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.302 adult patients with chronic laryngeal symptoms were prospectively enrolled at three centers between 1/2018-10/2020 [age 57.2±15.2 years; 30% males; BMI 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.DAPC identified five groups, with significant differences across symptoms, hiatal hernia size, and number of reflux events (p<0.01). Group A had the greatest hiatal hernia size (3.1cm±1.0;p<0.001) and reflux events (37.5±51;p<0.001), with frequent cough, laryngeal symptoms, heartburn and regurgitation. Group B had the highest body mass index (28.2kg/m2±4.6;p<0.001) and salivary pepsin (150ng/ml±157;p=0.03), with frequent cough, laryngeal symptoms, globus, heartburn and regurgitation. Group C frequently reported laryngeal symptoms (93%;p<0.001), and had fewest esophageal symptoms (9.6%;p<0.001) and reflux events (10.7±11.0;p<0.001). Group D commonly reported cough (88%;p<0.001) and heartburn. Group E (18%) was oldest (62.9y±14.3;p<0.001) and distinguished by highest integrated relaxation pressure.DAPC identified distinct clinico-physiologic 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; Group E, Mixed/Possible obstructive esophago-gastric junction. Phenotypic differences may inform targeted clinical trials design and improve outcomes.
Rena Yadlapati, Alexander M Kaizer, Daniel R Sikavi, Madeline Greytak, Jennifer X Cai, Thomas L Carroll, Samir Gupta, Sachin Wani, Paul Menard-Katcher, Tsung-Chin Wu, Philip Weissbrod, Andrew M Vahabzadeh-Hagh, John E Pandolfino, Walter W Chan