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Background & aimsDiscerning 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.MethodsThis 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 β coefficients informed a weighted model. The validation phase assessed performance characteristics of the weighted model.ResultsA 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.ConclusionsThe 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.

BackgroundMyotomy length in type 3 achalasia is generally tailored based on segment of spasticity on high-resolution manometry (HRM). Potential of length of tertiary contractions on barium esophagram (BE) or length of thickened circular muscle on endoscopic ultrasound (EUS) to guide tailored myotomy is less understood. This study aimed to assess agreement between spastic segments lengths on HRM, BE, and EUS among patients with type 3 achalasia.MethodsThis retrospective study included adults with type 3 achalasia on HRM between November 2019 and August 2022 who underwent evaluation with EUS and/or BE. Spastic segments were defined as HRM-distance between proximal borders of lower esophageal sphincter and high-pressure area (isobaric contour ≥70 mmHg); EUS-length of thickened circular muscle (≥1.2 mm) from proximal border of esophagogastric junction (EGJ) to the transition to a non-thickened circular muscle; BE-distance between EGJ to proximal border of tertiary contractions. Pairwise comparisons assessed for correlation (Pearson's) and intraclass correlation classification (ICC) agreement.Key resultsTwenty-six patients were included: mean age 66.9 years (SD 13.8), 15 (57.7%) male. Spastic segments were positively correlated on HRM and BE with good agreement (ICC 0.751, [95% CI 0.51, 0.88]). Spastic segments were negatively correlated with poor agreement on HRM and EUS (ICC -0.04, [-0.45, 0.39]) as well as BE and EUS (ICC -0.03, [-0.47, 0.42]).Conclusions & inferencesLength of spastic segment was positively correlated on HRM and BE while negatively correlated when compared to EUS, supporting the common use of HRM and highlighting the uncertain role for EUS in tailoring myotomy length for type 3 achalasia.

Gastroesophageal reflux disease (GERD) is primarily diagnosed based on symptoms and response to a proton-pump inhibitor (PPI) trial. Gold standard testing requires an invasive endoscopic procedure, often with ambulatory pH monitoring. Salivary pepsin is a potential noninvasive modality for GERD diagnosis. This study aimed to assess diagnostic performance of salivary pepsin thresholds for GERD and determine optimal collection protocol of saliva in an external validation cohort. Over 10 months, adults with symptoms of GERD undergoing esophagogastroduodenoscopy with wireless pH-monitoring off PPI were enrolled. Saliva was self-collected by participants over 4 days across three different time points: fasting ante meridiem (AM), post-prandial, and bedtime (PM). Pepsin levels were calculated via Peptest. Pepsin variability and agreement were determined using linear mixed effects models and intraclass correlation. Validation of diagnostic threshold and performance characteristics were evaluated by receiver-operator curve analysis. Twenty participants enrolled in the study; 50% with physiologic acid exposure (acid exposure time

BackgroundType II achalasia (Ach2) is distinguished from other achalasia sub-types by the presence of panesophageal pressurization (PEP) of ≥30 mmHg in ≥20% swallows on high-resolution manometry (HRM). Variable manometric features in Ach2 have been observed, characterized by focal elevated pressures (FEPs) (focal/segmental pressures ≥70 mmHg within the PEP band) and/or high compression pressures (PEP ≥70 mmHg). This study aimed to examine clinical and physiologic variables among sub-groups of Ach2.MethodsThis retrospective single center study performed over 3 years (1/2019-1/2022) included adults with Ach2 on HRM who underwent endoscopic ultrasound (EUS), functional lumen imaging probe (FLIP), and/or barium esophagram (BE) prior to therapy. Patients were categorized into two overarching sub-groups: Ach2 without FEPs and Ach2 with FEPs. Demographic, clinical, and physiologic data were compared between these sub-groups utilizing unpaired univariate analyses.Key resultsOf 53 patients with Ach2, 40 (75%) were without FEPs and 13 (25%) had FEPs. Compared with the Ach2 sub-group without FEPs, the Ach2 sub-group with FEPs demonstrated a significantly thickened distal esophageal circular muscle on EUS (1.4 mm [SD 0.9] vs. 2.1 [0.7]; p = 0.02), higher prevalence of tertiary contractions on BE (46% vs. 100%; p = 0.0006), lower esophagogastric junction distensibility index (2.2mm2 /mmHg [0.9] vs 0.9 [0.4]; p = 0.0008) as well as higher distensive pressure (31.0 mmHg [9.8] vs. 55.4 [18.8]; p = 0.01) at 60 cc fill on FLIP, and higher prevalence of chest pain on Eckardt score (p = 0.03).Conclusions and inferencesWe identified a distinct sub-group of type II achalasia on HRM, defined as type II achalasia with focal elevated pressures. This sub-group uniquely exhibits spastic features and may benefit from personalized treatment approaches.

