J Neurogastroenterol Motil 2023; 29(3): 314-325  https://doi.org/10.5056/jnm22099
Proton Pump Inhibitor-unresponsive Laryngeal Symptoms Are Associated With Psychological Comorbidities and Sleep Disturbance: A Manometry and Impedance-pH Monitoring Study
Wen-Hsuan Tseng,1,2 Wei-Chung Hsu,1,3 Tsung-Lin Yang,1,2 Tzu-Yu Hsiao,1 Jia-Feng Wu,4 Hui-Chuan Lee,4 Hsiu-Po Wang,5 Ming-Shiang Wu,5 and Ping-Huei Tseng5*
Departments of 1Otolaryngology, 4Pediatrics, and 5Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 2Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; and 3Department of Otolaryngology, College of Medicine, National Taiwan University, Taipei, Taiwan
Correspondence to: *Ping-Huei Tseng, MD, PhD
Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan
Tel: +886-2-2312-3456 (ext. 63313), Fax: +886-2-2341-2775, E-mail: pinghuei@ntu.edu.tw
Received: June 27, 2022; Revised: September 20, 2022; Accepted: October 26, 2022; Published online: July 30, 2023
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Laryngeal symptoms are largely treated with empiric proton pump inhibitor (PPI) therapy if no apparent pathology shown on ear, nose, and throat evaluation and reflux-related etiologies are suspected. However, treatment response remains unsatisfactory. This study aimed to investigate the clinical and physiological characteristics of patients with PPI-refractory laryngeal symptoms.
Patients with persistent laryngeal symptoms despite PPI treatment for ≥ 8 weeks were recruited. A multidisciplinary evaluation comprising validated questionnaires for laryngeal symptoms (reflux symptom index [RSI]), gastroesophageal reflux disease symptoms, psychological comorbidity (5-item brief symptom rating scale [BSRS-5]) and sleep disturbance (Pittsburgh sleep quality index [PSQI]), esophagogastroduodenoscopy, ambulatory impedance-pH monitoring, and high-resolution impedance manometry were performed. Healthy asymptomatic individuals were also recruited for comparison of psychological morbidity and sleep disturbances.
Ninety-seven adult patients and 48 healthy volunteers were analyzed. The patients had markedly higher prevalence of psychological distress (52.6% vs 2.1%, P < 0.001) and sleep disturbance (82.5% vs 37.5%, P < 0.001) than the healthy volunteers. There were significant correlations between RSI and BSRS-5 scores, and between RSI and PSQI scores (r = 0.26, P = 0.010, and r = 0.29, P = 0.004, respectively). Fifty-eight patients had concurrent gastroesophageal reflux disease symptoms. They had more prominent sleep disturbances (89.7% vs 71.8%, P < 0.001) than those with laryngeal symptoms alone but similar reflux profiles and esophageal motility.
PPI-refractory laryngeal symptoms are mostly associated with psychological comorbidities and sleep disturbances. Recognition of these psychosocial comorbidities may help optimize management in these patients.
Keywords: Gastroesophageal reflux; Larynx disease; Manometry; Psychological factors; Sleep disorder

Gastroesophageal reflux disease (GERD) is a condition that develops when the reflux of gastric content causes troublesome symptoms.1 It can be further classified into esophageal and extra-esophageal syndromes according to the Montreal Definition and Classification of GERD.2 Esophageal manifestations such as heartburn and regurgitation are common. Laryngeal symptoms, including chronic cough, hoarseness, globus sensation, and laryngitis,3,4 are the most common extra-esophageal symptoms. An association between laryngopharyngeal reflux (LPR) and GERD has been established.2

