An Endoscopic Scoring System for Achalasia: The CARS score.

BACKGROUND AND AIMS: The diagnosis of achalasia is associated with an average delay of two years. Endoscopic features may prompt an earlier diagnosis. We aimed to develop and test a novel endoscopic CARS score for the prediction of achalasia. METHODS: Part 1: Twenty endoscopic videos were taken from patients undergoing endoscopy for dysphagia or reflux. A survey with videos and endoscopic criteria options was distributed to 6 esophagologists and 6 general gastroenterologists. Inter-rater reliability (IRR) was measured and logistic regression was used to evaluate predictive performance. Three rounds of review were conducted to select the final score of four components. PART 2: A retrospective review was conducted for consecutive patients who had comprehensive esophageal testing. Each patient had a CARS endoscopic score calculated based on findings reported at endoscopy. RESULTS: From a video review and analysis of score components, IRR ranged from 0.23 to 0.57 for score components. The final CARS score was selected based on the following four components: Contents, Anatomy, Resistance, and Stasis. In a mixed effects model, the mean score across raters was higher for achalasia compared to non-achalasia subjects (4.44 vs. 0.87, p = < 0.01). In part 2 of the study, achalasia patients had a higher mean CARS score compared to those with no / ineffective motility disorder (mean 4.1 vs 1.3, p = < 0.01). CONCLUSIONS: We developed a CARS score based on reliability performance in a video-based survey and tested the score in clinical setting. The CARS score performed well in predicting achalasia.

Effect of esophageal body recoil on clinical outcomes in non-spastic achalasia.

BACKGROUND: Despite the established efficacy of achalasia treatments on symptomatic outcomes, there are limited data evaluating the treatment effect on esophageal dilatation. This study aimed to assess the effect achalasia treatment on esophageal dilatation and the effect of esophageal width reduction ("recoil") on clinical outcomes. METHODS: Patients with type I or type II achalasia that completed high-resolution manometry (HRM), functional lumen imaging probe (FLIP), and timed barium esophagram (TBE) pre and post treatment were included. Esophageal width was measured using TBE. Focused subgroup analysis was performed on patients with normal posttreatment EGJ opening on FLIP. Good clinical outcomes were defined as barium column height of <5 cm at 5 min and Eckardt Score ≤3. KEY RESULTS: Sixty-nine patients (41% type I and 59% type II) were included. Esophageal width decreased from pre to post treatment mean (SD) 4.2 (1.3) cm-2.8 (1.2) cm; p < 0.01. In the normal post treatment EGJ opening subgroup, esophageal width was less in patients with good TBE outcome compared to poor outcome mean (SD) 2.2 (0.7) cm versus 3.2 (1.4) cm (p < 0.01), but did not differ in good versus poor symptomatic outcome groups. Esophageal width recoil >25% posttreatment was associated with a greater rate of good TBE outcome (71% vs. 50%, p = 0.04) and good symptomatic outcome (88% vs. 50%; p = 0.04). CONCLUSIONS AND INFERENCES: Esophageal recoil was associated with good achalasia treatment outcome in patients without posttreatment EGJ obstruction. This suggests that mechanical properties of the esophageal wall, likely associated with tissue remodeling, play a role in clinical outcomes following achalasia treatment.

Neurological disorders leading to mechanical dysfunction of the esophagus: an emergent behavior of a neuromechanical dynamical system.

An understanding how neurological disorders lead to mechanical dysfunction of the esophagus requires knowledge of the neural circuit of the enteric nervous system. Historically, this has been elusive. Here, we present an empirically guided neural circuit for the esophagus. It has a chain of unidirectionally coupled relaxation oscillators, receiving excitatory signals from stretch receptors along the esophagus. The resulting neuromechanical model reveals complex patterns and behaviors that emerge from interacting components in the system. A wide variety of clinically observed normal and abnormal esophageal responses to distension are successfully predicted. Specifically, repetitive antegrade contractions (RACs) are conclusively shown to emerge from the coupled neuromechanical dynamics in response to sustained volumetric distension. Normal RACs are shown to have a robust balance between excitatory and inhibitory neuronal populations, and the mechanical input through stretch receptors. When this balance is affected, contraction patterns akin to motility disorders are observed. For example, clinically observed repetitive retrograde contractions emerge due to a hyper stretch sensitive wall. Such neuromechanical insights could be crucial to eventually develop targeted pharmacological interventions.