BackgroundThe Reflux Band, an external upper esophageal sphincter (UES) compression device, reduces esophago-pharyngeal reflux events. This study aimed to assess device efficacy as an adjunct to proton pump inhibitor (PPI) therapy in patients with laryngopharyngeal reflux (LPR).MethodsThis two-phase prospective clinical trial enrolled adults with at least 8 weeks of laryngeal symptoms (sore throat, throat clearing, dysphonia) not using PPI therapy at two tertiary care centers over 26 months. Participants used double dose PPI for 4 weeks in Phase 1 and the external UES compression device nightly along with PPI for 4 weeks in Phase 2. Questionnaire scores and salivary pepsin concentration were measured throughout the study. The primary endpoint of symptom response was defined as reflux symptom index (RSI) score ≤ 13 and/or > 50% reduction in RSI.ResultsThirty-one participants completed the study: 52% male, mean age 47.9 years (SD 14.0), and mean body mass index (BMI) 26.2 kg/m2 (5.1). Primary endpoint was met in 11 (35%) participants after Phase 1 (PPI alone) and 17 (55%) after Phase 2 (Device + PPI). Compared to baseline, mean RSI score (24.1 (10.9)) decreased at end of Phase 1 (PPI alone) (21.9 (9.7); p = 0.06) and significantly decreased at end of Phase 2 (Device + PPI) (15.5 (10.3); p

Background & aimsHeterogeneous presentations and disease mechanisms among patients with laryngeal symptoms account for misdiagnosis of laryngopharyngeal reflux (LPR), variations in testing, and suboptimal outcomes. We aimed to derive phenotypes of patients with laryngeal symptoms based on clinical and physiologic data and to compare characteristics across phenotypes.MethodsA total of 302 adult patients with chronic laryngeal symptoms were prospectively enrolled at 3 centers between January 2018 to October 2020 (age 57.2 ± 15.2 years; 30% male; body mass index 27.2 ± 6.0 kg/m2). Discriminant analysis of principal components (DAPC) was applied to 12 clinical and 11 physiologic variables collected in stable condition to derive phenotypic groups.ResultsDAPC identified 5 groups, with significant differences across symptoms, hiatal hernia size, and number of reflux events (P < .01). Group A had the greatest hiatal hernia size (3.1 ± 1.0 cm; P < .001) and reflux events (37.5 ± 51; P < .001), with frequent cough, laryngeal symptoms, heartburn, and regurgitation. Group B had the highest body mass index (28.2 ± 4.6 kg/m2; P < .001) and salivary pepsin (150 ± 157 ng/mL; P = .03), with frequent cough, laryngeal symptoms, globus, heartburn, and regurgitation. Group C frequently reported laryngeal symptoms (93%; P < .001), and had fewest esophageal symptoms (9.6%; P < .001) and reflux events (10.7 ± 11.0; P < .001). Group D commonly reported cough (88%; P < .001) and heartburn. Group E (18%) was oldest (62.9 ± 14.3 years; P < .001) and distinguished by highest integrated relaxation pressure.ConclusionsDAPC identified distinct clinicophysiologic phenotypes of patients with laryngeal symptoms referred for reflux evaluation: group A, LPR and gastroesophageal reflux disease (GERD) with hiatal hernia; group B, mild LPR/GERD; group C, no LPR/No GERD; group D, reflex cough; and group E, mixed/possible obstructive esophagogastric junction. Phenotypic differences may inform targeted clinical trials design and improve outcomes.

