Comparison of Los Angeles Grades of Erosive Esophagitis Scored by Local Investigators vs Central Adjudicators in a Clinical Trial.

Approximately 30% of patients with typical gastroesophageal reflux disease (GERD) symptoms have endoscopic evidence of erosive esophagitis (EE).1 The severity of EE is commonly graded using the Los Angeles (LA) classification system as grade A (minimal) to D (very severe), depending on the extent of endoscopically visible mucosal breaks (Supplementary Figure 1).2 Accurate grading of EE severity is crucial in clinical trials of medical EE treatments, as EE severity strongly influences both initial rates of healing and the likelihood of recurrence during maintenance treatment.3,4 Almost all EE treatment studies have relied exclusively on local investigators' grading of EE severity to determine study eligibility and response to treatment. Those few studies that included central adjudication did not assess the reliability of grading by local investigators.5 Unlike typical studies of EE treatment, the phase III clinical trial of vonoprazan versus lansoprazole for the treatment of EE (NCT04124926) mandated central adjudication of endoscopic grading for study participation.6 The aim of the present investigation was to evaluate the rate of agreement between local investigators and central adjudicators for EE grading during screening for entrance into that clinical trial.

The impact of lung transplantation on esophageal motility and inter-relationships with reflux and lung mechanics in patients with restrictive and obstructive respiratory disease.

BACKGROUND: For many patients with lung disease the only proven intervention to improve survival and quality of life is lung transplantation (LTx). Esophageal dysmotility and gastroesophageal reflux (GER) are common in patients with respiratory disease, and often associate with worse prognosis following LTx. Which, if any patients, should be excluded from LTx based on esophageal concerns remains unclear. Our aim was to understand the effect of LTx on esophageal motility diagnosis and examine how this and the other physiological and mechanical factors relate to GER and clearance of boluses swallowed. METHODS: We prospectively recruited 62 patients with restrictive (RLD) and obstructive (OLD) lung disease (aged 33-75 years; 42 men) who underwent high resolution impedance manometry and 24-h pH-impedance before and after LTx. KEY RESULTS: RLD patients with normal motility were more likely to remain normal (p = 0.02), or if having abnormal motility to change to normal (p = 0.07) post-LTx than OLD patients. Esophageal length (EL) was greater in OLD than RLD patients' pre-LTx (p < 0.001), reducing only in OLD patients' post-LTx (p = 0.02). Reduced EL post-LTx associated with greater contractile reserve (r = 0.735; p = 0.01) and increased likelihood of motility normalization (p = 0.10). Clearance of reflux improved (p = 0.01) and associated with increased mean nocturnal baseline impedance (p < 0.001) in RLD but not OLD. Peristaltic breaks and thoraco-abdominal pressure gradient impact both esophageal clearance of reflux and boluses swallowed (p < 0.05). CONCLUSIONS AND INFERENCES: RLD patients are more likely to show improvement in esophageal motility than OLD patients post-LTx. However, the effect on GER is more difficult to predict and requires other GI, anatomical and pulmonary factors to be taken into consideration.

Number of bottles of esophageal biopsies in the evaluation of eosinophilic esophagitis and clinical outcomes.

BACKGROUND: The number of bottles of esophageal biopsies needed for the evaluation of eosinophilic esophagitis (EoE) is unclear, despite cost differences. AIMS: Assess the clinical outcomes between patients with one and two bottles of esophageal biopsies for the assessment of EoE. METHODS: Retrospective study of adults who underwent esophagogastroduodenoscopy (EGD) for esophageal symptoms between January 2015 and June 2021 and findings of ≥15 eosinophils per high power field (eos/hpf). Patients with one bottle (1 bottle-EoE) had biopsies from the entire or proximal esophagus. Patients with two bottles had biopsies separated from the distal and proximal esophagus and were separated into those with ≥ 15 eos/hpf in both bottles (2 bottle Dif-EoE), or the distal bottle alone (2 bottle Lim-EoE). The primary outcomes were endoscopic findings at follow-up EGD as assessed by the Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) and the presence of ≥15 eos/hpf. RESULTS: Of 85 patients with esophageal eosinophilia who met inclusion criteria, 49 had 2 bottle Dif-EoE, 18 had 2 bottle Lim-EoE, and 18 had 1 bottle-EoE. At median follow-up of 3.3-5.6 months, more patients with 1 bottle EoE had dysphagia (p = 0.029), however there were no differences in the EREFS (p = 0.14) or presence of ≥15 eos/hpf (p = 0.39). More patients with 2 bottle Dif-EoE were treated with topical steroids (16.3% vs. 0% vs. 0%, p = 0.039) and diet (20.4% vs. 0% vs. 5.6%, p = 0.05). CONCLUSION: Endoscopic and histologic outcomes were similar in patients who had one and two bottles for esophageal biopsies in the evaluation of EoE.