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.

Secondary peristalsis and esophagogastric junction distensibility in symptomatic post-fundoplication patients.

BACKGROUND: The impact of esophageal dysmotility among patients with post-fundoplication esophageal symptoms is not fully understood. This study aimed to investigate secondary peristalsis and esophagogastric junction (EGJ) opening biomechanics using functional lumen imaging probe (FLIP) panometry in symptomatic post-fundoplication patients. METHODS: Eighty-seven adult patients post-fundoplication who completed FLIP for symptomatic esophageal evaluation were included. Secondary peristaltic contractile response (CR) patterns and EGJ opening metrics (EGJ distensibility index (EGJ-DI) and maximum EGJ diameter) were evaluated on FLIP panometry and analyzed against high-resolution manometry (HRM), patient-reported outcomes, and fundoplication condition seen on esophagram and/or endoscopy. KEY RESULTS: FLIP CR patterns included 14 (16%) normal CR, 30 (34%) borderline CR, 28 (32%) impaired/disordered CR, 13 (15%) absent CR, and 2 (2%) spastic reactive CR. Compared with normal and borderline CRs (i.e., CR patterns with distinct, antegrade peristalsis), patients with impaired/disordered and absent CRs demonstrated significantly greater time since fundoplication (2.4 (0.6-6.8) vs. 8.9 (2.6-14.5) years; p = 0.002), greater esophageal body width on esophagram (n = 50; 2.3 (2.0-2.8) vs. 2.9 (2.4-3.6) cm; p = 0.013), and lower EGJ-DI (4.3 (2.7-5.4) vs. 2.6 (1.7-3.7) mm2/mmHg; p = 0.001). Intact fundoplications had significantly higher rates of normal CRs compared to anatomically abnormal (i.e., tight, disrupted, slipped, herniated) fundoplications (9 (28%) vs. 5 (9%); p = 0.032), but there were no differences in EGJ-DI or EGJ maximum diameter. CONCLUSIONS & INFERENCES: Symptomatic post-fundoplication patients were characterized by frequent abnormal secondary peristalsis after fundoplication, potentially worsening with time after fundoplication or related to EGJ outflow resistance.

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.

The Severity of Reduced Esophageal Distensibility Parallels Eosinophilic Esophagitis Disease Duration.

BACKGROUND & AIMS: Chronic inflammation of eosinophilic esophagitis (EoE) results in progressive, fibrostenotic remodeling of the esophageal wall. This study aimed to demonstrate objective changes in esophageal distensibility relative to duration of EoE disease using a functional lumen imaging probe (FLIP). METHODS: Adult patients with EoE who completed a 16-cm FLIP protocol during endoscopy were evaluated in a cross-sectional study. FLIP analysis focused on distensibility plateau (DP) of the esophageal body. The time from onset of symptoms to time of endoscopy with FLIP was assessed, as was time from symptom onset to EoE diagnosis (ie, diagnostic delay). RESULTS: A total of 171 patients (mean age 38 ± 12 years; 31% female) were included; the median symptom duration was 8 (interquartile range, 3-15) years and diagnostic delay was 4 (interquartile range, 1-12) years. At the time of endoscopy with FLIP, there were 54 patients (39%) in histologic remission (<15 eosinophils per high-power field [eos/hpf]). Symptom duration and diagnostic delay were negatively correlated with DP (rho = -0.326 and -0.309; P values < .001). Abnormal esophageal distensibility (DP ≤17 mm) was more prevalent with increased duration of symptoms (P < .004): 23% at <5 years to 64% at ≥25 years. When stratifying the cohort based on mucosal eosinophil density, patients with ≥15 eos/hpf had significantly lower DP with greater symptom duration (P = .004), while there was not a significant difference among patients with <15 eos/hpf (P = .060). CONCLUSIONS: Esophageal distensibility objectively measured with FLIP was reduced in EoE patients with greater symptom duration and diagnostic delay. This supports that EoE is a progressive, fibrostenotic disease and that FLIP may be a useful tool to monitor disease progression in EoE.

