Society: AGA

Background
Discerning whether laryngeal symptoms are related to reflux (laryngopharyngeal reflux; LPR) is a challenge. Consequently, patients see numerous specialists, undergo multiple diagnostic tests and empirically trial proton pump inhibitors (PPIs), often with inconsistent response. A clinically practical method to ascertain the likelihood of LPR among patients with laryngeal symptoms is critical. In this study we aimed to develop a clinical risk prediction score for LPR.

Methods
This prospective single center study included adult patients with laryngeal symptoms (throat clearing, sore throat, dysphonia, cough, globus, mucus in throat) referred for LPR evaluation over 3 years (07/19-08/22). Patients were categorized as LPR+ or LPR- based on presence or absence of conclusive GERD as follows: Los Angeles C/D esophagitis and/or long segment Barrett’s esophagus on endoscopy, acid exposure time (AET) ≥6% and/or ≥80 reflux events/24h on ambulatory reflux monitoring off PPI, or AET ≥2% and/or ≥40 reflux events on 24h impedance-pH on PPI.

Independent variables with p-value <0.15 for LPR+ vs LPR- informed development of permutations for multiple logistic regression models. An optimal predictive model was discriminated by area under the curve (AUC) of the receiver operating characteristics. Beta coefficients informed a weighted risk prediction model. The a priori goal was to identify a lower threshold with high confidence to rule out LPR (<20% false negative rate) and upper threshold with high confidence to rule in LPR (<20% false positive rate). Analyses were completed with R v4.2.0 (Vienna, Austria).

Results
Of 304 patients, 130 (43%) met criteria for LPR+ and 174 (57%) LPR- (Table 1). The optimal predictive model [AUC of 0.68 (95% CI 0.62, 0.74)] consisted of Cough symptom (OR 1.6 (1.0, 2.8)), Obesity/overweight (body mass index (BMI) ≥25kg/m2) (OR 1.4 (0.9, 2.3)), Globus symptom (OR 0.5 (0.3, 0.9)), Hiatal hernia ≥1cm (OR 1.9 (1.1, 3.2)), Regurgitation symptom (OR 1.9 (1.1, 3.2)), and male seX (OR 2.0 (1.2, 3.4)). The weighted prediction model, the COuGH RefluX score [AUC of 0.67 (0.61, 0.73)], ranged from -0.5 to 9.0 with a lower threshold of 3.0 (80% sensitive (95% CI 72%, 87%)) and upper threshold of 5.5 (81% specific (74%, 86%)) for LPR. Amongst the cohort 34% had a COuGH RefluX score ≤3.0, 37% had a score 3.5 to 5.0, and 29% had a score ≥5.5 (Figure 1).

Conclusions
The COuGH RefluX risk score consists of widely available clinical data (Cough, Obesity/overweight, Globus (negative predictor), presence of Hiatal hernia, Regurgitation, male seX) to enable stratification of patients with laryngeal symptoms referred for LPR evaluation as low likelihood of LPR (score ≤3.0), high likelihood of LPR (score ≥5.5), and inconclusive for LPR (score 3.5 to 5.0) for which further testing may be indicated. External validation of the COuGH RefluX score is underway.