The association between menopausal hormone therapy and gastroesophageal reflux disease: a systematic review and meta-analysis.

IMPORTANCE AND OBJECTIVE: Gastroesophageal reflux disease (GERD) is a chronic condition associated with several risk factors, but little is known about the association between hormone therapy (HT) and GERD in postmenopausal women. EVIDENCE REVIEW: We investigated the association between ever or current menopausal HT use and GERD using a systematic review and meta-analysis. Studies published between 2008 and August 31, 2022, were pooled using a DerSimonian and Laird random-effects model, and outcomes were reported as adjusted odds ratios (aOR) with a corresponding 95% CI. FINDINGS: The pooled analysis of five studies found a significant direct association between estrogen use and GERD (aOR, 1.41; 95% CI, 1.16-1.66; I2 = 97.6%), and progestogen use and GERD (two studies: aOR, 1.39; 95% CI, 1.15-1.64; I2 = 0.0%). The use of combined HT was also associated with GERD (1.16; 95% CI, 1.00-1.33; I2 = 87.9%). Overall, HT use was associated with 29% higher odds for GERD (aOR, 1.29; 95% CI, 1.17-1.42; I2 = 94.8%). The large number of pooled participants, differences in study design, geography, patient characteristics, and outcome assessment resulted in significant high heterogeneity. CONCLUSIONS AND RELEVANCE: There is a significant association between ever or current HT use and GERD. However, the results should be interpreted with caution, given the small number of included studies and high heterogeneity. This warrants careful evaluation of GERD risk factors when prescribing HT to reduce the risk of potential GERD complications.

Vonoprazan Versus Lansoprazole for Healing and Maintenance of Healing of Erosive Esophagitis: A Randomized Trial.

BACKGROUND & AIMS: For decades, proton pump inhibitors (PPIs) have been the mainstay of treatment for erosive esophagitis. The potassium-competitive acid blocker vonoprazan provides more potent acid inhibition than PPIs, but data on its efficacy for erosive esophagitis are limited. METHODS: Adults with erosive esophagitis were randomized to once-daily vonoprazan, 20 mg, or lansoprazole, 30 mg, for up to 8 weeks. Patients with healing were rerandomized to once-daily vonoprazan, 10 mg, vonoprazan, 20 mg, or lansoprazole, 15 mg, for 24 weeks. Primary end points, percentage with healing by week 8 endoscopy, and maintenance of healing at week 24 endoscopy, were assessed in noninferiority comparisons (noninferiority margins, 10%), with superiority analyses prespecified if noninferiority was demonstrated. Analyses of primary and secondary end points were performed using fixed-sequence testing procedures. RESULTS: Among 1024 patients in the healing phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the exploratory analysis of healing (92.9 vs 84.6%; difference, 8.3%; 95% confidence interval [CI], 4.5%-12.2%). Secondary analyses showed vonoprazan was noninferior in heartburn-free days (difference, 2.7%; 95% CI, -1.6% to 7.0%), and superior in healing Los Angeles Classification Grade C/D esophagitis at week 2 (difference, 17.6%; 95% CI, 7.4%-27.4%). Among 878 patients in the maintenance phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the secondary analysis of maintenance of healing (20 mg vs lansoprazole: difference, 8.7%; 95% CI, 1.8%-15.5%; 10 mg vs lansoprazole: difference, 7.2%; 95% CI, 0.2%-14.1%) and secondary analysis of maintenance of healing Grade C/D esophagitis (20 mg vs lansoprazole: difference, 15.7%; 95% CI, 2.5%-28.4%; 10 mg vs lansoprazole: difference, 13.3%; 95% CI, 0.02%-26.1%). CONCLUSIONS: Vonoprazan was noninferior and superior to the PPI lansoprazole in healing and maintenance of healing of erosive esophagitis. This benefit was seen predominantly in more severe erosive esophagitis. (ClinicalTrials.gov: NCT04124926).