A Mechanics-Based Perspective on the Function of Human Sphincters During Functional Luminal Imaging Probe Manometry.

Functional luminal imaging probe (FLIP) is used to measure cross-sectional area (CSA) and pressure at sphincters. It consists of a catheter surrounded by a fluid filled cylindrical bag, closed on both ends. Plotting the pressure-CSA hysteresis of a sphincter during a contraction cycle, which is available through FLIP testing, offers information on its functionality, and can provide diagnostic insights. However, limited work has been done to explain the mechanics of these pressure-CSA loops. This work presents a consolidated picture of pressure-CSA loops of different sphincters. Clinical data reveal that although sphincters have a similar purpose (controlling the flow of liquids and solids by opening and closing), two different pressure-CSA loop patterns emerge: negative slope loop (NSL) and positive slope loop (PSL). We show that the loop type is the result of an interplay between (or lack thereof) two mechanical modes: (i) neurogenic mediated relaxation of the sphincter muscle or pulling applied by external forces, and (ii) muscle contraction proximal to the sphincter which causes mechanical distention. We conclude that sphincters which only function through mechanism (i) exhibition NSL whereas sphincters which open as a result of both (i) and (ii) display a PSL. This work provides a fundamental mechanical understanding of human sphincters. This can be used to identify normal and abnormal phenotypes for the different sphincters and help in creating physiomarkers based on work calculation.

Presence of esophageal contractility after achalasia treatment is associated with improved esophageal emptying.

BACKGROUND AND AIMS: Some achalasia patients exhibit esophageal contractile activity on follow-up after treatment, yet its importance remains unclear. We aimed to identify factors associated with presence of contractility after treatment and to assess its impact on timed barium esophagram (TBE) and clinical outcomes. METHODS: Patients with type I or II achalasia on baseline high-resolution manometry (HRM) who completed HRM, TBE, and functional lumen imaging probe (FLIP) after treatment were retrospectively identified. Contractility was defined on post-treatment HRM as presence of at least 1 supine swallow with DCI ≥100 mmHg s cm. KEY RESULTS: One hundred twenty-two patients were included (mean age 48 ± 17 years, 50% female). At follow-up evaluation after treatment (54% peroral endoscopic myotomy, 24% pneumatic dilation, 22% laparoscopic Heller myotomy), 61 (50%) patients had contractility on HRM. Patients with contractility (compared to those without) more frequently had type II achalasia (84% vs 57%, p = 0.001) and a post-treatment normal EGJ opening classification on FLIP (69% vs 49%; p < 0.001). In the subgroup of patients with post-treatment integrated relaxation pressure <15 mmHg and normal EGJ opening on FLIP (n = 53), those with contractility had a lower median column height on TBE at 1 min (4 vs 7 cm, p = 0.002) and 5 min (0 vs 5 cm, p = 0.001). In patients with "abnormal" EGJ metrics, patients with contractility showed lower symptom scores (median Eckardt score 2 vs 3, p = 0.03). CONCLUSIONS & INFERENCES: Occurring more frequently in type II achalasia, and if adequate EGJ opening is achieved after treatment, esophageal contractility may contribute to improved esophageal emptying and improved symptoms in non-spastic achalasia. Preservation of esophageal body muscle could improve outcomes in these patients.

