, P = 0.037). CONCLUSIONS: Baseline peripheral eosinophilia independently predicts PPI nonresponse and food impaction in EoE patients. Peripheral AEC may help therapy selection in EoE and prevent delays in achieving histologic remission.

Rectal Evacuation Disorders are Associated With Poor Bowel Preparation in Patients With Chronic Constipation: Results From Two Centers.

INTRODUCTION: We evaluated factors that can predict the adequacy of bowel preparation in patients with chronic constipation undergoing colonoscopy. MATERIALS AND METHODS: We identified patients with chronic constipation who underwent anorectal manometry and at least 1 colonoscopy at 2 tertiary referral centers from 2003 to 2019. We also identified a subgroup of patients who underwent colonic transit testing through radiopaque marker testing. We determined demographic, medical, and constipation-related factors associated with poor bowel preparation and their effect on standardized quality metrics using univariate and multivariate analyses. RESULTS: We identified 274 patients with chronic constipation who underwent anorectal manometry testing. Both outlet dysfunction (prolonged balloon expulsion) and slow-transit constipation were associated with suboptimal bowel preparation. Outlet dysfunction was also associated with decreased cecal intubation rates, adenoma detection rates, and sessile serrated polyp detection rates. In multivariable analyses controlling for demographics and known factors associated with poor bowel preparation, outlet dysfunction was associated with an almost 3-fold odds of suboptimal bowel preparation [odds ratio (OR): 2.9; 95% confidence interval (CI): 1.6-5.1] and a 3-fold reduction in cecal intubation rates (OR: 0.3; 95% CI: 0.1-0.8). Among those with radiopaque marker colonic transit testing available, slow-transit constipation was associated with a >2-fold odds of suboptimal bowel preparation (OR: 2.2; 95% CI: 1.1-4.4). CONCLUSIONS: Among a cohort of patients with chronic constipation undergoing colonoscopy, outlet dysfunction was associated with suboptimal bowel preparation and other quality metrics. Constipated patients with a rectal evacuation disorder may represent a subgroup of patients that could benefit from individualized strategies for better bowel preparation.

CSP01, a Novel Superabsorbent Hydrogel, Reduces Colonic Transit Time in Patients With Chronic Idiopathic Constipation in a Randomized, Double-blind, Controlled Pilot Clinical Trial.

Background/Aims: CSP01 is a novel superabsorbent hydrogel that absorbs gastrointestinal fluids and maintains high viscoelastic properties into the colon, where these fluids are released. Methods: We conducted a single-center, randomized, double-blind, parallel-group, placebo-controlled pilot study comparing change in colonic transit time (CTT) among patients with chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) treated for 21 days with either CSP01 hydrogel, active control (carboxymethylcellulose [CMC]) or placebo. CTT was measured using wireless motility capsule transit testing at pre-treatment and end-of-treatment. The primary endpoint was change in CTT. Results: Forty subjects (20 CSP01, 11 CMC, 9 placebo) were enrolled and 38 completed the study. There was no significant change in mean CTT by treatment group (P = 0.297). In the placebo group, CTT increased by 15.3 minutes between baseline and end of treatment, increased by 366.4 minutes for CMC, and decreased by 727.4 minutes for CSP01. In post hoc analyses among those with CIC, mean CTT decreased by 1079 minutes for CSP01 (P = 0.025 compared to placebo), 919 minutes for CMC (P = 0.117 compared to placebo) and increased by 1113 minutes for placebo. Among patients with IBS-C, there was no significant difference in change in CTT for any treatment group. One subject in the CSP01 arm developed back pain attributed to constipation and withdrew without a second CTT measurement; there were no other adverse events. Conclusion: CSP01 significantly decreased CTT compared to placebo among patients with CIC, but not in patients with IBS-C.

Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center.

BACKGROUND: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality. RESULTS: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84-0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72-0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race. CONCLUSIONS: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.

Colonic Stool Burden a Useful Surrogate for Slow Transit Constipation as Determined by a Radiopaque Transit Study.