Intestinal chemosensitivity in irritable bowel syndrome associates with small intestinal TRPV channel expression.

BACKGROUND: Irritable bowel syndrome (IBS) patients often experience meal-associated symptoms. However, the underlying mechanisms are unclear. AIM: To determine small intestinal mechanisms of lipid-induced symptoms and rectal hypersensitivity in IBS METHODS: We recruited 26 IBS patients (12 IBS-C, 14 IBS-D) and 15 healthy volunteers (HV). In vivo permeability was assessed using saccharide excretion assay. Rectal sensitivity was assessed using a barostat before and after small bowel lipid infusion; symptoms were assessed throughout. Next, an extended upper endoscopy with probe-based confocal laser endomicroscopy (pCLE) was performed with changes induced by lipids. Duodenal and jejunal mucosal biopsies were obtained for transcriptomics. RESULTS: Following lipid infusion, a higher proportion of HV than IBS patients reported no pain, no nausea, no fullness and no urgency (P < 0.05 for all). In a model adjusted for sex and anxiety, IBS-C and IBS-D patients had lower thresholds for first rectal sensation (P = 0.0007) and pain (P = 0.004) than HV. In vivo small intestinal permeability and mean pCLE scores were similar between IBS patients and HV. Post-lipid, pCLE scores were higher than pre-lipid but were not different between groups. Baseline duodenal transient receptor potential vanilloid (TRPV) 1 and 3 expression was increased in IBS-D, and TRPV3 in IBS-C. Duodenal TRPV1 expression correlated with abdominal pain (r = 0.51, FDR = 0.01), and inversely with first rectal sensation (r = -0.48, FDR = 0.01) and pain (r = -0.41, FDR = 0.02) thresholds. CONCLUSION: Lipid infusion elicits a greater symptom response in IBS patients than HV, which is associated with small intestinal expression of TRPV channels. TRPV-mediated small intestinal chemosensitivity may mediate post-meal symptoms in IBS.

Extent of eosinophilic esophagitis predicts response to treatment.

Background and study aim The clinical impact of eosinophilic esophagitis (EoE) limited to the distal esophagus (Lim-EE) vs. diffuse involvement (Dif-EE) is unknown. This study compared clinical characteristics and outcomes of Lim-EE vs. Dif-EE. Patients and methods This retrospective, single-center study of patients with EoE between December 2011 and December 2019 evaluated treatment response based on repeated pathology and/or clinical improvement using comparative statistics. Results 479 patients were identified (126 Lim-EE, 353 Dif-EE). Lim-EE patients had a higher incidence of endoscopically identified esophagitis (23.0 % vs. 14.7 %; P  = 0.04), were older (50.8 [SD 16.2] vs. 46.4 [SD 15.3] years; P  = 0.007), and were more likely to present with iron deficiency anemia (5.6 % vs. 1.7 %; P  = 0.05), dyspepsia (15.1 % vs. 8.8 %; P  = 0.06) or for Barrett's surveillance (10.3 % vs. 3.7 %; P  = 0.02). Patients with Dif-EE presented more frequently with dysphagia (57.2 % vs. 45.2 %; P  = 0.02). Both groups had similar proton pump inhibitor (87.2 % vs. 83.3 %; P  = 0.37) and steroid (12.8 % vs. 21.4 %; P  = 0.14) use. Patients with Lim-EE had a better clinicopathologic response (61.5 % vs. 44.8 %; P  = 0.009). On multivariate analysis, EoE extent predicted treatment response with an odds ratio of 1.89 (95 % confidence interval 1.13-3.20; P  = 0.02). However, treatment response based only on repeat biopsy results showed no statistical difference between Lim-EE (52.5 %) and Dif-EE (39.7 %; P  = 0.15). Conclusions Lim-EE may represent a distinct phenotype separate from Dif-EE, with more overlap with gastroesophageal reflux disease and better treatment response.

