MEASURES OF PROXIMAL REFLUX ON IMPEDANCE-PH TESTING ARE INDEPENDENT PREDICTORS OF PULMONARY FUNCTION DECLINE OVER 1 YEAR IN RESTRICTIVE LUNG DISEASE

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.