Since most laryngeal symptoms in the absence of apparent pathologies on laryngopharyngeal local examination are frequently suspected to be reflux-related, a proton-pump inhibitor (PPI) trial plus diet and lifestyle modifications is generally recommended.5,6 With erratic clinical response to therapy, patients with refractory laryngeal symptoms are increasingly recognized by general physicians, lung specialists, gastrointestinal specialists, and otolaryngologists.7 In non-responsive cases, after assessing treatment compliance, patients could benefit from a personalized therapeutic scheme, as assessed by additional gastrointestinal surveys, including esophagogastroduodenoscopy (EGD), multichannel intraluminal impedance and pH (MII-pH) monitoring and esophageal manometry.5 MII-pH monitoring assesses the presence, proximal extent, and consistency of the refluxate in cases of acid and non-acid reflux.8 High-resolution impedance manometry (HRIM) measures both bolus movement and esophageal contractile activity, providing better characterization of esophageal motility disorders.9

Meanwhile, psychogenic problems and stress are thought to trigger the globus sensation.10 Rome IV11 introduced the concept of functional esophageal disorders, which include heartburn and reflux hypersensitivity, and usually contribute to troublesome GERD symptoms despite PPI therapy.12 Treatment strategies involving psychological interventions have been suggested to provide more symptomatic control when given in combination with anti-reflux medications.13 These lines of evidence suggest that psychological comorbidities may be included as an important target in the multidisciplinary approach in the case of patients who have troublesome laryngeal symptoms but who have failed PPI therapy.

In cases of persistent laryngeal symptoms despite PPI treatment, EGD and further reflux monitoring test is recommended in the most recent guideline by the American College of Gastroenterology.14 The purpose of this study was to comprehensively investigate the clinical features of such patients based on a combination of EGD, MII-pH monitoring, HRIM, and validated symptom questionnaires. Comparisons of clinical characteristics between patients with or without concurrent GERD symptoms were also evaluated.

Material and Methods

Study Design and Participants

From December 2014, consecutive patients who were referred to the motility laboratory at the National Taiwan University Hospital (NTUH) for evaluation of persistent laryngeal symptoms, including hoarseness, throat clearing, throat pain, globus sensation in the throat, or chronic cough, despite a standard dose of PPI treatment for at least 8 weeks, were eligible for enrollment. To be included, the participants had to be of ≥ 20 years old, and not have any apparent pathologies in the pharynx and larynx on ear, nose, and throat (ENT) evaluation with laryngoscopy. Exclusion criteria consisted of major esophageal motility disorders and history of prior upper gastrointestinal surgical treatment. Also, patients with proven GERD on EGD (Los Angeles classification grade C and D, peptic strictures and Barrett’s esophagus), or abnormal acid exposure (> 6%) and excessive reflux number (> 80 in 24 hours) evidenced by ambulatory pH or pH-impedance monitoring based on the updated Lyon consensus were excluded considering such patients should be managed with GERD treatment.15,16 Patients who remained on PPIs on enrollment were asked to cease the drug 2 weeks prior to the study (wash out period). All patients provided basic demographic information and underwent a comprehensive diagnostic work-up, consisting of validated symptom questionnaires, EGD, 24-hour MII-pH monitoring, and esophageal HRIM. EGD was performed by an experienced gastroenterologist (P.H.T.) to inspect the oropharynx, hypopharynx, larynx, esophagus, stomach, and duodenum. We adopted the Los Angeles classification, the most commonly used and validated guideline, to diagnose and grade the severity of esophagitis.17,18 Validated symptom questionnaires were completed on the day of enrollment. The presence of concurrent GERD symptoms was defined with a gastroesophageal reflux disease questionnaire (GerdQ) score ≥ 8.19

In addition, we investigated the prevalence of psychological morbidity and sleep disturbance between patients with PPI-unresponsive laryngeal symptoms and healthy asymptomatic individuals, who were recruited through advertisement or by word of mouth. This study was approved by the Institutional Ethics Committee of NTUH (No. 201505131RND). All participants provided written informed consent prior to the study.