Background: Esophageal dysmotility and reflux have been associated with restrictive lung disease (RLD), with a likely bidirectional relationship: micro-aspiration may induce pulmonary damage and restrictive chest wall mechanics may worsen esophageal function. Measures of overall reflux burden have been associated with more rapid short-term lung disease decline; however, predictors of longer-term changes and the value of proximal reflux metrics on objective testing are not well elucidated.
Aim: To determine the association between proximal reflux metrics on multichannel intraluminal impedance-pH testing (MII-pH) and change in pulmonary function test (PFT) measures in 1 year in patients with RLD.
Methods: RLD patients undergoing routine esophageal testing for pre-lung transplant evaluation were enrolled. MII-pH metrics collected included total/proximal bolus reflux episodes, bolus exposure time (BET), and total/proximal acid exposure time (AET). High-resolution manometry (HRM) measures and diagnoses per Chicago Classification v4.0 were assessed. Validated surveys were collected, including GERDQ, reflux symptom index (RSI), and global symptom severity (GSS). Lung disease severity was quantified by %-predicted FEV1 and %-predicted FVC via PFT and were evaluated at time of esophageal testing and at 1-year follow-up. Univariate (Spearman correlation) and multivariable (general linear regression) analyses were performed, adjusting for age, sex, BMI, and smoking history.
Results: 87 adults (mean age 60.8±11.6 years, 51.7% female, 83.9% interstitial lung disease) were enrolled. On univariate analyses, both proximal reflux metrics (total proximal episodes and proximal AET) were associated with a larger decline in %-predicted FEV1 and FVC, while measures of distal reflux burden (distal AET, total reflux episodes, BET) correlated with a greater decline in %-predicted FVC only (Table 1). Other reflux measures, esophageal dysmotility on HRM, and patient-reported symptom scores were not significantly associated with 1-year PFT decline. After covariate adjustment, total proximal reflux episodes (β=-0.224, p=0.016) and proximal AET (β=-9.62, p=0.001) remained independently associated with decline in %-predicted FVC (Table 2). Only proximal AET (β=-10.6, p=0.002) remained correlated with change in %-predicted FEV1, though proximal reflux episodes trended towards significance. Distal reflux burden metrics did not significantly predict 1-year decline in both %-predicted FEV1 and FVC.
Conclusion: Proximal reflux metrics on MII-pH, but not distal measures, independently predicted one-year decline in lung function in RLD. Despite their exclusion from consensus guidelines on interpretation of reflux testing, proximal reflux measures may be relevant for specific populations such as those with suspected extraesophageal reflux.

<b>Table 1: </b>Univariate analyses correlating MII-pH metrics with 1-year change in %-predicted PFT outcomes in RLD patients.

Table 1: Univariate analyses correlating MII-pH metrics with 1-year change in %-predicted PFT outcomes in RLD patients.

<b>Table 2: </b>Multivariate analyses for associations between MII-pH metrics and change in %-predicted PFT outcomes over 1 year, after adjustment for possible cofounders including age, sex, BMI, and smoking history.

Table 2: Multivariate analyses for associations between MII-pH metrics and change in %-predicted PFT outcomes over 1 year, after adjustment for possible cofounders including age, sex, BMI, and smoking history.

Backgrounds and aims:
The Lyon Consensus designates Los Angeles (LA) grade C/D esophagitis or acid exposure time (AET) >6% on impedance-pH monitoring (MII-pH) as conclusive for gastroesophageal reflux disease (GERD). LA grade A and B are considered inconclusive and require confirmation using MII-pH. We hypothesized that objective reflux metrics in patients with LA grade B esophagitis will provide objective GERD evidence. Accordingly, we evaluated proportions with objective GERD among symptomatic patients with LA grade A, B, and C esophagitis on endoscopy.

Methods: Consecutive patients reporting GERD symptoms underwent endoscopy and MII-pH performed off anti-reflux medications at two tertiary referral centres. Symptoms and voluptuary habits were recorded for all patients. An adequate response to PPI was defined when heartburn relief was higher than 60% on a VAS questionnaire. Patients with normal endoscopy or grade D esophagitis were excluded. Esophageal AET, number of reflux events, symptom-reflux correlation (Symptom Index, SI and Symptom Association Probability, SAP), mean nocturnal baseline impedance (MNBI, normal value >2292 ohms and chemical clearance of reflux (post-reflux swallowed induced peristaltic wave index, PSPW, normal value >61%) were calculated. Continuous data are described as median/interquartile range (Q1-Q3), and categorical data as counts and percent. Kruskal-Wallis Rank Sum Test and Pearson’s Chi-Square test were used as appropriate. Significance threshold was p<0.05.

