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

Abstract

Background & aims: Heterogeneous 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.

Methods: A 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.

Results: DAPC 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.

Conclusions: DAPC 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.

Keywords: Esophageal Manometry; Gastroesophageal Reflux Disease; Proton Pump Inhibitor.

Figure 1.. Five Phenotype Cluster Groups.

1A)Group A, B, E do not overlap with the other five groups; groups C and D have minimal overlap. 1B)Waterfall plot of individual probabilities for five groups. X-axis represents a patient; y-axis represents membership probability. 1C)Boxplot of posterior probability for each group based on group membership

Figure 2.. Loading Variables Driving Group Membership.

The total contribution of variable to loading sums to 1.0 within each loading (1 and 2). This barplot is a graphical representation of loading variables that had a measure >0.001, and reflect a relative measure of the contribution of each original variable to the discriminant functions of the DAPC.

Figure 3.

Distribution of Variables Within Each Group.

Figure 4.. Representative Depiction of Phenotypic Cluster Groups.

Five distinct clusters depicted based on symptom presentation (left bullets) and clinical/physiologic profiles (right arrows) with arrow representing directionality and degree (bolding) of relationship. Group A: Commonly presented with hiatal hernia, ineffective esophageal peristalsis, cough, laryngeal symptoms, heartburn and regurgitation; higher BMI, AET on PPI, number of reflux and LPR events, salivary pepsin; lowest DMNBI. Group B: Presented with highest BMI and salivary pepsin concentration; commonly presented with cough, laryngeal symptoms, globus, heartburn and regurgitation. Group C: Lowest proportion with hiatal hernia and number of reflux events; commonly presented with laryngeal symptoms and globus, however rarely with esophageal symptoms. Group D: highest proportion of patients with cough and commonly presented with heartburn. Group E: presented with the highest mean LES IRP, and predominantly with symptoms of cough; lowest salivary pepsin concentration.

Figure 5.. Conceptual Diagram of Clinical Approach to Identifying Phenotypes of Patients with Suspected LPR.

This diagram synthesizes results from this study and clinical experiences. The first step is assessment of symptoms, BMI, and presence of hiatal hernia. Patients with high BMI and concomitant heartburn/regurgitation likely fall into GERD groups A (LPR/GERD with hiatal hernia) or B (LPR/mild GERD), and testing including ambulatory reflux monitoring should be performed for further characterization. Those without heartburn/regurgitation likely belong to group C (no LPR/no GERD) or possibly group D (reflex cough) or E (Mixed/Possible obstructive EGJ). Evaluation can include upper gastrointestinal endoscopy with real-time functional luminal impedance-planimetry, esophageal HRM, and/or barium esophagram. In absence of obstructive physiology, ambulatory reflux monitoring should be performed to further stratify patients into groups with GERD (groups A, B, or potentially D) versus those without GERD (group C).