BackgroundThe Reflux Band, an external upper esophageal sphincter (UES) compression device, reduces esophago-pharyngeal reflux events. This study aimed to assess device efficacy as an adjunct to proton pump inhibitor (PPI) therapy in patients with laryngopharyngeal reflux (LPR).MethodsThis two-phase prospective clinical trial enrolled adults with at least 8 weeks of laryngeal symptoms (sore throat, throat clearing, dysphonia) not using PPI therapy at two tertiary care centers over 26 months. Participants used double dose PPI for 4 weeks in Phase 1 and the external UES compression device nightly along with PPI for 4 weeks in Phase 2. Questionnaire scores and salivary pepsin concentration were measured throughout the study. The primary endpoint of symptom response was defined as reflux symptom index (RSI) score ≤ 13 and/or > 50% reduction in RSI.ResultsThirty-one participants completed the study: 52% male, mean age 47.9 years (SD 14.0), and mean body mass index (BMI) 26.2 kg/m2 (5.1). Primary endpoint was met in 11 (35%) participants after Phase 1 (PPI alone) and 17 (55%) after Phase 2 (Device + PPI). Compared to baseline, mean RSI score (24.1 (10.9)) decreased at end of Phase 1 (PPI alone) (21.9 (9.7); p = 0.06) and significantly decreased at end of Phase 2 (Device + PPI) (15.5 (10.3); p

Uncertain diagnostic performance has limited clinical adoption of salivary pepsin, a noninvasive diagnostic tool for gastroesophageal reflux disease (GERD). This study aimed to assess diagnostic performance of salivary pepsin, and test validity of thresholds in an external cohort of patients with or without GERD. This two-phase prospective study conducted at two centers enrolled adult asymptomatic volunteers, patients with symptoms of GERD undergoing reflux monitoring, and patients with Barretts esophagus (BE). Fasting saliva samples were processed for pepsin concentration using Peptest. Phase 1 compared pepsin concentration between No GERD (volunteers/functional heartburn) and GERD (erosive reflux disease/nonerosive reflux disease (NERD)/BE). Phase 2 tested validity of the diagnostic thresholds identified from Phase 1 among external functional heartburn and NERD cohorts. Of 243 enrolled subjects, 156 met inclusion criteria. Phase 1 (n = 114): Pepsin concentrations were significantly higher in GERD (n = 84) versus No GERD (n = 30) (73.8 ng/mL vs. 21.1 ng/mL; P

The diverse human gut microbiome is comprised of approximately 40 trillion microorganisms representing up to 1000 different bacterial species. The human microbiome plays a critical role in gut epithelial health and disease susceptibility. While the interaction between gut microbiome and gastrointestinal pathology is increasingly understood, less is known about the interaction between the microbiome and the aerodigestive tract. This review of the microbiome of the aerodigestive tract in health, and alterations in microbiome across esophageal pathologies highlights important findings and areas for future research. First, microbiome profiles are distinct along the aerodigestive tract, spanning the oral cavity to the stomach. In patients with reflux-related disease such as gastro-esophageal reflux disease, Barrett's esophagus, and esophageal adenocarcinoma, investigators have observed an overall increase in gram negative bacteria in the esophageal microbiome compared to healthy individuals. However, whether differences in microbiome promote disease development, or if these shifts are a consequence of disease remains unknown. Interestingly, use of proton pump inhibitor therapy is also associated with shifts in the microbiome, with distinct shifts and patterns along the aerodigestive tract. The relationship between the human gut microbiome and esophageal pathology is a ripe area for investigation, and further understanding of these pathways may promote development of novel targets in prevention and therapy for esophageal diseases.

