Heartburn Relief Is the Major Unmet Need for Drug Development in Gastroesophageal Reflux Disease: Threshold Value Analysis.

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 (PCABs) 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 20 mg daily (an example of a PCAB), common over-the-counter or prescription proton pump inhibitor regimens, and no treatment over a 1-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 with healthy control subjects. Costs and quality-adjusted life years were reported. RESULTS: Without insurance coverage for appropriate therapy, patients spend $4443 and insurers spend $3784 on average per year for inadequately treated GERD symptoms. Our model estimates that PCABs could save at least $3000 in annual costs to patients and insurers, could generate quality-adjusted life year gains (+0.06 per year), and could be cost-saving to insurers as a covered option at a price up to $8.57 per pill, if these drugs are able to demonstrate similar effectiveness to proton pump inhibitors 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.

Centrally Distributed Adiposity as a Modifiable Risk Factor for Fecal Incontinence: United States Population-based Analysis.

BACKGROUND AND AIMS: Fecal incontinence (FI) is highly prevalent with substantial impacts on quality of life and health care utilization. The impact of obesity on FI remains unclear, with differing conclusions using body mass index (BMI) as a risk factor. We aimed to determine the association between obesity and FI, and whether this relationship is dependent on the distribution of adiposity (waist circumference-to-height ratio [WHtR]). METHODS: This was a population-based analysis of the National Health and Nutrition Examination Survey, including participants who responded to the bowel health survey in 2005 to 2010. FI was defined by the accidental bowel leakage of solid stool, liquid, or mucus at least once in the past month. Stepwise multivariable logistic regression models were constructed to assess risk factors for FI. RESULTS: A total of 7606 participants were included, with an overall FI prevalence of 9.2%. When stratified by quartiles of body measurements, FI was increasingly prevalent from the 1st to the 4th quartile for both WHtR (range, 5.3%-12.5%) and BMI (range, 7.1%-10.5%). WHtR was associated with FI and was a stronger predictor than BMI in all quartiles of body measurement. On multivariable analysis, WHtR remained a significant predictor of FI comparing the 4th with the 1st quartile of body measurements (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.11-2.80; P = .017), whereas BMI was not. A WHtR cutoff of >0.592 optimized the Youden index in prediction of FI in the overall sample. CONCLUSION: WHtR was independently associated with increased odds of FI in this nationally representative sample of United States adults, whereas BMI was not consistently correlated. This suggests bowel continence may depend more on how body mass is distributed.

High Diagnostic Yield of Abnormal Endoscopic Findings in the Evaluation of Laryngopharyngeal Reflux.

Esophagogastroduodenoscopy (EGD) is recommended in patients with typical gastroesophageal reflux disease (GERD) symptoms (heartburn, regurgitation, chest pain) in the setting of proton pump inhibitor (PPI) nonresponse. EGD evaluates for erosive disease, assesses antireflux barrier integrity, excludes non-GERD conditions, and, in the absence of erosive findings, is followed by reflux testing.1,2 The diagnostic utility of EGD is less clear in the evaluation for laryngopharyngeal reflux (LPR), and the current reference standard is ambulatory reflux monitoring.1,3,4 This study of patients referred for evaluation of chronic laryngeal symptoms had the following aims: (1) to characterize endoscopic findings, (2) to discern whether findings differed between patients with or without concomitant esophageal reflux symptoms, and (3) to measure the association between endoscopic findings and objective GERD on ambulatory reflux monitoring.

Validated Clinical Score to Predict Gastroesophageal Reflux in Patients With Chronic Laryngeal Symptoms: COuGH RefluX.

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 the 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 who underwent objective testing (upper gastrointestinal endoscopy and/or ambulatory reflux monitoring) between March 2018 and May 2023. The training phase identified a model with optimal receiver operating characteristic curves, and ß coefficients informed a weighted model. The validation phase assessed performance characteristics of the weighted model. RESULTS: A total of 856 adults, 304 in the training cohort and 552 in the validation cohort, were included. In the training phase, the optimal predictive model (area under the curve, 0.68; 95% CI, 0.62-0.74), was the Cough, Overweight/obesity, Globus, Hiatal Hernia, Regurgitation, and male seX (COuGH RefluX) score, with a lower threshold of 2.5 and an upper threshold of 5.0 to predict proven GERD. In the validation phase, the COuGH RefluX score had an area under the curve of 0.67 (95% CI, 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 the 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.

