Microbiome of the Aerodigestive Tract in Health and Esophageal Disease

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

Diagnostic thresholds and optimal collection protocol of salivary pepsin for gastroesophageal reflux disease.

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

Diagnostic performance of salivary pepsin for gastroesophageal reflux disease.

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 < 0.001). Area under the curve for pepsin concentration was 0.74 (95% CI 0.65, 0.83). A salivary pepsin threshold of 24.9 ng/mL optimized the true negative rate and 100.0 ng/mL optimized the true positive rate. Phase 2 (n = 42): Pepsin concentrations were significantly higher in NERD (n = 22) versus Functional Heartburn (n = 20) (176.0 ng/mL vs. 53.3 ng/mL, P < 0.001). Applying Phase 1 thresholds in this external cohort, salivary pepsin 24.9 ng/mL was 86% sensitive (64%, 97%) and 100.0 ng/mL was 72% specific for distinguishing NERD from functional heartburn. Given modest sensitivity and specificity for GERD, salivary pepsin may have clinical utility as a noninvasive office based diagnostic screening tool for GERD

Diagnostic methods to measure spastic segment and guide tailored myotomy length in type 3 achalasia

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

Type II achalasia with focal elevated pressures: A distinct manometric and clinical sub‐group

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

Upper Esophageal Sphincter Compression Device as an Adjunct to Proton Pump Inhibition for Laryngopharyngeal Reflux.

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 < 0.01). Compared to non-responders, responders to Device + PPI had a significantly lower BMI (p = 0.02) and higher salivary pepsin concentration (p = 0.01).ConclusionThis clinical trial highlights the potential efficacy of the external UES compression device (Reflux Band) as an adjunct to PPI for patients with LPR (ClinicalTrials.Gov NCT03619811)

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

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

Distinct Clinical Physiologic Phenotypes of Patients With Laryngeal Symptoms Referred for Reflux Evaluation

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