Symptom Evaluation

All participants were assessed using validated symptom questionnaires. Reflux symptom index (RSI) was used to evaluate and document the severity of laryngeal symotoms.20 GerdQ involves 4 positive (heartburn, regurgitation, sleep disturbance due to reflux symptoms, and use of over-the-counter medication) and 2 negative (epigastric pain and nausea) predictors of GERD.19 The patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) is composed of 20 items and 6 subscales.21 In addition, 5-item brief symptom rating scale (BSRS-5) screens for common psychiatric morbidities such as anxiety, depression, and related disorders; a BSRS-5 score ≥ 6 indicates psychiatric morbidity.22 The Pittsburgh sleep quality index (PSQI) is a 7-item self-rated questionnaire assessing sleep disturbance over a 1-month period.23 A global PSQI score > 5 indicates poor sleep quality and sleep disturbance.

Multichannel Intraluminal Impedance and pH Monitoring

The catheter contained a single pH and 8 ring electrodes (Medical Measurement Systems, Enschede, Netherlands). It was introduced transnasally and the pH sensor was placed about 5 cm above the lower esophagus sphincter (LES), which was confirmed with the esophageal HRIM. The 6 impedance segments defined the 6 zones along the esophagus, Z1 to Z6, which were centered at 17, 15, 9, 7, 5, and 3 cm above the LES, respectively. All impedance and pH data were recorded over the following 24 hours. Each MII tracing was automatically analyzed using the package analytic software (Medical Measurement Systems), and was then reviewed manually and interpreted by the same experienced gastroenterologist (P.H.T.).24,25

The parameters obtained from pH monitoring included the total number of reflux episodes, the symptom index and symptom association probability. In addition, an acid exposure time (AET; the percentage of time that esophageal acid exposure was below a pH of 4.0) was also obtained. An AET < 4.0% was considered normal.15 An episode of acid reflux was defined as a drop in intraesophageal pH ≤ 4 for 5 seconds or more.

High-resolution Impedance Manometry

After an ≥ 8-hour fast, all patients underwent an HRIM study performed by an experienced gastroenterologist (P.H.T.).26 We used a 4.2 mm diameter HRIM catheter, with 22 closely spaced water-perfused pressure sensors, and 12 impedance channels at 2-cm intervals (Medical Measurement Systems). After calibration, the catheter was transnasally introduced into the esophagus in an upright position. The upper esophageal sphincter and LES were identified based on the presence of upper and lower high-pressure zones, respectively. After 5 minutes of accommodation in supine position, basal upper esophageal sphincter and LES pressures were obtained, and participants were then asked to perform 10 liquid swallows of 5 mL saline at 30-second intervals. Data were analyzed using the package analysis software (Solar GI HRIM water-perfused system, Medical Measurement Systems) and assessed by P.H.T. LES relaxation and esophageal body contraction were evaluated, and esophageal motility disorders were diagnosed using the criteria stipulated by the Chicago Classification version 3.0.27

Statistical Methods

Quantitative data are summarized as mean ± standard deviation (SD) for continuous data and were compared using independent sample t tests; categorical variables are summarized as percentages and were compared using chi-square tests. Pearson correlation coefficients were used to evaluate the relationship between RSI scores and scores of other symptom questionnaires. P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 26 (SPSS, Chicago, IL, USA).


Participant Demographics and Clinical Characteristics

In the pilot exploratory study, we initially planned to enroll 100 participants to investigate the clinical features of patients with persistent laryngeal symptoms despite PPI treatment. However, non-urgent and non-time sensitive endoscopies and esophageal motility studies were put on pause during the severe Coronavirus Disease 19 outbreak in Taiwan in 2021 and case enrollment of the present study was thus terminated early. As a result, a total of 97 patients (56 women; mean age, 49 years; range, 18-85 years) were included in the final analysis. Of all the patients, 5.2% had been on lansoprazole 30 mg once daily, 6.2% on rabeprazole 20 mg once daily, 4.1% on pantoprazole 40 mg once daily, 1.0% on omeprazole 20 mg once daily, 25.8% on esomeprazole 40 mg once daily and 57.8% on dexlansoprazole 60 mg once daily. Fifty-eight patients (59.8%) had concurrent GERD symptoms (Laryngeal-GERD symptomatic). There was no significant difference between the subgroups of patients with laryngeal symptoms only and Laryngeal-GERD symptoms in terms of their age, sex, body mass index, tobacco use, and alcohol consumption (Table 1).