A Composite Score of Physiomechanical Esophageal Function Using Functional Lumen Imaging Probe Panometry in Eosinophilic Esophagitis.

BACKGROUND AND AIMS: The evaluation provided by functional lumen imaging probe (FLIP) Panometry includes esophageal distensibility/compliance (mechanics) of the esophageal body and esophagogastric junction (EGJ) and esophageal motility (secondary peristalsis). We aimed to develop a composite score using these parameters to characterize physiomechanical function in patients with eosinophilic esophagitis (EoE). METHODS: 215 adult patients with EoE that completed FLIP Panometry during sedated endoscopy with esophageal biopsies were included. FLIP metrics of esophageal body Compliance, Contractile response, Distensibility plateau, and maximum EGJ Diameter (C2D2) were scored as 0 for normal, vs 1 or 2 for increasing degree of abnormality. Scores were summed to calculate the composite "C2D2" score. RESULTS: The C2D2 score had a significant positive correlation with mucosal eosinophil count (rho=0.241) and total endoscopic (EREFS) score (rho=0.467). Among patients off treatment at baseline evaluation (n=46), future proton pump inhibitor (PPI)-responders (i.e. achieved mucosal eosinophil count <15 per hpf after PPI treatment) had lower C2D2 scores than PPI-non-responders (median (IQR) 2 (1-3) vs 4 (2-6); P=0.003). A regression model (that controlled for age, sex, and baseline eosinophil count) showed a C2D2 score ≤3 had an odds ratio (95% confidence interval) of 14.5 (2.6-85) to predict future PPI-response. However, total EREFS scores (P=0.142) and baseline eosinophil count (P=0.480) did not differ between PPI-responders and PPI-non-responders. CONCLUSIONS: This composite score of FLIP Panometry metrics, the C2D2 score, may facilitate characterizing physiomechanical function in EoE and serve as an objective outcome measure.

Assessing mechanical function of peristalsis with functional lumen imaging probe panometry: Contraction power and displaced volume.

BACKGROUND AND AIMS: The distal contractile integral (DCI) quantifies the contractile vigor of primary peristalsis on high-resolution manometry (HRM), whereas no such metric exists for secondary peristalsis on functional lumen imaging probe (FLIP) panometry. This study aimed to evaluate novel FLIP metrics of contraction power and displaced volume in asymptomatic controls and a patient cohort. METHODS: Thirty-five asymptomatic controls and adult patients (with normal esophagogastric junction outflow/opening and without spasm) who completed HRM and FLIP panometry were included. The patient group also completed timed barium esophagram (TBE). Contraction power (estimate of esophageal work over time) and displaced volume (estimate of contraction-associated fluid flow) were computed from FLIP. HRM was analyzed per Chicago Classification v4.0. KEY RESULTS: In controls, median (5th-95th percentile) contraction power was 27 mW (10-44) and displaced volume was 43 mL (17-66). 95 patients were included: 72% with normal motility on HRM, 17% with ineffective esophageal motility (IEM), and 12% with absent contractility. Among patients, DCI was significantly correlated with both contraction power (rho = 0.499) and displaced volume (rho = 0.342); p values < 0.001. Both contraction power and displaced volume were greater in patients with normal motility versus IEM or absent contractility, complete versus incomplete bolus transit, and normal versus abnormal retention on TBE; p values < 0.02. CONCLUSIONS: FLIP panometry metrics of contraction power and displaced volume appeared to effectively quantify peristaltic vigor. These novel metrics may enhance evaluation of esophageal motility with FLIP panometry and provide a reliable surrogate to DCI on HRM.

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.

Suprabasal cells retain progenitor cell identity programs in eosinophilic esophagitis-driven basal cell hyperplasia.

