PUBLICATIONS

2024

Hiramoto B, McCarty TR, Lodhia NA, et al. Quantified Metrics of Gastric Emptying Delay by GLP-1 Agonists: A Systematic Review and Meta-Analysis with Insights for Periprocedural Management. The American journal of gastroenterology. Published online 2024. doi:10.14309/ajg.0000000000002820

INTRODUCTION: Divergent recommendations for periprocedural management of GLP-1 receptor agonist (GLP-1 RA) medications rely on limited evidence. We performed a systematic review and meta-analysis to provide quantitative measures of gastric emptying relevant to mechanisms of weight loss and to periprocedural management of GLP-1 RA. We hypothesized that the magnitude of gastric emptying delay would be low and of limited clinical significance to procedural sedation risks.

METHODS: A protocolized search identified studies on GLP-1 RA that quantified gastric emptying measures. Pooled estimates using random effects were presented as weighted mean difference with 95% confidence intervals (CI). Univariate meta-regression was performed to assess the influence of GLP-1 RA type, short- vs long-acting mechanism of action, and duration of treatment on gastric emptying.

RESULTS: Fifteen studies met inclusion criteria. Five studies (n=247) utilized scintigraphy (GES). Mean T1/2 was 138.4 minutes (CI:74.5-202.3) for GLP-1 RA versus 95.0 minutes (CI:54.9-135.0) for placebo, with pooled mean difference of 36.0 minutes (CI:17.0-55.0, p<0.01, I2=79.4%). Ten studies (n=411) utilized the acetaminophen absorption test (AAT), with no significant delay in gastric emptying measured by Tmax, AUC4hr, and AUC5hr with GLP-1 RA (p>0.05). On meta-regression, type of GLP-1 RA, mechanism of action, and treatment duration did not impact gastric emptying (p>0.05).

CONCLUSIONS: While a gastric emptying delay of ∼36 minutes is quantifiable on GLP-1 RA medications, it is of limited magnitude relative to standard periprocedural fasting periods. There were no substantial differences in gastric emptying on modalities reflective of liquid emptying (AAT), particularly at time points relevant to periprocedural care.

Krause AJ, Greytak M, Kaizer AM, et al. Diagnostic Yield of Ambulatory Reflux Monitoring Systems for Evaluation of Chronic Laryngeal Symptoms. The American journal of gastroenterology. 2024;119(4):627-634. doi:10.14309/ajg.0000000000002557

INTRODUCTION: Among patients with chronic laryngeal symptoms, ambulatory reflux monitoring off acid suppression is recommended to evaluate for laryngopharyngeal reflux (LPR). However, reflux monitoring systems are diverse in configuration and monitoring capabilities, which present a challenge in creating a diagnostic reference standard in these patients. This study aimed to compare diagnostic yield and performance between reflux monitoring systems in patients with chronic laryngeal symptoms.

METHODS: This multicenter, international study of adult patients referred for evaluation of LPR over a 5-year period (March 2018-May 2023) assessed and compared diagnostic yield of pathologic gastroesophageal reflux (GER+) on ambulatory reflux monitoring off acid suppression.

RESULTS: Of 813 patients, 296 (36%) underwent prolonged wireless pH, 532 (65%) underwent 24-hour pH-impedance monitoring, and 15 (2%) underwent both tests. Overall diagnostic yield for GER+ was 36% and greater for prolonged wireless pH compared with that for 24-hour pH-impedance monitoring (50% vs 27%; P < 0.01). Among 15 patients who underwent both prolonged wireless pH and 24-h pH-impedance monitoring, concordance between systems for GER+ was 40%. The most common source of discordance was strong evidence of GER+ across multiple days on prolonged wireless pH compared with no evidence of GER+ on pH-impedance.

DISCUSSION: In this multicenter international study of patients with chronic laryngeal symptoms referred for LPR evaluation, diagnostic yield of ambulatory reflux monitoring off acid suppression was 36% and rose to 50% when using wireless pH monitoring. In patients referred for chronic laryngeal symptoms, 24-hour pH-impedance monitoring may risk a low negative predictive value in patients with unproven GER+ disease.