Table 1 . Demographics and Clinical Characteristics

CharacteristicsTotal (n = 97) Laryngeal symptoms alone (n = 39)Concurrent laryngeal and GERD symptoms (n = 58)P-value
Age (yr)49.30 ± 13.4846.62 ± 14.1451.10 ± 12.820.109
20-4025 (25.8%)15 (38.5%)10 (17.2%)
40-6052 (53.6%)16 (41.3%)36 (62.1%)
> 6020 (20.6%)8 (20.5%)12 (20.7%)
Female56 (57.7%)21 (53.8%)35 (60.3%)0.538
BMI (kg/m2)22.13 ± 3.3922.04 ± 3.4822.20 ± 3.360.824
Waist (cm)77.97 ± 9.7977.22 ± 10.7678.48 ± 9.150.535
Smoking12 (12.4%)5 (12.8%)7 (12.1%)> 0.999
Drinking13 (13.4%)4 (10.3%)9 (15.5%)0.553
RSI total score16.28 ± 6.8615.65 ± 7.1216.71 ± 6.720.456
RSI total score ≥ 1364 (66.0)24 (61.5)40 (67.0)0.515
Hoarseness or other voice problemsa40 (41.2)15 (38.5)25 (43.1)0.679
Clearing throata56 (57.7)21 (53.8)35 (60.3)0.538
Excess throat mucus or postnasal dripa58 (59.8)27 (69.2)31 (53.4)0.143
Difficulty swallowing food, liquid, or pillsa17 (17.5)6 (15.4)11 (19.0)0.788
Coughing after eating or after lying downa18 (18.6)8 (20.5)10 (17.2)0.791
Breathing difficulties or choking episodesa10 (10.3)5 (12.8)5 (8.6)0.517
Troublesome or annoying cougha19 (16)7 (17.9)12 (20.7)0.799
Sensations of something sticking in throat or lump in throata73 (75.3)26 (66.7)47 (81.0)0.150
Heartburn, chest pain, indigestion, or stomach acid coming upa64 (66.0)13 (33.3)41 (70.7)< 0.001

aScore ≥ 3 (moderate symptom) on the item.

Data are presented as mean ± SD or n (%).

The most common laryngeal symptoms, based on the RSI, were “sensations of something sticking in throat or lump in throat” (75.3%), “heartburn, chest pain, indigestion, or stomach acid coming up” (66.0%), and “excess throat mucus” (59.8%) for subjects across the whole study. On the other hand, “excess throat mucus” (69.2%), “sensations of something sticking in throat or lump in throat” (66.7%), and “clearing throat” (53.8%) were most common in patients with laryngeal symptoms alone, while “lump in throat” (81.0%), “heartburn, chest pain, indigestion, or stomach acid coming up” (70.7%), and “clearing throat” (60.3%) were most common in Laryngeal-GERD symptomatic patients .

Gastrointestinal Symptoms and Objective Evaluation of Gastroesophageal Characteristics

Patients reported a GerdQ score of 9.16 ± 2.68, with “nausea” and “pain in the middle of the upper stomach area” being the 2 most prominent symptoms. The total score on PAGI-SYM was 1.13 ± 0.74, and the parameters with the 2 highest scores were “bloating” (1.69 ± 1.37) and “heartburn/regurgitation” (1.64 ± 1.10) (Table 2).