Eosinophilic esophagitis (EoE) is an esophageal immune-mediated disease characterized by eosinophilic inflammation and epithelial remodeling, including basal cell hyperplasia (BCH). Although BCH is known to correlate with disease severity and with persistent symptoms in patients in histological remission, the molecular processes driving BCH remain poorly defined. Here, we demonstrate that BCH is predominantly characterized by an expansion of nonproliferative suprabasal cells that are still committed to early differentiation. Furthermore, we discovered that suprabasal and superficial esophageal epithelial cells retain progenitor identity programs in EoE, evidenced by increased quiescent cell identity scoring and the enrichment of signaling pathways regulating stem cell pluripotency. Enrichment and trajectory analyses identified SOX2 and KLF5 as potential drivers of the increased quiescent identity and epithelial remodeling observed in EoE. Notably, these alterations were not observed in gastroesophageal reflux disease. These findings provide additional insights into the differentiation process in EoE and highlight the distinct characteristics of suprabasal and superficial esophageal epithelial cells in the disease.

Relaxation of the lower esophageal sphincter in response to reduced volume distension during FLIP Panometry.

BACKGROUND: The esophageal response to stepwise distension during the functional lumen imaging probe (FLIP) Panometry study often parallels high-resolution manometry (HRM) motility diagnoses. This study aimed to describe the changes in FLIP metrics during FLIP emptying, that is, reduced volume distension. METHODS: Adult patients who completed FLIP and HRM for esophageal motility evaluation were included. Esophagogastric junction (EGJ) opening parameters were assessed during stepwise FLIP filling to volumes of 60 mL ("filling 60 mL"), then 70 mL, and then back to 60 mL ("emptying 60 mL"). HRM studies were analyzed per Chicago classification version 4.0 (CCv4.0). KEY RESULTS: Among 265 patients included, HRM/CCv4.0 diagnoses included achalasia in 80 patients (30%), normal motility in 70 (26%), and ineffective esophageal motility (IEM) in 43 (16%). EGJ-distensibility index (DI) and EGJ diameter were greater during emptying 60 mL than filling 60 mL in achalasia, normal motility, and IEM (p values <0.002). If applying the emptying 60 mL EGJ-DI (vs. filling 60 mL EGJ-DI), EGJ opening classification changed from reduced EGJ opening to borderline EGJ opening in 31% of achalasia patients and in 2% of patients with normal motility or IEM. EGJ opening classification was unchanged in 69% achalasia and 96% of normal motility/IEM. CONCLUSIONS AND INFERENCES: This study suggests that isotonic or auxotonic relaxation of the lower esophageal sphincter occurs with reduced volume distension in patients with achalasia and normal motility. The study also supports the importance of utilizing a standardized FLIP motility study protocol (i.e., controlled, stepwise filling to 50 mL, 60 mL, then 70 mL) to provide reliable and generalizable FLIP metrics to facilitate diagnosis of esophageal motility disorders.

Advances in the Diagnosis and Management of Achalasia and Achalasia-Like Syndromes: Insights From HRM and FLIP.

High-resolution manometry, Chicago Classification v4.0, the functional lumen imaging probe, Panometry, and peroral endoscopic myotomy (POEM) are all now integral parts of the landscape for managing achalasia or, more precisely, achalasia-like syndromes. This narrative review examines the impact of these innovations on the management of achalasia-like syndromes. High-resolution manometry was the disruptive technology that prompted the paradigm shift to thinking of motility disorders as patterns of obstructive physiology involving the esophagogastric junction and/or the distal esophagus rather than as siloed entities. An early observation was that the cardinal feature of achalasia-impaired lower esophageal sphincter relaxation-can occur in several subtypes: without peristalsis, with pan-esophageal pressurization, with premature (spastic) distal esophageal contractions, or even with preserved peristalsis (esophagogastric junction outlet obstruction). Furthermore, there being no biomarker for achalasia, no manometric pattern is perfectly sensitive or specific for 'achalasia' and there is also no 'gold standard' for the diagnosis. Consequently, complimentary physiological testing with a timed barium esophagram or functional lumen imaging probe are employed both to improve the detection of patients likely to respond to treatments for 'achalasia' and to characterize other syndromes also likely to benefit from achalasia therapies. These findings have become particularly relevant with the development of a minimally invasive technique for performing a tailored esophageal myotomy, POEM. Now and in the future, optimal achalasia management is to render treatment in a phenotype-specific manner, that is, POEM calibrated in a patient-specific manner for obstructive physiology including the distal esophagus and more conservative strategies such as a short POEM or pneumatic dilation for obstructive physiology limited to the lower esophageal sphincter.