Lechien JR, Vaezi MF, Chan WW, et al. The Dubai Definition and Diagnostic Criteria of Laryngopharyngeal Reflux: The IFOS Consensus. The Laryngoscope. 2024;134(4):1614-1624. doi:10.1002/lary.31134

OBJECTIVE: The objective of this work was to gather an international consensus group to propose a global definition and diagnostic approach of laryngopharyngeal reflux (LPR) to guide primary care and specialist physicians in the management of LPR.

METHODS: Forty-eight international experts (otolaryngologists, gastroenterologists, surgeons, and physiologists) were included in a modified Delphi process to revise 48 statements about definition, clinical presentation, and diagnostic approaches to LPR. Three voting rounds determined a consensus statement to be acceptable when 80% of experts agreed with a rating of at least 8/10. Votes were anonymous and the analyses of voting rounds were performed by an independent statistician.

RESULTS: After the third round, 79.2% of statements (N = 38/48) were approved. LPR was defined as a disease of the upper aerodigestive tract resulting from the direct and/or indirect effects of gastroduodenal content reflux, inducing morphological and/or neurological changes in the upper aerodigestive tract. LPR is associated with recognized non-specific laryngeal and extra-laryngeal symptoms and signs that can be evaluated with validated patient-reported outcome questionnaires and clinical instruments. The hypopharyngeal-esophageal multichannel intraluminal impedance-pH testing can suggest the diagnosis of LPR when there is >1 acid, weakly acid or nonacid hypopharyngeal reflux event in 24 h.

CONCLUSION: A global consensus definition for LPR is presented to improve detection and diagnosis of the disease for otolaryngologists, pulmonologists, gastroenterologists, surgeons, and primary care practitioners. The approved statements are offered to improve collaborative research by adopting common and validated diagnostic approaches to LPR.

LEVEL OF EVIDENCE: 5 Laryngoscope, 134:1614-1624, 2024.

Lodhia NA, Hiramoto B, Horton L, Goldin AH, Thompson CC, Chan WW. Obesity Is Associated with Altered Rectal Sensitivity in Chronic Constipation. Digestive diseases and sciences. 2024;69(3):884-891. doi:10.1007/s10620-023-08246-z

BACKGROUND: Defecation dysfunction may contribute to chronic constipation (CC), but the impact of obesity on anorectal physiology in CC remains unclear. We aimed to evaluate the relationship between obesity and anorectal function on physiologic testing in patients presenting with CC.

METHODS: This was a retrospective cohort study of consecutive adults who underwent high resolution anorectal manometry (HRAM) at a tertiary center for CC. Patient demographics, clinical history, surgical/obstetric history, medications, and HRAM results were reviewed. Patients were classified into obese (BMI > 30 kg/m2) vs non-obese (BMI < 30 kg/m2) groups at the time of HRAM. Fisher-exact/student t-test for univariate analyses and general linear regression for multivariable analysis were performed.

RESULTS: 383 adults (mean 50.3 years; 85.8% female) with CC were included. On HRAM, patients with obesity had lower anal sphincter resting tone (37.3 vs 48.5 mmHg, p = 0.005) and maximum squeeze pressure (104.8 mmHg vs 120.0 mmHg, p = 0.043). No significant differences in dyssynergia (61% vs 53%, p = 0.294) and failed balloon expulsion (18% vs 25%, p = 0.381) were found between obese and non-obese groups. On balloon distention testing, the maximum tolerated (163.5 vs 147.6 mL, p = 0.042) and urge sensation (113.9 vs 103.7 mL, p = 0.048) volumes were significantly increased among patients with obesity. After adjusting for potential confounders, obesity remained independently associated with increased maximum tolerated volume (β-coefficient 13.7, p = 0.049).

CONCLUSION: Obesity was independently associated with altered rectal sensitivity among patients with CC. Altered rectal sensation may play an important role in CC among patients with obesity. Anorectal physiology testing should be considered to understand the pathophysiology and guide management.