Results:
Of 155 patients (LA grade A: 74 patients, B: 61 patients, C: 20 patients), demographics, and presentation were similar across LA grades. AET>6% was seen in 1.4%, 52.5% and 75% respectively in LA grades A, B and C. Using additional MII-pH metrics, an additional 16.2% with LA grade A, and 47.5% with LA grade B esophagitis had AET 4-6% with low MNBI and PSPW index (Figure 1); there were no additional gains using numbers of reflux episodes or symptom-reflux association metrics. Compared to LA grade C (100% conclusive GERD based on endoscopic findings), 100% of LA grade B esophagitis also had objective GERD, but only 17.6% with LA grade A esophagitis (p<0.001 compared to each). PPI response was comparable between LA grades B and C (74% and 70% respectively) but low in LA grade A (39%, p<0.001).Table 1 and 2 report clinical and MII-pH data of the three groups.

Conclusion:
Patients with LA grade B esophagitis are similar to patients with conclusive endoscopic diagnosis of GERD per Lyon Consensus in terms of MII-pH findings and treatment response, in contrast to LA grade A esophagitis. All of those with LA Grade B esophagitis diagnosed at tertiary centres had objective evidence of GERD on MII-pH. Therefore, we conclude that LA Grade B esophagitis in symptomatic patients is adequate for an objective diagnosis of GERD in tertiary referral settings.

Background/Aims:
Altered acid sensitivity may occur in patients with gastroesophageal reflux disease (GERD). Patients with typical GERD symptoms and normal acid exposure time (AET) are classified as either reflux hypersensitivity (RH) or functional heartburn (FH), who may or may not respond to proton pump inhibitors (PPIs) therapy. This study aimed to test the hypothesis whether esophageal acid sensitivity could predict the PPI response in symptomatic patients despite normal AET.
Methods:
We prospectively recruited adult patients with heartburn sensation and/or acid regurgitation diagnosed with RH (AET<4%, positive symptom association probability, SAP) or FH (AET<4%, negative SAP) on the basis 24-h impedance-pH monitoring off PPI. Mucosal integrity was evaluated using mean nocturnal baseline impedance (MNBI). All participants completed validated questionnaires assessing patient-reported outcomes, including GERD questionnaire (GERDQ) and esophageal hypervigilance and anxiety scale (EHAS). Symptom response was defined as at least 50% reduction in GERDQ score. Infusion of hydrochloric acid (0.1 N) into the mid-esophagus was performed to evaluate for acid sensitivity, during which the time to initial typical symptom perception (lag time) was recorded. Potential factors influencing PPIs response were identified using a generalized linear model.
Results:
Of 74 study participants (age 21-64 years, 63.5% women), who completed the study, 40 had RH and 34 had FH. PPIs response was seen in 33 patients (44.6%), 50.0% in RH and 44.1% in FH. There was no significant difference in age, gender, BMI, reflux symptom severity, EHAS, AET, MNBI, or PPI response rate between patients with RH and FH (Table 1). RH patients had shorter lag time than FH patients (60.6 sec vs. 105.4 sec, P=0.048). In a generalized linear regression model evaluating potential factors predicting PPIs response, only shorter time (β=-0.131, CI=-0.261 ~ -0.002, P=0.047) and lower MNBI (β=-0.267, CI=-0.458 ~ -0.076, P=0.007) correlated with PPI response (Table 2).
Conclusion:
Our study demonstrates that enhanced acid sensitivity (shorter lag time) and lower mucosal integrity are independently associated with PPIs response in patients with RH and FH. Therefore, lower mucosal integrity indicating mucosal acid damage, and esophageal acid sensitivity indicating early symptom reporting could be physiomarkers of PPIs response in symptomatic patients despite normal AET.

<b>Table 1.</b> Clinical characteristics between patients with RH and FH.