Table 2 . Associated Gastrointestinal Symptoms

CharacteristicsTotal (n = 97) Laryngeal symptoms alone (n = 39)Concurrent laryngeal and GERD symptoms (n = 58)P-value
Burning feeling behind the breastbone (heartburn)1.31 ± 1.310.44 ± 0.821.90 ± 1.25< 0.001
Stomach contents moving up to the throat or mouth (regurgitation)1.79 ± 1.181.10 ± 1.022.26 ± 1.05< 0.001
Pain in the middle of the upper stomach area2.10 ± 1.152.23 ± 1.112.02 ± 1.180.373
Nausea2.44 ± 0.972.36 ± 1.012.50 ± 0.940.485
Trouble getting a good night’s sleep because of heartburn or regurgitation1.01 ± 1.240.33 ± 0.661.47 ± 1.33< 0.001
Need for over-the-counter medicine for heartburn or regurgitation, in addition to the medicine your doctor prescribed0.51 ± 1.070.10 ± 0.500.78 ± 1.260.002
Total score9.16 ± 2.686.56 ± 1.2910.91 ± 1.81< 0.001
Heartburn/regurgitation1.64 ± 1.101.46 ± 1.141.77 ± 1.070.176
Nausea/vomiting0.65 ± 0.870.76 ± 0.960.58 ± 0.800.320
Postprandial fullness/early satiety0.95 ± 0.931.04 ± 1.090.88 ± 0.810.405
Bloating1.69 ± 1.371.51 ± 1.261.81 ± 1.440.297
Upper abdominal pain1.34 ± 1.311.44 ± 1.491.28 ± 1.180.558
Lower abdominal pain0.48 ± 0.930.32 ± 0.660.59 ± 1.060.169
Total score1.13 ± 0.741.11 ± 0.801.15 ± 0.700.753

There are statistically significant differences (P < 0.05) between laryngeal symptoms and Laryngeal-gastroesophageal reflux disease (GERD) symptoms groups.

GerdQ, gastroesophageal reflux disease questionnaire; PAGI-SYM, patient assessment of upper gastrointestinal symptom severity index.

Data are presented as mean ± SD.

On endoscopy, 23 (23.7%) patients had erosive esophagitis (EE) and 1 (1.0%) patient had hiatal hernia. On pH-impedance monitoring, abnormal pH testing was present in 16 (16.5%) patients. 19 (19.6%) patients had an abnormal AET in the upright position. On impedance monitoring, the average number of reflux episodes was 38.13 ± 26.80. Of these, 20.55 ± 18.38 were acidic, 15.91 ± 14.05 were weakly acidic, and 1.86 ± 4.18 were non-acidic. 14.78 ± 16.62% and 25.50 ± 20.18% of all reflux episodes reached the proximal extent of 17 cm and 15 cm above the LES, respectively. On HRIM, the LES 4-second integrated relaxation pressures (IRP-4s) was 7.81 ± 5.61 mmHg. Twenty-three (23.7%) patients had ineffective esophageal motility and 12 (12.4%) had hiatal hernia as defined by manometry (Table 3).