Optimizing the Management Algorithm for Esophageal Dysphagia After Index Endoscopy: Cost-Effectiveness and Cost-Minimization Analysis.

INTRODUCTION: Guidelines advise esophageal motility testing for dysphagia when structural disorders are ruled out, but cost concerns impede adoption. We evaluated cost-effective positioning of esophageal motility testing in the algorithm to evaluate esophageal dysphagia. METHODS: We developed a decision analytic model comparing 3 strategies: (i) esophageal manometry, (ii) screening impedance planimetry followed by esophageal manometry if needed, or (iii) nonalgorithmic usual care. Diagnostic test accuracy was adapted to expected rates of esophageal motility disorders in general gastroenterology populations. We modeled routine testing for all patients with nonstructural/mechanical dysphagia compared with selective testing with strong suspicion for achalasia. Cost outcomes were defined on national commercial and Medicare datasets stratified on age and sex. Health outcomes were modeled on populations with achalasia. The time horizon was 1 year. RESULTS: Motility testing was preferred over nonalgorithmic usual care due to cost savings rather than health gains. To commercial insurers, routine esophageal manometry for nonstructural/mechanical dysphagia would be cost-saving below a reimbursed cost of $2,415. Screening impedance planimetry would be cost saving below a reimbursed cost of $1,130. The limit for reimbursed costs would be lower for patients older than 65 years to achieve cost savings mainly due to insurance. Sex did not significantly influence cost-effectiveness. Patients and insurers preferred routine screening impedance planimetry before manometry when the index of suspicion for achalasia was below 6%. DISCUSSION: Aligning with practice guidelines, routine esophageal motility testing seems cost saving to patients and insurers compared with nonalgorithmic usual care to evaluate nonstructural/mechanical dysphagia. Choice of testing should be guided by index of suspicion.

Impact of Body Composition on Esophagogastric Junction Opening Measures: Discordant FLIP and Manometric Findings Are More Common With Increased Body Mass Index.

INTRODUCTION: Increased intra-abdominal pressure in patients with elevated body mass index (BMI) may affect measurements of esophagogastric junction (EGJ) opening. METHODS: Findings from adult patients who underwent both impedance planimetry with functional luminal imaging probe (FLIP) and high-resolution manometry (HRM) were compared by BMI. RESULTS: Among patients with no EGJ outflow obstruction on HRM, abnormal EGJ classifications on FLIP were more common among those with elevated than normal BMI (61.1% vs 31.6%, P = 0.037). DISCUSSION: Discordant results between FLIP and HRM on EGJ opening are more common in patients with elevated BMI. Body composition may impact EGJ function and measures on current testing modalities.

Quantified Metrics of Gastric Emptying Delay by Glucagon-Like Peptide-1 Agonists: A Systematic Review and Meta-Analysis With Insights for Periprocedural Management.

INTRODUCTION: Divergent recommendations for periprocedural management of glucagon-like peptide-1 (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 a weighted mean difference with 95% confidence intervals (CIs). Univariate meta-regression was performed to assess the influence of GLP-1 RA type, short-acting vs long-acting mechanism of action, and duration of treatment on gastric emptying. RESULTS: Fifteen studies met the inclusion criteria. Five studies (n = 247) utilized gastric emptying scintigraphy. Mean T 1/2 was 138.4 minutes (95% CI 74.5-202.3) for GLP-1 RA vs 95.0 minutes (95% CI 54.9-135.0) for placebo, with a pooled mean difference of 36.0 minutes (95% CI 17.0-55.0, P < 0.01, I2 = 79.4%). Ten studies (n = 411) utilized the acetaminophen absorption test, with no significant delay in gastric emptying measured by T max , area under the curve (AUC) 4hr , and AUC 5hr with GLP-1 RA ( P > 0.05). On meta-regression, the type of GLP-1 RA, mechanism of action, and treatment duration did not impact gastric emptying ( P > 0.05). DISCUSSION: 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 (acetaminophen absorption test), particularly at time points relevant to periprocedural care.

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.