Background: Surgical bariatric interventions, while highly effective, can be associated with post‐operative esophageal symptoms, gastroesophageal reflux disease and esophageal dysmotility. Whether pre‐operative physiology impacts this risk is unknown, in part because expected values on esophageal manometry in patients with obesity are not well understood. This study seeks to establish normative values on esophageal high resolution manometry (HRM) and the prevalence of esophageal dysmotility in the asymptomatic patient with obesity. Methods: This retrospective study included adult patients with body mass index (BMI) ≥35 kg m−2 without esophageal symptoms undergoing preoperative bariatric surgical evaluation, including HRM, at a single tertiary care center between February, 2019 and February, 2020. Results: Of 104 asymptomatic patients with obesity, HRM identified normal esophageal motility in 94 (90.4%) with the remaining 10 having ineffective esophageal motility (3.8%), manometric esophagogastric junction outflow obstruction (3.8%), distal esophageal spasm (1.0%), and hypercontractile esophagus (1.0%). Mean of median lower esophageal sphincter integrated relaxation pressure (LES IRP) was 10.6 mmHg supine (95th percentile 21.5 mmHg) and 8.5 mmHg upright (95th percentile 21.3 mmHg). 86% of patients had intragastric pressure above 8 mmHg. Mean of mean distal contractile integral (DCI) was 2261.6 mmHg cm s−1 (95th percentile 5889.5 mmHg cm s−1). Conclusion: The vast majority of asymptomatic patients with obesity had normal manometry. LES IRP and DCI were higher than that observed in non‐obese cohorts. Additionally, BMI correlated to increased intragastric pressure. These data suggest that normative values in patients with obesity should be adjusted to prevent overdiagnosis of EGJOO or hypercontractile esophagus. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic laryngopharyngeal symptoms, with or without pathologic reflux, frequently have poor response to standard therapies, which may be a result of overlapping cognitive‐affective processes. Therefore, the aims of this study included measuring psychosocial distress and laryngeal‐specific cognitive distress in patients with chronic laryngopharyngeal symptoms (LPS) as well as comparing these among laryngeal symptomatic patients with and without conclusive gastroesophageal reflux disease (GERD). Methods: This prospective, single‐center study enrolled adults with chronic LPS from 9/22 to 6/23. Patients completed eight questionnaires on quality of life, symptom burden, and psychosocial distress. The laryngeal cognitive affective tool (LCAT) assessed laryngeal‐specific hypervigilance and anxiety; LCAT scores ≥33 were elevated. All patients underwent objective testing with endoscopy and/or ambulatory reflux monitoring and were categorized as proven GERD (GER+) or no proven GERD (GER−). Key Results: One hundred twenty‐nine patients were included: 66% female, mean age 54.1 (17.5) years, mean BMI 27.6 (6.8) kg/m2, 66% Caucasian, 57% with an elevated LCAT, and 53% GER+. Moderate‐to‐severe anxiety was found in 39% and moderate‐to‐severe depression in 19%. An elevated LCAT alone or with an elevated anxiety/depression score was found in 58%. Patient‐reported outcomes scores, including LCAT scores (32.9 (13.8) GER− vs. 33.1 (12.6) GER+, p = 0.91), were similar between patients with and without GER+. Conclusions and Inferences: Patients with chronic LPS experience heightened levels of hypervigilance, symptom‐specific anxiety, and psychosocial distress, regardless of the presence of pathologic GER. [ABSTRACT FROM AUTHOR]

Bile acids in refluxate contribute to esophageal and laryngeal symptoms and are quantifiable. The aim of this study was to compare salivary bile acid concentrations across healthy controls and symptomatic patients (esophageal or laryngeal) with or without objective gastroesophageal reflux disease (GERD). This prospective study enrolled adults into three groups: esophageal symptoms (heartburn, regurgitation, chest pain); laryngeal symptoms (cough, throat clearing, sore throat, dysphonia); and controls. Symptomatic patients primarily underwent prolonged wireless reflux monitoring off acid suppression and were categorized as symptomatic no GERD (acid exposure time <4%) or esophageal/laryngeal symptoms with GERD (acid exposure time ≥4%). Controls did not undergo reflux monitoring nor upper endoscopy. Saliva samples were provided for bile acid analysis via ultraperformance liquid chromatography tandem mass spectrometry. Thirty-five participants were enrolled (mean age 47.4 years [SD 18.9], 16 [46%] male), including 10 controls and 25 symptomatic: 9 no GERD, 5 esophageal symptoms + GERD, and 11 laryngeal symptoms + GERD. Total salivary bile acids were highest in the laryngeal symptoms + GERD group (24.2 nM [SD 24.7]) compared to other groups (controls: 5.8 [6.0], P  = 0.03; symptomatic no GERD: 3.1 [4.4]; P  < 0.01; esophageal symptoms + GERD: 7.1 [7.1], P  = 0.10). Bile acids were elevated in 45% (5/11) of the laryngeal symptoms + GERD group compared to 0% of the other three groups (P  < 0.01). Salivary bile acids were higher among patients with laryngeal symptoms and objective GERD versus other groups. Salivary bile acids are a quantifiable biomarker with diagnostic potential for laryngopharyngeal reflux. [ABSTRACT FROM AUTHOR]