Table 3 . Objective Evaluation of Gastroesophageal Characteristics

CharacteristicsTotal (n = 97) Laryngeal symptoms alone (n = 39)Concurrent laryngeal and GERD symptoms (n = 58)P-value
Endoscopic findings
Erosive esophagitis23 (23.7)9 (23.1)14 (24.1)0.701
LA Grade A20 (20.6)8 (20.5)12 (20.7)
LA Grade B3 (3.1)1 (2.6)2 (3.4)
Hiatal hernia1 (1.0)0 (0.0)1 (1.7)
24-hour pH-impedance monitoring
Esophageal acid exposure (%)3.04 ± 9.003.76 ± 13.482.56 ± 3.830.522
Abnormal acid exposure > 4%16 (16.5)5 (12.8)11 (19.0)0.579
Abnormal acid exposure > 6%9 (9.3)4 (10.3%)5 (8.6%)> 0.999
Upright reflux time (%)4.02 ± 8.954.21 ± 12.133.89 ± 6.060.862
Abnormal acid exposurea19(19.6)6 (15.4)13 (22.4)0.445
Supine reflux time (%)1.69 ± 9.983.07 ± 15.510.75 ± 2.230.264
Abnormal acid exposureb15 (15.5)6 (15.4)9 (15.5)> 0.999
DeMeester score10.10 ± 29.9212.82 ± 45.178.27 ± 11.780.466
Number of symptoms5.77 ± 7.974.28 ± 6.136.78 ± 8.910.131
Positive SI22 (22.7)8 (20.5)14 (24.1)0.806
Positive SAP32 (33.0)11 (28.2)21 (36.2)0.510
Number of reflux episodes on impedance38.13 ± 26.8035.74 ± 29.1539.74 ± 25.240.474
Acidic reflux20.55 ± 18.3819.18 ± 20.3421.47 ± 17.070.551
Weakly acidic reflux15.91 ± 14.0513.59 ± 12.7117.47 ± 14.790.184
Non-acidic reflux1.86 ± 4.182.64 ± 5.661.33 ± 2.700.129
Proximal extent (%)
Extent 17 cm14.78 ± 16.6213.39 ± 18.1015.69 ± 15.680.511
Extent 15 cm25.50 ± 20.1822.74 ± 20.7427.31 ± 19.770.280
Extent 9 cm62.86 ± 22.7061.11 ± 25.0864.02 ± 21.140.542
Extent 7 cm74.34 ± 22.6374.53 ± 25.3374.22 ± 20.890.949
Extent 5 cm94.90 ± 21.9094.74 ± 22.6395.00 ± 21.620.954
Extent 3 cm95.83 ± 20.0994.74 ± 22.6396.55 ± 18.410.667
High-resolution impedance manometry
LES resting pressure (mmHg)21.25 ± 11.3721.05 ± 10.1621.39 ± 12.190.889
LES IRP-4s (mmHg)7.81 ± 5.618.28 ± 5.307.49 ± 5.830.502
Intact peristalsis (%)66.29 ± 37.4569.49 ± 34.8664.14 ± 39.250.493
Weak peristalsis (%)15.93 ± 23.5016.03 ± 22.4815.86 ± 24.350.973
Failed peristalsis (%)17.78 ± 31.2514.49 ± 29.2220.00 ± 32.610.397
DCI, mmHg∙s∙cm1015.12 ± 853.591055.50 ± 778.84989.61 ± 903.420.719
Break size (cm)3.93 ± 5.673.44 ± 3.784.24 ± 6.600.513
Ineffective esophageal motility23 (23.7)9 (23.1)14 (24.1)0.381
Hiatal hernia12 (12.4)4 (10.3)8 (13.8)0.757

aAbnormal esophageal acid exposure in the upright positions was defined as a pH < 4 for more than 6% of the time.

bAbnormal esophageal acid exposure in the supine positions was defined as a pH < 4 for more than 1% of the time.

There are statistically significant differences (P < 0.05) between laryngeal symptomatic and Laryngeal-gastroesophageal reflux disease (GERD) asymptomatic groups.

LA, Los Angeles classification of the severity of reflux esophagitis; SI, symptom index; SAP, symptom association probability; IRP-4s, 4-second integrated relaxation pressure; DCI, distal contractile integral.

Data are presented as mean ± SD or n (%).

Psychological Characteristics

The patient group reported a significantly higher BSRS-5 score (6.52 ± 4.55 vs 1.33 ± 2.00, P < 0.001) and PSQI (10.41 ± 4.57 vs 4.60 ± 3.18, P < 0.001) than healthy volunteers (Table 4). The prevalence of psychiatric morbidity (52.6% vs 2.1%, P < 0.001) and sleep disturbance (82.5% vs 37.5%, P < 0.001) was also significantly higher. For individual items on questionnaires, the patients reported significantly higher scores on all items except for “feeling inferior to others” on BSRS-5 and “sleep duration” on PSQI. Furthermore, in the patient group, 42 out of 97 (43.3%) reported use of sleep medication (Question 6: During the past month, how often have you taken medicine, prescribed or over-the-counter, to help you sleep? In PSQI). Among them, 9.5% used it less than once a week, 16.7% reported once to twice a week, and 73.8% reported 3 or more times a week. While only 2 (4.2%) in healthy volunteer group reported medication use, with 1 less than once a week and another 3 or more times a week.