OBJECTIVES: Plain film abdominal x-ray (AXR) is frequently used in the evaluation of constipation, but studies assessing the association between stool burden on AXR and colonic transit have been limited. We sought to investigate the relationship between colonic stool burden and slow transit constipation, as determined by a radiopaque marker (ROM) transit study. METHODS: A retrospective cohort population was assembled, consisting of adult patients with chronic constipation who underwent testing with both a ROM study and anorectal manometry at 2 tertiary care centers over 5 years. Stool burden was graded by 2 independent observers, with colonic transit being assessed by the Hinton method. RESULTS: Of 361 patients, 145 (40.3%) had slow transit constipation, and women were more likely than men to have slow transit constipation (42.3% vs 26.5%, P = 0.04). The mean stool burden scores by observer 1 and observer 2 for patients with slow transit constipation were significantly higher than the mean stool burden scores for patients with normal transit constipation (8.1 ± 1.6 vs 6.9 ± 1.9, P < 0.0001; 8.5 ± 1.5 vs 5.8 ± 1.6, P < 0.0001). The Pearson correlation coefficient for the stool burden score and number of remaining ROMs was 0.31 (moderate) for observer 1 (P < 0.0001) and 0.62 (strong) for observer 2 (P < 0.0001), whereas the Pearson correlation coefficient for interrater reliability of the stool burden score was 0.58 (P < 0.0001), indicating a strong correlation. The ideal score cutoff for both observers was 7, with moderate agreement by Cohen's kappa (0.43, P < 0.0001). CONCLUSIONS: Stool burden assessment on AXR may be a reliable alternative ROM study in the assessment of colonic transit.

Colonic motor response to wakening is blunted in slow transit constipation as detected by wireless motility capsule.

BACKGROUND: Chronic constipation may be categorized as normal transit (NTC), slow transit (STC), or outlet obstruction. Colonic wake response is a relative increase in colonic motility upon awakening. Colonic manometry studies have demonstrated attenuated wake response in STC. We sought to evaluate wake response among healthy (H), NTC, and STC patients using wireless motility capsule (WMC). METHODS: A retrospective study of WMC data from a multicenter clinical trial and a tertiary gastroenterology clinic was performed. WMC motility parameters of contraction frequency (Ct) and area under the contraction curve (AUC) were analyzed in 20-min windows 1-h before and after awakening. T-tests compared parameters between H, NTC, and STC. Linear regression analysis was performed to determine if outlet obstruction confounded data. A receiver operating characteristic curve demonstrated optimal Ct cut-offs to define blunted wake response. RESULTS: A total of 62 H, 53 NTC and 75 STC subjects were analyzed. At 20, 40, and 60 min after awakening, STC subjects had significantly lower mean Ct when compared to H (p < 0.001) and NTC (p < 0.01). Linear regression demonstrated that outlet obstruction was not associated with a decreased wake response (ß = 3.94, (CI -3.12-1.00), P = 0.27). Defined at the Ct threshold of 64 at 20-min post-wake, blunted wake response sensitivity was 84% and specificity was 32% for chronic constipation. CONCLUSION: Findings of an impaired wake response in subjects with STC and not NTC adds further evidence to neuronal dysfunction as an etiology of STC, and identifies a possible temporal target for pharmacologic intervention.

EMR is superior to rectal suction biopsy for analysis of enteric ganglia in constipation and dysmotility.