The Perils and Pitfalls of Esophageal Dysmotility in Idiopathic Pulmonary Fibrosis.

INTRODUCTION: Gastroesophageal reflux plays a significant role in idiopathic pulmonary fibrosis (IPF). Given the morbidity and mortality associated with IPF, understanding the mechanisms responsible for reflux is essential if patients are to receive optimal treatment and management, especially given the lack of clear benefit of antireflux therapies. Our aim was to understand the inter-relationships between esophageal motility, lung mechanics and reflux (particularly proximal reflux-a prerequisite of aspiration), and pulmonary function in patients with IPF. METHODS: We prospectively recruited 35 patients with IPF (aged 53-75 years; 27 men) who underwent high-resolution impedance manometry and 24-hour pH-impedance, together with pulmonary function assessment. RESULTS: Twenty-two patients (63%) exhibited dysmotility, 16 (73%) exhibited ineffective esophageal motility (IEM), and 6 (27%) exhibited esophagogastric junction outflow obstruction. Patients with IEM had more severe pulmonary disease (% forced vital capacity: P = 0.032) and more proximal reflux (P = 0.074) than patients with normal motility. In patients with IEM, intrathoracic pressure inversely correlated with the number of proximal events (r = -0.429; P = 0.098). Surprisingly, inspiratory lower esophageal sphincter pressure (LESP) positively correlated with the percentage of reflux events reaching the proximal esophagus (r = 0.583; P = 0.018), whereas in patients with normal motility, it inversely correlated with the bolus exposure time (r = -0.478; P = 0.098) and number of proximal events (r = -0.542; P = 0.056). % forced vital capacity in patients with IEM inversely correlated with the percentage of reflux events reaching the proximal esophagus (r = -0.520; P = 0.039) and inspiratory LESP (r = -0.477; P = 0.062) and positively correlated with intrathoracic pressure (r = 0.633; P = 0.008). DISCUSSION: We have shown that pulmonary function is worse in patients with IEM which is associated with more proximal reflux events, the latter correlating with lower intrathoracic pressures and higher LESPs.

Hiatal Hernia Associated with Higher Odds of Dysplasia in Patients with Barrett's Esophagus.

BACKGROUND: Patients with Barrett's esophagus (BE) are more likely to have associated hiatal hernia (HH) compared to the general population. Studies show that HH are typically longer and wider in patients with BE. AIMS: To determine whether patients with HH have associated increased odds of coexistence of BE by examining inpatient prevalence, as well as determining other inpatient outcomes. METHODS: This was a case-control study using the NIS 2016, the largest public inpatient database in the USA. All patients with ICD10CM codes for BE were included. None were excluded. The primary outcome was determining the association between BE and HH in hospitalized patients, stratified by grade of dysplasia. Secondary outcomes included measuring use of endoscopic ablation in patients with BE and HH compared to patients with BE and no HH, determining the degree of association between HH and esophagitis in patients with or without BE, as well as the association between esophagitis and dysplasia in patients with BE and HH. RESULTS: A total of 118,750 patients with BE were identified, of which 24,030 had associated HH. Adjusted odds of having associated BE in patients with HH was 10.9 (p < 0.01) compared to patients without HH. Patients with HH also displayed significantly higher odds of both low-grade dysplasia (aOR 34.5, p < 0.01) and high-grade dysplasia (aOR 14.7, p < 0.01). For secondary outcomes, the odds of undergoing ablation for BE was higher 4.77 (p < 0.01) in patients with HH. CONCLUSIONS: Patients with HH have significantly higher odds of having associated BE, regardless of the level of dysplasia. Furthermore, the odds of undergoing ablation are much higher, likely reflecting higher odds of dysplasia. This highlights the importance of BE in patients with HH, and potentially consider these patients as higher risk.

Lymphocytic Esophagitis: Assessing Risk Factors and Clinical Outcomes.