Lo WK, Muftah M, Goldberg HJ, Sharma N, Chan WW. Concurrent abnormal non-acid reflux is associated with additional chronic rejection risk in lung transplant patients with increased acid exposure. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus. Published online 2024. doi:10.1093/dote/doae020

Acid reflux has been associated with allograft injury and rejection in lung transplant patients; however, the pathogenic role of non-acid reflux remains debated. We aimed to evaluate the impact of concurrent abnormal non-acid reflux with acid reflux on chronic rejection in lung transplant patients with acid reflux. This was a retrospective cohort study of lung transplant recipients who underwent pre-transplant combined impedance-pH study off acid suppression. Only subjects with acid exposure >4% were included. Non-acid reflux (pH > 4) episodes >27 was considered abnormal per prior normative studies. Chronic rejection was defined as chronic lung allograft dysfunction (CLAD) per International Society for Heart and Lung Transplantation criteria. Time-to-event analyses were performed using Cox proportional hazards and Kaplan-Maier methods, with censoring at death, anti-reflux surgery, or last follow-up. In total, 68 subjects (28 abnormal/40 normal non-acid reflux) met inclusion criteria for the study. Baseline demographic/clinical characteristics were similar between groups. Among this cohort of patients with increased acid exposure, subjects with concurrent abnormal non-acid reflux had significantly higher risk of CLAD than those without on Kaplan-Meier analysis (log-ranked P = 0.0269). On Cox multivariable regression analysis controlling for body mass index, age at transplantation, and proton pump inhibitor use, concurrent abnormal non-acid reflux remained independently predictive of increased CLAD risk (hazard ratio 2.31, confidence interval: 1.03-5.19, P = 0.04). Presence of concurrent abnormal non-acid reflux in lung transplant subjects with increased acid exposure is associated with additional risk of chronic rejection. Non-acid reflux may also contribute to pathogenicity in lung allograft injury/rejection, supporting a potential role for impedance-based testing in this population.

Shah ED, Curley MA, Patel A, Lo WK, Chan WW. Heartburn Relief is the Major Unmet Need for Drug Development in Gastroesophageal Reflux Disease: Threshold Value Analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. Published online 2024. doi:10.1016/j.cgh.2024.01.049

BACKGROUND AND AIMS: Heartburn symptoms contribute to healthcare-seeking among patients with gastroesophageal reflux disease (GERD). Despite clinical guidance, management is often dictated by insurance restrictions. Several potassium-competitive acid blockers (PCAB) are under development as a new class of therapy. We performed economic analyses to align GERD drug development with the needs of gastroenterologists, insurers and patients in a value-based environment.

METHODS: A decision-analytic model was constructed to compare vonoprazan 20mg daily (an example of a potassium-competitive acid blocker[PCAB]), common over-the-counter or prescription proton pump inhibitor (PPI) regimens, and no treatment over a one-year time horizon. Clinical responses were evaluated based on the proportions of heartburn-free days in a recent phase 3 multicenter trial. Healthcare utilization for persistent reflux symptoms was derived from national observational studies compared to healthy controls. Costs and quality-adjusted life years [QALY] were reported.

RESULTS: Without insurance coverage for appropriate therapy, patients spend $4,443 and insurers spend $3,784 on average per year for inadequately treated GERD symptoms. Our model estimates that PCABs could save at least $3,000 in annual costs to patients and insurers, could generate QALY gains (+0.06/year), and could be cost-saving to insurers as a covered option at a price up to $8.57/pill, if these drugs are able to demonstrate similar effectiveness to PPIs in future trials evaluating heartburn relief and erosive esophagitis healing to regulators. Threshold prices reflect pricing after all pharmacy benefits manager rebates and discounts.

DISCUSSION: We demonstrate that aiming GERD-related drug development toward heartburn relief appears critical to align cost-effective incentives for industry and insurers with those of patients and gastroenterologists.

Muftah M, Barshop K, Redd WD, Goldin AH, Lo WK, Chan WW. Baseline Peripheral Eosinophil Count Independently Predicts Proton Pump Inhibitor Response in Eosinophilic Esophagitis. Journal of clinical gastroenterology. 2024;58(3):242-246. doi:10.1097/MCG.0000000000001845

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.

Muftah M, Goldin AH, Barshop K, et al. Twice Daily PPI Induces Higher Remission Rate in Eosinophilic Esophagitis Than Once Daily Regimen Regardless of Total Daily Dose. The American journal of gastroenterology. Published online 2024. doi:10.14309/ajg.0000000000002712

BACKGROUND: The optimal proton pump inhibitor (PPI) regimen for eosinophilic esophagitis (EoE) is unclear. We compared histologic response rates of different dosing combinations.