BACKGROUND AND AIMS: Patients with chronic constipation or motility disorders may be referred for rectal suction biopsy (RSB) to rule out Hirschsprung's disease (HD). RSB may not be successful beyond infancy because of the increased thickness of the rectal mucosa. EMR could improve the diagnostic yield for HD when compared with traditional RSB because larger and deeper samples are acquired for analysis. METHODS: In this prospective, single-center study, patients referred for RSB were offered enrollment for concurrent EMR. Specimens were analyzed pathologically for size, submucosal ganglionic tissue, and acetylcholinesterase or calretinin staining. Biopsy results were compared with transit studies, anorectal manometry, and constipation severity through validated questionnaires. RESULTS: Seventeen patients (2 male, 15 female; mean age, 35.8 years; range, 22-61 years) were enrolled in the study from 2008 to 2014. All patients underwent anorectal manometry (88% with anorectal dysfunction, 68% with outlet obstruction) and transit studies (41% with delayed transit). There were no reports of adverse events from the RSB and EMR procedures. The RSB sample volumes were significantly lower than the EMR sample volumes (0.023 cm3 vs 0.26 cm3, P = .001). There was diagnostic tissue for submucosal visualization by RSB in 53% (9/17) of cases compared with 100% (17/17) with EMR (P = .003). No cases of HD were diagnosed by RSB; one patient had rare ganglions observed by EMR. CONCLUSIONS: EMR provides greater tissue volume and can improve the characterization of ganglion cells in rectal tissue compared with RSB in patients with moderate to severe constipation with suspected HD.

Depression but Not Symptom Severity is Associated With Work and School Absenteeism in Refractory Chronic Constipation.

GOALS: We sought to determine the patient characteristics associated with increased absenteeism and Emergency Department (ED) utilization among patients with constipation. BACKGROUND: Chronic constipation is associated with significant direct and indirect economic costs. There has been limited study of the predictors of direct and indirect costs in a population with refractory constipation. STUDY: We conducted a cross-sectional cohort study of patients with chronic constipation who presented to a tertiary care center for anorectal manometry. We used standardized instruments to assess disease severity, quality of life, somatization, and psychiatric comorbidities. We used multivariable logistic regression to determine the predictors of work and school absenteeism as well as ED visits for constipation. RESULTS: There were 148 consecutive patients enrolled (87% female, mean age 43) of whom 32 (21.6%) had high absenteeism and 36 (24.3%) visited the ED for constipation in the past year. Patients with high absenteeism and ED visits were more likely to be depressed (56.3% vs. 18.5%, P<0.0001 for high absenteeism; 47.2% vs. 19.6%, P<0.01 for ED visits). After multivariable adjustment and sensitivity analyses, only depression (OR, 4.41; P<0.01) was associated with increased absenteeism while there was a trend toward an association between depression and ED visits (OR, 2.57; P=0.067). Symptom severity was not associated with high absenteeism or ED utilization. CONCLUSIONS: Among patients with chronic constipation, depression is a stronger predictor of absenteeism than symptom severity. Depression may drive a portion of the indirect costs of chronic constipation.

Eluxadoline in irritable bowel syndrome with diarrhea: rationale, evidence and place in therapy.

Irritable bowel syndrome (IBS) is the most common gastrointestinal (GI) disorder worldwide, however treatment options for diarrhea-predominant IBS (IBS-D) remain limited. Eluxadoline, a µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist, was recently approved for the treatment of IBS-D. A novel compound first described in 2008, eluxadoline was shown to normalize GI transit, with a subsequent phase I demonstrating its safety and tolerability in healthy adults. In 2016, two randomized, double-blind, placebo-controlled phase III trials studying eluxadoline use at 75 mg and 100 mg twice daily over 26 weeks demonstrated a significant improvement in stool consistency and many global symptoms of IBS. However, the data did not demonstrate a significant advantage over placebo using the United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA) endpoints for abdominal pain. Safety and tolerability data, pooled from both phase II and III studies, suggest that eluxadoline is generally well tolerated with the most common adverse events (AEs) occurring in approximately 3-8% of patients and included nausea, constipation, and abdominal pain. The most common serious adverse event (SAE) is pancreatitis, which had a 0.4% incidence. Recent US FDA reports reporting severe pancreatitis and sphincter of Oddi dysfunction after short-term use of eluxadoline in patients without a gallbladder has added a history of cholecystectomy as an important contraindication. Eluxadoline is also contraindicated in patients with a history of biliary duct obstruction, sphincter of Oddi dysfunction, active alcohol abuse, history of pancreatitis or known pancreatic duct obstruction, severe hepatic impairment, severe or chronic constipation, or known mechanical gastrointestinal obstruction. As a new drug to enter the IBS-D market, the place of eluxadoline in the hierarchy of IBS treatments is still to be determined. In this article, we review the development and clinical trial data behind the approval of eluxadoline with a focus on safety data and its use in clinical practice.