Optimizing the Management Algorithm for Adults With Functional Constipation Failing a Fiber/Laxative Trial in General Gastroenterology: Cost-Effectiveness and Cost-Minimization Analysis.

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.

Diagnostic Yield of Ambulatory Reflux Monitoring Systems for Evaluation of Chronic Laryngeal Symptoms.

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.

Update on extraesophageal manifestations of gastroesophageal reflux.

PURPOSE OF REVIEW: Symptoms/complications related to extraesophageal reflux (EER) are increasingly prevalent presentations and pose significant challenges for clinicians. We summarize and discuss clinical advances and developments in pathophysiology, testing and treatment algorithms of upper/lower airway manifestations of EER. RECENT FINDINGS: Growing evidence supports likely multifactorial causes of laryngeal symptoms, including EER, oropharyngeal pathologies, allergic conditions, and cognitive-affective processes (brain-larynx interaction). Diagnostic paradigm for laryngopharyngeal reflux (LPR) is shifting towards a personalized approach with noninvasive strategies/prediction tools to risk-stratify patients for upfront reflux testing over empiric acid suppression trials. Management should be multipronged to include antireflux therapies and treatments targeting other causes. Lower airway complications of EER may result in lung dysfunction and poor transplant outcomes. Esophageal symptoms are often absent and routine esophageal/reflux testing to guide timely antireflux therapies may lead to improved outcomes. Modalities that leverage impedance technology may be important, given the potential role of nonacidic reflux. Novel impedance-based metrics such as mean nocturnal baseline impedance and postreflux swallow-induced peristaltic wave index may provide adjunctive diagnostic values. SUMMARY: Standardized approach to diagnosis/management of EER should include multidisciplinary care teams and consider different phenotypes, nonreflux contributors, and the complex gut-airway relationships. Prompt antireflux therapies after careful candidate selection may improve outcomes of these airway complications.

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.

Allergic phenotype identified on allergen testing is associated with proton pump inhibitor nonresponse in eosinophilic esophagitis.

BACKGROUND AND AIM: Food/environmental allergens have been associated with eosinophilic esophagitis (EoE); however, the correlation between allergy profiles and disease responsiveness to proton pump inhibitor (PPI) therapy remains unclear. We aimed to assess the association between food/environmental allergies identified on allergen testing and histologic response to PPI in patients with treatment-naive EoE. METHODS: Adults with newly diagnosed EoE who underwent formal testing for food/environmental allergies at a tertiary center were included. All patients underwent twice-daily PPI for 8 weeks with subsequent repeat endoscopy and biopsy to assess histologic response. Patients with <15 eosinophils/hpf on post-PPI mucosal biopsies were classified as responders (PPI-r-EoE), while those with ≥15 eosinophils/hpf were nonresponders (PPI-nr-EoE). RESULTS: Sixty-one patients met inclusion criteria (21 PPI-r-EoE vs 40 PPI-nr-EoE). Demographic, clinical, and endoscopic finding variables were similar between groups. Positive food allergen test was more prevalent among PPI-nr-EoE patients (82.5% vs 42.9%, P = 0.003). On multivariable analysis, positive food allergen testing remained an independent predictor for PPI nonresponse (aOR 0.15, CI: 0.04-0.58, P = 0.0006). Positive environmental allergen testing was highly prevalent, with no significant differences between groups (77.5% vs 95.2%, P = 0.14). However, higher number of positive environmental allergens (23.3% [≥5 allergens] vs 73.3% [<5 allergens], P = 0.003) and specific aeroallergens correlated with PPI-nr-EoE. CONCLUSION: Positive food allergy testing and increased environmental allergens predicted lower likelihood of histologic response to PPI in EoE. Our findings support an allergic phenotype of EoE that may less likely respond to PPI therapy. Formal allergen testing may play a role in therapy selection and tailored management in EoE.

Obesity Is Associated with Altered Rectal Sensitivity in Chronic Constipation.

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 (ß-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.

Concurrent abnormal non-acid reflux is associated with additional chronic rejection risk in lung transplant patients with increased acid exposure.

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.

Optimizing the Management Algorithm for Heartburn in General Gastroenterology: Cost-Effectiveness and Cost-Minimization Analysis.