BACKGROUND: Lymphocytic esophagitis is a rare esophageal condition. Our knowledge of potential risk factors and treatment outcomes of lymphocytic esophagitis is limited. AIM: To investigate potential risk factors associated with the development of lymphocytic esophagitis and compare clinical characteristics and treatment outcomes of patients diagnosed with lymphocytic esophagitis to patients diagnosed with eosinophilic esophagitis. METHODS: This is a multicenter retrospective study. Lymphocytic esophagitis patients were identified based on pathology results between 1997 and 2019. Control groups consisted of patients with normal esophageal biopsies and patients diagnosed with eosinophilic esophagitis. Thirteen potential risk factors for lymphocytic esophagitis were analyzed using univariate and multivariate models including IBD, achalasia, hyperlipidemia, hypothyroidism, celiac sprue, CVID, H. pylori, thymoma, aspirin, opioids, ACE-I, metformin, and statin use. Comparative statistics were performed. RESULTS: Ninety-four adult patients with lymphocytic esophagitis, 344 with eosinophilic esophagitis, and 5202 control patients with normal esophageal biopsies were analyzed. Age older than 60 [adjusted odd ratio (AOR) 1.03, 95% CI 1.02-1.05, p = 0.001], aspirin use (2.7, 95% CI 1.4-4.9, p = 0.001), statin use (2.2, 95% CI 1.2-4.2, p = 0.01), or a diagnosis of achalasia (2.4, 95% 1.08-5.67, p = 0.03) were associated with lymphocytic esophagitis. Compared to eosinophilic esophagitis, lymphocytic esophagitis patients were more likely to respond to medical treatment (95% CI 2.54-12.8, p = 0.0001). CONCLUSIONS: Our data suggests that lymphocytic esophagitis is more likely to be found in older female patients and is significantly associated with achalasia, statin, and aspirin use. Compared to eosinophilic esophagitis, lymphocytic esophagitis is more likely to respond to treatment with medical therapy.

Creation of a score to predict risk of high conscious sedation requirements in patients undergoing endoscopy.

BACKGROUND AND AIMS: The administration of intravenous conscious sedation to patients undergoing GI endoscopy carries a risk of cardiopulmonary adverse events. Our study aim was to create a score that stratifies the risk of occurrence of either high-dose conscious sedation requirements or a failed procedure. METHODS: Patients receiving endoscopy via endoscopist-directed conscious sedation were included. The primary outcome was occurrence of sedation failure, which was defined as one of the following: (1) high-dose sedation, (2) the need for benzodiazepine/narcotic reversal agents, (3) nurse-documented poor patient tolerance to the procedure, or (4) aborted procedure. High-dose sedation was defined as >10 mg of midazolam and/or >200 µg of fentanyl or the meperidine equivalent. Patients with sedation failure (n = 488) were matched to controls (n = 976) without a sedation failure by endoscopist and endoscopy date. RESULTS: Significant associations with sedation failure were identified for age, sex, nonclonazepam benzodiazepine use, opioid use, and procedure type (EGD, colonoscopy, or both). Based on these 5 variables, we created the high conscious sedation requirements (HCSR) score, which predicted the risk of sedation failure with an area under the curve of 0.70. Compared with the patients with a risk score of 0, risk of a sedation failure was highest for patients with a score ≥3.5 (odds ratio, 17.31; P = 2 × 10-14). Estimated area under the curve of the HCSR score was 0.68 (95% confidence interval, 0.63-0.72) in a validation series of 250 cases and 250 controls. CONCLUSIONS: The HCSR risk score, based on 5 key patient and procedure characteristics, can function as a useful tool for physicians when discussing sedation options with patients before endoscopy.

Unilateral Versus Bilateral Lung Transplantation: Do Different Esophageal Risk Factors Predict Chronic Allograft Failure?

