Five Distinct Clusters of Patients With Laryngeal Symptoms Identified

Man holding chest with red highlight to indicate discomfort from reflux symptoms

Many patients who present with laryngeal symptoms are diagnosed with laryngopharyngeal reflux (LPR) and receive empiric proton pump inhibitor therapy. This is often true even if the patient doesn’t have any typical esophageal symptoms of gastroesophageal reflux disease (GERD).

In other disease states, including heart failure and diabetes, one-size-fits-all initial approaches are being replaced with efforts to classify patients according to clinical characteristics and physiologic profiles. It’s hoped more precise diagnosis will allow for more personalized care as well as targeted clinical trial design.

In the first study of its kind, Walter W. Chan, MD, PhD, director of the Center for Esophageal/Gastrointestinal Disorders at Brigham and Women’s Hospital, Rena Yadlapati, MD, MSHS, of the University of California San Diego, and colleagues identified “clusters” of patients with laryngeal symptoms who were evaluated for reflux. The team presents the classification in Clinical Gastroenterology and Hepatology, along with a suggested diagnostic algorithm and suggestions on how to tailor treatment.


At three academic medical centers, the researchers analyzed data prospectively collected between January 2018 and October 2020 on 302 adults. All patients had presented with at least an eight-week history of one or more extraesophageal symptoms of GERD (e.g., dysphonia, sore throat, throat clearing), with or without concomitant esophageal symptoms.

All patients underwent esophageal high-resolution impedance manometry (HRIM). 251 of them also agreed to ambulatory reflux monitoring and 77 had salivary pepsin quantified.


Using a sophisticated phenotyping method called discriminant analysis of principal components, the researchers identified five distinct patient subgroups:

Group A—LPR/GERD + hiatal hernia (9%)

  • Disrupted antireflux barrier and higher reflux burden
  • Common signs and symptoms: Cough, laryngeal symptoms, regurgitation, hiatal hernia and ineffective esophageal peristalsis
  • Tended to be high in body mass index, acid exposure time on proton pump inhibitor, number of reflux events, number of LPR events and salivary pepsin concentration
  • Had the lowest distal mean nocturnal baseline impedance
  • These patients are optimal candidates for escalated antireflux therapy, possibly including surgery

Group B—LPR/mild GERD (24%)

  • Similar to group A but less likely to have hiatal hernia; potential for reflux hypersensitivity
  • Common symptoms: Cough, laryngeal symptoms, globus, heartburn and regurgitation
  • The youngest group had the highest BMI and salivary pepsin concentration
  • These patients are candidates for acid suppression or alginates; consider neuromodulation or behavioral interventions for patients with reflux hypersensitivity; more invasive interventions such as surgery should generally be avoided due to unclear benefit

Group C—No LPR, no GERD (31%)

  • Common symptoms: Laryngeal symptoms and globus; esophageal symptoms were rare
  • Least likely to have hiatal hernia and had the fewest reflux events
  • Consider other etiologies of laryngeal symptoms in these patients, such as allergy, postnasal drip, vocal cord dysfunction and visceral hypersensitivity

Group D—Reflex cough (19%)

  • Common symptoms: Laryngeal symptoms, heartburn
  • Was the group most likely to report cough
  • Note: The vagally mediated reflex mechanism that leads to bronchoconstriction can lead to laryngeal symptoms
  • These patients are candidates for acid suppression or alginates; consider gabapentin, other neuromodulators and voice therapy; more invasive interventions such as surgery should generally be avoided due to unclear benefit

Group E—Mixed/possible obstructive esophagogastric junction (17%)

  • Common symptom: Cough
  • This was the oldest group and had the highest lower esophageal sphincter (LES) integrated relaxation pressure
  • Had the lowest salivary pepsin concentration
  • Note: Elevated supine median integrated relaxation pressure during HRIM doesn’t necessarily indicate LES dysfunction; it may be a catheter artifact or effect of hiatal hernia
  • Patients with confirmed obstruction at the esophagogastric junction may benefit from LES-directed therapy

In a sensitivity analysis, patients were assigned to five clusters based on symptoms alone. 80% of the patients originally assigned to group C were again assigned into a cluster with rare esophageal symptoms.

Guidance for Diagnosis

A diagnostic algorithm in the article summarizes the testing the researchers suggest in order to categorize patients with laryngeal symptoms. The most important point is that patients who report laryngeal symptoms but no esophageal symptoms typical of GERD are unlikely to have LPR.

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