Cannabis Abuse Is Increasing and Associated with Increased Emergency Department Utilization in Gastroenterology Patients.

BACKGROUND: The role of cannabinoids in gastrointestinal diseases is controversial and of great interest, yet their use in patients has not been critically examined. AIM: To determine the prevalence and effects of cannabis abuse on healthcare utilization, as measured by emergency department (ED) visits, in a large, tertiary gastroenterology practice. METHODS: All patients seen in the gastroenterology clinic at a tertiary care center during a 27-year period (1986-2013) were included in our study to determine the overall prevalence of cannabis abuse. We matched cannabis abusers 1:2 with non-abusing controls to determine the effect of cannabis on ED utilization, our primary outcome. We used multivariate linear regression to adjust for confounders and define the independent effect of cannabis abuse on ED utilization. RESULTS: Our prevalence study cohort included 190,303 GI clinic patients with an overall cannabis abuse prevalence of 0.80 % (1520 patients). From 1986 to 2012, the prevalence of cannabis abuse in this clinic increased by 0.73 % (0.03 %/year) (p < 0.0001). From the 1520 cannabis abusers identified, 467 patients were randomly selected as cases and were matched to 934 controls. From this retrospective cohort, the median ED visits/year for cannabis abusers was 1.88 versus 0.89 for non-abusers (p < 0.0001). After multivariate adjustment, cannabis abuse was associated with a 1.47-fold increase (95 % CI 1.23-1.76, p < 0.0001) in median ED visits/year. CONCLUSIONS: Reported cannabis abuse in GI clinic patients is less prevalent than in the adult US population, but is increasing. Cannabis abuse among gastroenterology patients is associated with increased ED visits.

Patients with irritable bowel syndrome-diarrhea have lower disease-specific quality of life than irritable bowel syndrome-constipation.

AIM: To determine effect of irritable bowel syndrome (IBS) subtype on IBS-specific quality of life (QOL) questionnaire and its subscales. METHODS: We studied IBS patients visiting our functional gastroenterology disorder clinic at a tertiary care center of Unites States. IBS and IBS subtype were diagnosed using Rome-III questionnaire. QOL was assessed using IBS-QOL questionnaire. IBS-QOL assesses quality of life along eight subscales: dysphoria, interference with activities, body image, health worry, food avoidance, social reactions, sexual health, and effect on relationships. IBS-QOL and its subscales were both scored on a range of 0-100 with higher scores suggestive of better QOL. Results of overall IBS-QOL scores and subscale scores are expressed as means with 95%CI. We compared mean IBS-QOL score and its subscales among various IBS-subtypes. Analysis of variance (ANOVA) was used to compare the mean difference between more than two groups after controlling for age and gender. A post-hoc analysis using Bonferroni correction was used only when P value for ANOVA was less than 0.05. RESULTS: Of 542 patients screened, 243 had IBS as per Rome-III criteria. IBS-mixed (IBS-M) was the most common IBS subtype (121 patients, 49.8%) followed by IBS- diarrhea (IBS-D) (56 patients, 23.1%), IBS-constipation (IBS-C) (54 patients, 22.2%) and IBS-unspecified (IBS-U) (12 patients, 4.9%). Overall IBS-QOL scores were significantly different among various IBS-subtypes (P = 0.01). IBS-QOL of patients with IBS-D (61.6, 95%CI: 54.0-69.1) and IBS-M (63.0, 95%CI: 58.1-68.0) was significantly lower than patients with IBS-C (74.5, 95%CI: 66.9-82.1) (P = 0.03 and 0.02 respectively). IBS-D patients scored significantly lower than IBS-C on food avoidance (45.0, 95%CI: 34.8-55.2 vs 61.1, 95%CI: 50.8-71.3, P = 0.04) and interference with activity (59.6, 95%CI: 51.4-67.7 vs 82.3, 95%CI: 74.1-90.6, P < 0.001). IBS-M patients had more interference in their activities (61.6, 95%CI: 56.3-66.9 vs 82.3, 95%CI: 74.1-90.6, P = 0.001) and greater impact on their relationships (73.3, 95%CI: 68.4-78.2 vs 84.7, 95%CI: 77.2-92.2, P = 0.02) than IBS-C patients. Patients with IBS-M also scored significantly lower than IBS-C on food avoidance (47.2, 95%CI: 40.7-53.7 vs 61.1, 95%CI: 50.8-71.3, P = 0.04) and social reaction (66.1, 95%CI: 61.1-71.1 vs 80.0, 95%CI: 72.1-87.7, P = 0.005). CONCLUSION: IBS-D and IBS-M patients have lower IBS-QOL than IBS-C patients. Clinicians should recognize food avoidance, effects on daily activities and relationship problems in these patients.