The impact of primary peristalsis, contractile reserve, and secondary peristalsis on esophageal clearance measured by timed barium esophagogram.

BACKGROUND: Primary and secondary peristalsis facilitate esophageal bolus transport; however, their relative impact for bolus clearance remains unclear. We aimed to compare primary peristalsis and contractile reserve on high-resolution manometry (HRM) and secondary peristalsis on functional lumen imaging probe (FLIP) Panometry with emptying on timed barium esophagogram (TBE) and incorporate findings into a comprehensive model of esophageal function. METHODS: Adult patients who completed HRM with multiple rapid swallows (MRS), FLIP, and TBE for esophageal motility evaluation and without abnormal esophagogastric junction outflow/opening or spasm were included. An abnormal TBE was defined as a 1-min column height >5 cm. Primary peristalsis and contractile reserve after MRS were combined into an HRM-MRS model. Secondary peristalsis was combined with primary peristalsis assessment to describe a complementary neuromyogenic model. KEY RESULTS: Of 89 included patients, differences in rates of abnormal TBEs were observed with primary peristalsis classification (normal: 14.3%; ineffective esophageal motility: 20.0%; absent peristalsis: 54.5%; p = 0.009), contractile reserve (present: 12.5%; absent: 29.3%; p = 0.05), and secondary peristalsis (normal: 9.7%; borderline: 17.6%; impaired/disordered: 28.6%; absent contractile response: 50%; p = 0.039). Logistic regression analysis (akaike information criteria, area under the receiver operating curve) demonstrated that the neuromyogenic model (80.8, 0.83) had a stronger relationship predicting abnormal TBE compared to primary peristalsis (81.5, 0.82), contractile reserve (86.8, 0.75), or secondary peristalsis (89.0, 0.78). CONCLUSIONS AND INFERENCES: Primary peristalsis, contractile reserve, and secondary peristalsis were associated with abnormal esophageal retention as measured by TBE. Added benefit was observed when applying comprehensive models to incorporate primary and secondary peristalsis supporting their complementary application.

A PhysioMechanical Model of Esophageal Function in Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is characterized by eosinophilic inflammation, but also heterogeneous presentations involving fibrostenotic esophageal remodeling and esophageal dysmotility. We aimed to define and evaluate phenotypes of EoE using functional lumen imaging probe (FLIP) panometry (ie, a PhysioMechanical classification of EoE). METHODS: Patients with EoE who completed FLIP during endoscopy were included in a cross-sectional study. FLIP studies were analyzed for distensibility plateau and compliance of the esophageal body, maximum esophagogastric junction diameter, and contractile response pattern. These FLIP features were then applied to define PhysioMechanical classifications. RESULTS: A total of 215 patients with EoE (mean [standard deviation] age 38 [12] years; 31% female) were included. Seven PhysioMechanical classifications were identified that differed by various clinical characteristics, including symptom duration (P < .001) and Endoscopic EoE Reference Scores (EREFS) (P < .001). In particular, patients with "nonreactive fibrostenosis" (n = 14), had greater symptom duration (median [interquartile range] 20 [10-30] years) and more frequently had EREFS grade 2 or 3 ring scores (14 of 14 patients) than patients with a "normal" PhysioMechanical classification (symptom duration: 3 [1-8] years; 4 of 50 [8%] had EREFS grade 2 or 3 rings). In addition, among patients off treatment at cross-sectional evaluation (n = 46), there was a difference between PhysioMechanical classifications in future proton pump inhibitor (PPI) response rates (ie, achieving peak mucosal eosinophil count <15 per high-powered field after PPI treatment); P = .009. PPI response ranged from 87% (13 of 15 patients) with "isolated esophagogastric junction outflow obstruction" to 11% (1 of 9 patients) with "spastic-reactive fibrostenosis." CONCLUSIONS: Classifying PhysioMechanical esophageal function in EoE based on FLIP panometry features may facilitate defining disease severity and directing management in EoE.