METHODS: 305 newly-diagnosed EoE patients received standard (omeprazole 20mg daily), once-daily moderate (40mg daily), twice-daily moderate (20mg twice daily), or high (40mg twice daily) dose PPI for ≥8 weeks.

RESULTS: 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 (aOR:6.75, CI:2.53-18.0,p=0.0008) and high (aOR:12.8, CI:4.69-34.8,p<0.0001) doses independently predicted histologic response.

CONCLUSION: Twice-daily PPI is associated with higher EoE histologic response rates than once-daily regimen.

Shah ED, Ahuja NK, Brenner DM, et al. Optimizing the Management Algorithm for Adults With Functional Constipation Failing a Fiber/Laxative Trial in General Gastroenterology: Cost-Effectiveness and Cost-Minimization Analysis. The American journal of gastroenterology. 2024;119(2):342-352. doi:10.14309/ajg.0000000000002515

INTRODUCTION: Anorectal function testing is traditionally relegated to subspecialty centers. Yet, it is an office-based procedure that appears capable of triaging care for the many patients with Rome IV functional constipation that fail empiric over-the-counter therapy in general gastroenterology, as an alternative to empirical prescription drugs. We aimed to evaluate cost-effectiveness of routine anorectal function testing in this specific population.

METHODS: We performed a cost-effectiveness analysis from the patient perspective and a cost-minimization analysis from the insurer perspective to compare 3 strategies: (i) empiric prescription drugs followed by pelvic floor physical therapy (PFPT) for drug failure, (ii) empiric PFPT followed by prescription drugs for PFPT failure, or (iii) care directed by up-front anorectal function testing. Model inputs were derived from systematic reviews of prospective clinical trials, national cost data sets, and observational cohort studies of the impact of chronic constipation on health outcomes, healthcare costs, and work productivity.

RESULTS: The most cost-effective strategy was upfront anorectal function testing to triage patients to appropriate therapy, in which the subset of patients without anal hypocontractility on anorectal manometry and with a balloon expulsion time of at least 6.5 seconds would be referred to PFPT. In sensitivity analysis, empiric PFPT was more cost effective than empiric prescription drugs except for situations in which the primary goal of treatment was to increase bowel movement frequency. If adopted, gastroenterologists would refer ∼17 patients per year to PFPT, supporting feasibility.

DISCUSSION: Anorectal function testing seems to be an emergent technology to optimize cost-effective outcomes, overcoming testing costs by phenotyping care.

Krause AJ, Kaizer AM, Carlson DA, et al. Validated Clinical Score to Predict Gastroesophageal Reflux in Patients with Chronic Laryngeal Symptoms: COuGH RefluX. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. Published online 2024. doi:10.1016/j.cgh.2024.01.021

BACKGROUND & AIMS: Discerning whether laryngeal symptoms result from gastroesophageal reflux is clinically challenging and a reliable tool to stratify patients is needed. We aimed to develop and validate a model to predict likelihood of gastroesophageal reflux disease (GERD) among patients with chronic laryngeal symptoms.

METHODS: This multicenter international study collected data from adults with chronic laryngeal symptoms that underwent objective testing (upper GI endoscopy and/or ambulatory reflux monitoring) between 3/2018-5/2023. The training phase identified a model with optimal receiver operating characteristic curves, and beta coefficients informed a weighted model. The validation phase assessed performance characteristics of the weighted model.

RESULTS: 856 adults, 304 in training cohort and 552 in the validation cohort, were included. In the training phase the optimal predictive model [AUC 0.68 (95% CI 0.62, 0.74)] - the COuGH RefluX score - consisted of Cough, Overweight/obesity, Globus, Hiatal Hernia, Regurgitation, and male seX with a lower threshold of 2.5 and upper threshold of 5.0 to predict proven GERD. In the validation phase, the COuGH RefluX score had an AUC of 0.67 (0.62, 0.71) with 79% sensitivity and 81% specificity for proven GERD.

CONCLUSIONS: The externally validated COuGH RefluX score is a clinically practical model to predict likelihood of proven GERD. The score classifies most patients with chronic laryngeal symptoms as low/high likelihood of proven GERD, with only 38% remaining as indeterminate. Thus, the COuGH RefluX score can guide diagnostic strategies and reduce inappropriate proton pump inhibitor use or testing for patients referred for evaluation of chronic laryngeal symptoms.