GOALS: To assess the effect of unilateral versus bilateral lung transplantation (LTx) on esophageal motility and gastroesophageal reflux, and the association with the development of obstructive chronic lung allograft dysfunction (o-CLAD). BACKGROUND: We have shown that esophagogastric junction outflow obstruction, incomplete bolus transit, and proximal reflux are all independent risk factors for the development of chronic allograft failure. However, it remains unclear whether these factors are influenced by the type of surgery and how this relates to allograft failure. STUDY: Patients post-LTx (n=48, 24 female; aged 20 to 73 y) completed high-resolution impedance manometry and 24-hour pH/impedance. RESULTS: Patients who had undergone unilateral LTx were more likely to exhibit esophagogastric junction outflow obstruction (47% vs. 18%; P=0.046) and less likely to exhibit hypocontractility (0% vs. 21%; P=0.058) than those who had undergone bilateral LTx. Although the proportion of patients exhibiting gastroesophageal reflux was no different between groups (33% vs. 39%; P=0.505), those undergoing bilateral LTx were more likely to exhibit proximal reflux (8% vs. 37%; P=0.067). Univariate Cox proportion hazards regression analysis did not show a difference between unilateral versus bilateral LTx in the development of o-CLAD (hazard ratio=1.17; 95% confidence interval, 0.48-2.85; P=0.723). CONCLUSION: The type of LTx performed seems to lead to different risk factors for the development of o-CLAD. Physicians should be aware of these differences, as they may need to be taken into account when managing patient's post-LTx.

Impaired Esophageal Motility and Clearance Post-Lung Transplant: Risk For Chronic Allograft Failure.

OBJECTIVES: Gastroesophageal reflux is common in patients post-lung transplantation (LTx) and thus considered a risk factor for aspiration and consequently allograft rejection and the development of chronic allograft failure. However, evidence supporting this remains unclear and often contradictory. Our aim was to examine the role played by esophageal motility on gastroesophageal reflux exposure, along with its clearance and that of boluses swallowed, and the relationship to development of obstructive chronic lung allograft dysfunction (o-CLAD). METHODS: Patients post-LTx (n=50, 26 female; mean age 55 years (range, 20-73 years)) completed high-resolution impedance manometry and 24-h pH/impedance. Esophageal motility abnormalities were classified based upon the Chicago Classification version 3.0. RESULTS: Esophagogastric junction outflow obstruction alone (EGJOOa) (P=0.01), incomplete bolus transit (IBT) (P=0.006) and proximal reflux (P=0.042) increased the risk for o-CLAD. Patients with EGJOOa were most likely to present with o-CLAD (77%); despite being less likely to exhibit abnormal numbers of reflux events (10%) compared with those with normal motility (o-CLAD: 29%, P<0.05; abnormal reflux events: 64%, P<0.05). Patients with EGJOOa had lower total reflux bolus exposure time than those with normal motility (0.6 vs. 1.5%; P<0.05). In addition, poor esophageal clearance documented by abnormal post-reflux swallow-induced peristaltic wave index associated with o-CLAD; inversely correlating with the proportion of reflux events reaching the proximal esophagus (r=-0.251; P=0.052). CONCLUSIONS: These observations support esophageal dysmotility, especially EGJOOa, and impaired clearance of swallowed bolus or refluxed contents, more so than just the presence of gastroesophageal reflux alone, as important risk factors in the development of o-CLAD.

Respiratory disease and the oesophagus: reflux, reflexes and microaspiration.

Gastro-oesophageal reflux is associated with a wide range of respiratory disorders, including asthma, isolated chronic cough, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease and cystic fibrosis. Reflux can be substantial and reach the proximal margins of the oesophagus in some individuals with specific pulmonary diseases, suggesting that this association is more than a coincidence. Proximal oesophageal reflux in particular has led to concern that microaspiration might have an important, possibly even causal, role in respiratory disease. Interestingly, reflux is not always accompanied by typical reflux symptoms, such as heartburn and/or regurgitation, leading many clinicians to empirically treat for possible gastro-oesophageal reflux. Indeed, costs associated with use of acid suppressants in pulmonary disease far outweigh those in typical GERD, despite little evidence of therapeutic benefit in clinical trials. This Review comprehensively examines the possible mechanisms that might link pulmonary disease and oesophageal reflux, highlighting the gaps in current knowledge and limitations of previous research, and helping to shed light on the frequent failure of antireflux treatments in pulmonary disease.