Suprabasal cells retaining stem cell identity programs drive basal cell hyperplasia in eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an esophageal immune-mediated disease characterized by eosinophilic inflammation and epithelial remodeling, including basal cell hyperplasia (BCH) and loss of differentiation. Although BCH correlates with disease severity and with persistent symptoms in patients in histological remission, the molecular processes driving BCH remain poorly defined. Here, we demonstrate that despite the presence of BCH in all EoE patients examined, no increase in basal cell proportion was observed by scRNA-seq. Instead, EoE patients exhibited a reduced pool of KRT15+ COL17A1+ quiescent cells, a modest increase in KI67+ dividing epibasal cells, a substantial increase in KRT13+ IVL+ suprabasal cells, and a loss of differentiated identity in superficial cells. Suprabasal and superficial cell populations demonstrated increased quiescent cell identity scoring in EoE with the enrichment of signaling pathways regulating pluripotency of stem cells. However, this was not paired with increased proliferation. Enrichment and trajectory analyses identified SOX2 and KLF5 as potential drivers of the increased quiescent identity and epithelial remodeling observed in EoE. Notably, these findings were not observed in GERD. Thus, our study demonstrates that BCH in EoE results from an expansion of non-proliferative cells that retain stem-like transcriptional programs while remaining committed to early differentiation.

Interrater Reliability of Functional Lumen Imaging Probe Panometry and High-Resolution Manometry for the Assessment of Esophageal Motility Disorders.

INTRODUCTION: High-resolution manometry (HRM) and functional lumen imaging probe (FLIP) are primary and/or complementary diagnostic tools for the evaluation of esophageal motility. We aimed to assess the interrater agreement and accuracy of HRM and FLIP interpretations. METHODS: Esophageal motility specialists from multiple institutions completed the interpretation of 40 consecutive HRM and 40 FLIP studies. Interrater agreement was assessed using intraclass correlation coefficient (ICC) for continuous variables and Fleiss' κ statistics for nominal variables. Accuracies of rater interpretation were assessed using the consensus of 3 experienced raters as the reference standard. RESULTS: Fifteen raters completed the HRM and FLIP studies. An excellent interrater agreement was seen in supine median integral relaxation pressure (ICC 0.96, 95% confidence interval 0.95-0.98), and a good agreement was seen with the assessment of esophagogastric junction (EGJ) outflow, peristalsis, and assignment of a Chicago Classification version 4.0 diagnosis using HRM (κ = 0.71, 0.75, and 0.70, respectively). An excellent interrater agreement for EGJ distensibility index and maximum diameter (0.91 [0.90-0.94], 0.92 [0.89-0.95]) was seen, and a moderate-to-good agreement was seen in the assignment of EGJ opening classification, contractile response pattern, and motility classification (κ = 0.68, 0.56, and 0.59, respectively) on FLIP. Rater accuracy for Chicago Classification version 4.0 diagnosis on HRM was 82% (95% confidence interval 78%-84%) and for motility diagnosis on FLIP Panometry was 78% (95% confidence interval 72%-81%). DISCUSSION: Our study demonstrates high levels of interrater agreement and accuracy in the interpretation of HRM and FLIP metrics and moderate-to-high levels for motility classification in FLIP, supporting the use of these approaches for primary or complementary evaluation of esophageal motility disorders.