Table 1. Clinical characteristics between patients with RH and FH.

<b>Table 2.</b> General linear model of predicting factors for PPI response in all patients.

Table 2. General linear model of predicting factors for PPI response in all patients.

Background
There is an unmet medical need in treatment of erosive esophagitis, especially in those with LA Grade C/D (moderate to severe), and those who do not achieve healing with currently available therapies. Linaprazan glurate (LG), a P-CAB and prodrug of its main metabolite linaprazan, has a favorable pharmacokinetic profile providing an excellent acid-control (1). This Phase 2 study was designed to support dose selection of LG for Phase 3 studies.
Methods
This was a randomized, double-blind, active comparator-controlled, 5-arm parallel group, dose-finding study of LG, with lansoprazole (LAN) for comparison of safety outcome, on 4-week endoscopic healing of erosive esophagitis, with safety and tolerability as secondary endpoints. Adult LA Grade C/D patients, and patients with unhealed erosive esophagitis (LA Grade A/B) with a history of preceding 8 weeks proton pump inhibitor therapy documented by the investigators, were eligible for inclusion. The sample size was estimated based on the C/D cohort, and dose selection was based on the C/D patient outcome. H. pylori status of all patients was identified at enrolment, but the presence of infection was not an exclusion criterion. Patients were randomized (1:1:1:1) to LG (25 mg, 50 mg, 75 mg, or 100 mg BID) or LAN (30 mg QD), followed by 4-week open-label LAN treatment for all patients. All endoscopic images and videos were assessed by a central review board, and primary endpoint was based on the central review output.
Results
A total of 248 patients were randomized to treatment, of which 228 underwent a 4-week endoscopy and completed the study. After central adjudication review of the screening videos, 66 (28.9%) patients were re-classified from erosive to non-erosive esophagitis, leaving 162 evaluable patients for the primary endpoint (LG, N=133 [C/D, n=53; A/B, n=80]; LAN, N=29 [C/D, n=8; A/B, n=21]). C/D patients receiving LG (full analysis set; all doses) had a 4-week healing rate of 73.6%, as compared to 37.5% for LAN (p=0.04). For A/B patients receiving LG, the 4-week healing rate was 83.8%, as compared to 81.0% for LAN. The healing rates for the individual doses of LG in C/D patients are presented in Figure 1, showing a clear dose-response trend for LG 25 mg to 75 mg. The safety profile was comparable across treatment groups (Table 1). One serious TEAE each was reported in the LG 25 mg and 75 mg groups; both were considered by the Investigator to be mild and unlikely related to study drug.
Conclusion
A high healing rate was seen after 4 weeks of LG treatment in the overall C/D cohort, with the highest healing rate seen for 75 mg. LG was generally well-tolerated, and the safety profile was comparable to that of LAN. These results support further development of LG for the treatment of erosive esophagitis.
References
1. Unge P, Andersson K. Gastroenterology, 2017.

<b>Figure 1. </b>Dose response diagram in LA Grade C/D patients.<b> </b>Healing rates with a clear dose response separation pattern seen in patients with LA Grade C/D with up to 89.5% healing by central review after 4 weeks of treatment. The LG 100 mg group had a lower healing rate than expected, in which 6 of 7 unhealed patients had improved to LA Grade A.

Figure 1. Dose response diagram in LA Grade C/D patients. Healing rates with a clear dose response separation pattern seen in patients with LA Grade C/D with up to 89.5% healing by central review after 4 weeks of treatment. The LG 100 mg group had a lower healing rate than expected, in which 6 of 7 unhealed patients had improved to LA Grade A.

<b>Table 1. </b>TEAE by preferred term occurring in ≥2% of total study population or >2 patients in any treatment arm in the double-blind Phase and full study.

Table 1. TEAE by preferred term occurring in ≥2% of total study population or >2 patients in any treatment arm in the double-blind Phase and full study.

Peter Unge

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