Rectosigmoid Localization of Radiopaque Markers Does Not Correlate with Prolonged Balloon Expulsion in Chronic Constipation: Results from a Multicenter Cohort.

OBJECTIVES: Ingestion of radiopaque markers (ROMs) is a common means of assessing colonic transit time in chronic constipation. Because anorectal manometry (ARM) testing for pelvic floor dysfunction is mostly limited to academic centers, clinicians frequently use rectosigmoid accumulation of markers as a surrogate for pelvic floor dysfunction. We sought to determine whether rectosigmoid localization of markers on a ROM study correlated with measures of pelvic floor dysfunction by ARM and balloon expulsion testing. METHODS: We assembled a multicenter, retrospective cohort of patients diagnosed with chronic constipation who underwent both transit testing by ROM transit testing and ARM with balloon expulsion testing. We compared the proportion of patients with outlet obstruction by rectoanal pressure gradient or prolonged balloon expulsion stratified by marker location. RESULTS: There were 610 patients with both ROM testing and ARM with balloon expulsion testing. The mean age was 44 years and 526 were women (86%). Eighty-one (13%) patients had markers confined to the rectosigmoid area alone and were compared with 529 patients with markers elsewhere (51%) or no retained markers (49%). Of those with markers confined to the rectosigmoid colon, 48 (59%) had a prolonged balloon expulsion compared with 276 (52%) who did not have rectosigmoid markers (P=0.28). The mean rectoanal gradient for patients with markers in the rectosigmoid colon was -29±46 mm Hg compared with -34±59 mm Hg for all others (P=0.59). CONCLUSIONS: Among patients with chronic constipation undergoing ROM transit testing, there is no association between rectosigmoid location of markers and rectoanal gradient or prolonged balloon expulsion.

The investigational drug camicinal for the treatment of gastroparesis.

Introduction: Gastroparesis is a syndrome of delayed gastric emptying in the absence of mechanical obstruction that presents with upper gastrointestinal symptoms. Despite its growing prevalence, there remains an unmet clinical need for more efficacious prokinetic treatment options. The current market includes prokinetic agents that reduce gastroparesis symptoms. However, adverse drug effects and tachyphylaxis with repeated dosing are among the factors that limit their use. Camicinal (GSK962040) is the most advanced, small-molecule, selective motilin receptor agonist with therapeutic potential to date. Areas covered: This article reviews the literature on the limitations of current prokinetic agents used in the treatment of gastroparesis. It also summarizes the current evidence and influential clinical trial results involving the investigational drug camicinal, and shares its preliminary findings from the literature. Expert opinion: Camicinal represents a new opportunity as a treatment in a clinical area in need of new agents. There is emerging literature to support how the drug addresses both gastroparesis symptoms and dysmotility with no significant adverse effects or tachyphylaxis reported to date. Challenges remain in getting a new compound approved for gastroparesis. However, careful design of future trials will help to continue the record of success camicinal trials have had thus far.