BACKGROUND AND AIMS: Heartburn is the most common symptom seen in gastroenterology practice. We aimed to optimize cost-effective evaluation and management of heartburn. METHODS: We developed a decision analytic model from insurer and patient perspectives comparing 4 strategies for patients failing empiric proton pump inhibitors (PPIs): (1) PPI optimization without testing, (2) endoscopy with PPI optimization for all patients, (3) endoscopy with PPI discontinuation when erosive findings are absent, and (4) endoscopy/ambulatory reflux monitoring with PPI discontinuation as appropriate for phenotypic management. Health outcomes were respectively defined on systematic reviews of clinical trials. Cost outcomes were defined on Centers for Medicare and Medicaid Services databases and commercial multipliers for direct healthcare costs, and national observational studies evaluating healthcare utilization. The time horizon was 1 year. All testing was performed off PPI. RESULTS: PPI optimization without testing cost $3784/y to insurers and $3128 to patients due to lower work productivity and suboptimal symptom relief. Endoscopy with PPI optimization lowered insurer costs by $1020/y and added 11 healthy days/y by identifying erosive reflux disease. Endoscopy with PPI discontinuation added 11 additional healthy days/y by identifying patients without erosive reflux disease that did not need PPI. By optimizing phenotype-guided treatment, endoscopy/ambulatory reflux monitoring with a trial of PPI discontinuation was the most effective of all strategies (gaining 22 healthy days/y) and saved $2183 to insurers and $2396 to patients. CONCLUSIONS: Among patients with heartburn, endoscopy with ambulatory reflux monitoring (off PPI) optimizes cost-effective management by matching treatment to phenotype. When erosive findings are absent, trialing PPI discontinuation is more cost-effective than optimizing PPI.

Association Between Anxiety/Depression and Gastroesophageal Reflux: A Systematic Review and Meta-Analysis.

INTRODUCTION: An association between gastroesophageal reflux disease (GERD) and common psychiatric conditions, most notably anxiety and depression, has been reported. However, the magnitude of this association is poorly understood. Therefore, we aimed to systematically assess this issue. METHODS: We comprehensively searched multiple bibliographic databases (Embase, PubMed, Scopus, and Web of Science) from inception to May 15, 2023. We retrieved observational studies that reported the prevalence of anxiety and/or depressive symptoms diagnosed by validated questionnaires in ≥100 adults (aged 18 years or older) with GERD. We also included cohort studies that explored the risk of incident GERD in subjects with anxiety/depression vice versa scenario. Finally, we included Mendelian randomization studies that assessed the cause-and-effect relationship between anxiety/depression and GERD. The extracted data were combined using a random-effects model. RESULTS: In total, 36 eligible studies were included. The pooled prevalences of anxiety and depressive symptoms were 34.4% (95% confidence interval [CI] 24.7-44.2; I2 = 99.4%) and 24.2% (95% CI 19.9-28.5; I2 = 98.8%) in subjects with GERD based on 30 studies, respectively. Both anxiety and depressive symptoms were more common in subjects with GERD compared with those in healthy controls (odds ratio = 4.46 [95% CI 1.94-10.25] and odds ratio = 2.56 [95% CI 1.11-5.87], respectively). According to 3 cohort studies, subjects with GERD were at an increased risk of developing anxiety/depression and vice versa. Finally, 3 Mendelian randomization studies showed that genetic liability to these mood disorders is linked to an increased risk of developing GERD and vice versa. DISCUSSION: Up to 1 in 3 subjects with GERD experience anxiety and depression. There is likely a bidirectional causal relationship between anxiety/depression and GERD.

Abnormal bolus reflux on impedance-pH testing independently predicts 3-year pulmonary outcome and mortality in pulmonary fibrosis.