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 (GER1) on ambulatory reflux monitoring off acid suppression. RESULTS: Of 813 patients, 296 (36%) underwent prolonged wireless pH, 532 (65%) underwent 24-hour pHimpedance monitoring, and 15 (2%) underwent both tests. Overall diagnostic yield for GER1was 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 pHimpedance monitoring, concordance between systems for GER1 was 40%. The most common source of discordance was strong evidence of GER1 across multiple days on prolonged wireless pH compared with no evidence of GER1 on pH-impedance. DISCUSSION: In this multicenter international study of patients with chronic laryngeal symptoms referred for LPR evaluation, diagnostic yield of ambulatory refluxmonitoring off acid suppression was36%and rose to 50% when using wireless pH monitoring. In patients referred for chronic laryngeal symptoms, 24-hour pHimpedance monitoring may risk a low negative predictive value in patients with unproven GER1 disease. [ABSTRACT FROM AUTHOR]

Background: Pathophysiologic mechanisms of disorders of esophagogastric junction (EGJ) outflow are poorly understood. We aimed to compare anatomic and physiologic characteristics among patients with disorders of EGJ outflow and normal motility. Methods: We retrospectively evaluated adult patients with achalasia types 1, 2, 3, EGJ outflow obstruction (EGJOO) or normal motility on high‐resolution manometry who underwent endoscopic ultrasound (EUS) from January 2019 to August 2022. Thickened circular muscle was defined as ≥1.6 mm. Characteristics from barium esophagram (BE) and functional lumen imaging probe (FLIP) were additionally assessed. Key Results: Of 71 patients (mean age 56.2 years; 49% male), there were 8 (11%) normal motility, 58 (82%) had achalasia (5 (7%) type 1, 32 (45%) classic type 2, 21 (30%) type 3 [including 12 type 2 with FEPs]), and 7 (7%) had EGJOO. A significantly greater proportion of type 3 achalasia had thickened distal circular muscle (76.2%) versus normal motility (0%; p < 0.001) or type 2 achalasia (25%; p < 0.001). Type 1 achalasia had significantly wider mean maximum esophageal diameter on BE (57.8 mm) compared to type 2 achalasia (32.8 mm), type 3 achalasia (23.4 mm), EGJOO (15.9 mm), and normal motility (13.5 mm). 100% type 3 achalasia versus 0% type 1 achalasia/normal motility had tertiary contractions on BE. Mean EGJ distensibility index on FLIP was lower for type 3 achalasia (1.2 mmHg/mm2) and EGJOO (1.2 mmHg/mm2) versus type 2 (2.3 mmHg/mm2) and type 1 achalasia (2.9 mmHg/mm2). Conclusions: Our findings suggest distinct pathologic pathways may exist: type 3 achalasia and EGJOO may represent a spastic outflow phenotype consisting of a thickened, spastic circular muscle, which is distinct from type 1 and 2 achalasia consisting of a thin caliber circular muscle layer with more prominent esophageal dilation. [ABSTRACT FROM AUTHOR]

Gastroesophageal reflux disease (GERD) is primarily diagnosed based on symptoms and response to a proton-pump inhibitor (PPI) trial. Gold standard testing requires an invasive endoscopic procedure, often with ambulatory pH monitoring. Salivary pepsin is a potential noninvasive modality for GERD diagnosis. This study aimed to assess diagnostic performance of salivary pepsin thresholds for GERD and determine optimal collection protocol of saliva in an external validation cohort. Over 10 months, adults with symptoms of GERD undergoing esophagogastroduodenoscopy with wireless pH-monitoring off PPI were enrolled. Saliva was self-collected by participants over 4 days across three different time points: fasting ante meridiem (AM), post-prandial, and bedtime (PM). Pepsin levels were calculated via Peptest. Pepsin variability and agreement were determined using linear mixed effects models and intraclass correlation. Validation of diagnostic threshold and performance characteristics were evaluated by receiver–operator curve analysis. Twenty participants enrolled in the study; 50% with physiologic acid exposure (acid exposure time < 4% no GERD) and 50% with elevated acid exposure (GERD). Mean pepsin concentrations were significantly lower in the AM (22.6 ± 25.2 ng/mL) compared to post-prandial (44.5 ± 36.7 ng/mL) and PM (55.4 ± 47.0 ng/mL). Agreement between pepsin concentrations across 3 days was substantial for AM samples (kappa 0.61), with lower agreement for post-prandial and PM samples. A single AM pepsin concentration of 25 ng/mL was 67% accurate for GERD with 56% sensitivity and 78% specificity. This validation study highlights fair accuracy and performance characteristics of a single fasting AM salivary pepsin concentration for the diagnosis of GERD. [ABSTRACT FROM AUTHOR]