BACKGROUND AND AIM: Gastroesophageal reflux has been associated with idiopathic pulmonary fibrosis (IPF), although the directionality of the relationship has been debated. Data on the value of objective reflux measures in predicting IPF disease progression and mortality remain limited. We aimed to evaluate the association between multichannel intraluminal impedance and pH testing (MII-pH) and 3-year pulmonary outcomes in IPF patients. METHODS: This was a retrospective cohort study of adults with IPF who underwent pre-lung transplant MII-pH off acid suppression at a tertiary center. Patients were followed for 3 years after MII-pH for poor pulmonary outcomes (hospitalization for respiratory exacerbation or death). A secondary analysis was performed using mortality as outcome of interest. Time-to-event analyses using Kaplan-Meier and Cox regression were performed to evaluate associations between MII-pH and poor outcomes. RESULTS: One hundred twenty-four subjects (mean age = 61.7 ± 8 years, 62% male) were included. Increased bolus exposure time (BET) on MII-pH was associated with decreased time to poor pulmonary outcomes and death (log-ranked P-value = 0.017 and 0.031, respectively). On multivariable Cox regression analyses controlling for potential confounders including age, sex, smoking history, body mass index, proton pump inhibitor use, baseline pulmonary function, and anti-fibrotic therapy, increased BET was an independent predictor for poor pulmonary outcomes [hazard ratio 3.18 (95% confidence interval: 1.25-8.09), P = 0.015] and mortality [hazard ratio 11.3 (95% confidence interval: 1.37-63.9), P = 0.025] over 3 years. CONCLUSIONS: Increased BET on MII-pH is an independent predictor of poor pulmonary outcomes and mortality over 3 years in IPF patients. These findings also support a role for gastroesophageal reflux in IPF disease progression and the potential impact of routine reflux testing and treatment.

Relationship Between Esophageal Disease and Pulmonary Fibrosis.

Esophageal disorders are prevalent among patients with chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). Gastroesophageal reflux disease (GERD) has been associated with IPF prevalence, severity, and respiratory decline. The pathophysiologic relationship between GERD and IPF is likely bidirectional, with aspiration of refluxate leading to lung inflammation and fibrosis, while the restrictive pulmonary physiology may contribute to altered transdiaphragmatic pressure gradient and increased reflux. Esophageal symptoms are frequently absent and do not predict esophageal dysfunction or pathologic reflux in patients with IPF, and objective diagnostic tools including upper endoscopy, ambulatory reflux monitoring, and high-resolution manometry are often needed. Impedance-based testing that identifies both weakly/non-acidic and acid reflux may provide important additional diagnostic value beyond pH-based acid testing alone. Novel metrics and maneuvers, including advanced impedance measures on impedance-pH study and provocative testing on HRM, may hold promise to future diagnostic advancements. The main treatment options include medical therapy with acid suppressants and anti-reflux surgery, although their potential benefits in pulmonary outcomes of IPF require further validations. Future directions of research include identifying phenotypes of IPF patients who may benefit from esophageal testing and treatment, determining the optimal testing strategy and protocol, and prospectively assessing the value of different esophageal therapies to improve outcomes while minimizing risks. This review will discuss the pathophysiology, evaluation, and management of esophageal diseases, particularly GERD, in patients with IPF, as informed by the most recent publications in the field, in hopes of identifying targets for future study and research.

Best Practices in Treatment of Laryngopharyngeal Reflux Disease: A Multidisciplinary Modified Delphi Study.

BACKGROUND: Laryngopharyngeal reflux (LPR) is a common otolaryngologic diagnosis. Treatment of presumed LPR remains challenging, and limited frameworks exist to guide treatment. METHODS: Using RAND/University of California, Los Angeles (UCLA) Appropriateness Methods, a modified Delphi approach identified consensus statements to guide LPR treatment. Experts independently and blindly scored proposed statements on importance, scientific acceptability, usability, and feasibility in a four-round iterative process. Accepted measures reached scores with ≥ 80% agreement in the 7-9 range (on a 9-point Likert scale) across all four categories. RESULTS: Fifteen experts rated 36 proposed initial statements. In round one, 10 (27.8%) statements were rated as valid. In round two, 8 statements were modified based on panel suggestions, and experts subsequently rated 5 of these statements as valid. Round three's discussion refined statements not yet accepted, and in round four, additional voting identified 2 additional statements as valid. In total, 17 (47.2%) best practice statements reached consensus, touching on topics as varied as role of empiric treatment, medication use, lifestyle modifications, and indications for laryngoscopy. CONCLUSION: Using a well-tested methodology, best practice statements in the treatment of LPR were identified. The statements serve to guide physicians on LPR treatment considerations.