Table 4 . Comparison of Psychological Characteristics and Sleep Quality Between Patients With Laryngeal Symptoms and Healthy Volunteers

CharacteristicsPatients (n = 97)Healthy volunteer (n = 48)P-value
Age (yr)49.30 ± 13.4845.56 ± 11.140.100
Female56 (57.7)22 (45.8)0.216
Trouble falling asleep1.92 ± 1.320.25 ± 0.53< 0.001
Feeling tense or keyed up1.52 ± 1.290.35 ± 0.64< 0.001
Feeling easily annoyed or irritated1.40 ± 1.310.33 ± 0.60< 0.001
Feeling depressed1.25 ± 1.200.17 ± 0.43< 0.001
Feeling inferior to others0.43 ± 0.910.23 ± 0.470.148
Total scores6.52 ± 4.551.33 ± 2.00< 0.001
Psychiatric comorbidity51 (52.6)1 (2.1)< 0.001
Sleep duration1.14 ± 1.570.83 ± 0.750.197
Sleep latency1.38 ± 1.080.40 ± 0.61< 0.001
Habitual sleep efficiency1.34 ± 1.060.46 ± 0.68< 0.001
Sleep disturbances2.45 ± 0.971.46 ± 1.17< 0.001
Subjective sleep quality1.87 ± 0.730.83 ± 0.60< 0.001
Use of sleeping medication1.14 ± 1.380.08 ± 0.45< 0.001
Daytime dysfunction1.08 ± 1.210.54 ± 0.87< 0.001
Total scores10.41 ± 4.574.60 ± 3.18< 0.001
Sleep disturbance80 (82.5)18 (37.5)< 0.001

Psychiatric comorbidity indicates a 5-item brief symptom rating scale (BSRS-5) total score ≥ 6.

Sleep disturbance indicates a Pittsburgh Sleep Quality Index (PSQI) score > 5.

Data are presented as mean ± SD or n (%).

Correlation Between Psychiatric Morbidity and Sleep Disturbance With Laryngeal Symptoms and Reflux Symptom Burden

Correlation analysis between RSI and BSRS-5 scores, and between RSI and PSQI scores, showed significant correlation (Pearson correlation coefficient r = 0.26, P = 0.010, and r = 0.29, P = 0.004, respectively) (Figure 1). Correlation analysis showed significant correlation between GerdQ and PSQI scores (Pearson correlation coefficient r = 0.34, P = 0.001) but not between GerdQ and BSRS-5 scores (Pearson correlation coefficient r = 0.12, P = 0.260).

Figure 1. Correlation between psychiatric morbidity and sleep disturbance with laryngeal symptoms and reflux symptoms burden. The score of Reflux Symptom Index (RSI) was significantly correlated with the scores of 5-item brief symptom rating scale (BSRS-5) (A) and Pittsburgh sleep quality index (PSQI) (B) (Pearson correlation coefficient r = 0.26, P = 0.010 and r = 0.29, P = 0.004, respectively). The score of gastroesophageal reflux disease questionnaire (GerdQ) was significantly correlated with the scores of PSQI (C) (Pearson correlation coefficient r = 0.34, P = 0.001) but not with BSRS-5 (D) (Pearson correlation coefficient r = 0.12, P = 0.260).

Comparison Between Patients With Proton Pump Inhibitor-refractory Laryngeal Symptoms Alone and Patients With Concurrent Gastroesophageal Reflux Disease Symptoms

Gastrointestinal symptoms

The total score on the GerdQ was 10.91 ± 1.81 in the Laryngeal-GERD symptomatic patient group, which was significantly higher for the laryngeal symptoms alone group (6.56 ± 1.29, P = 0.000). The Laryngeal-GERD symptomatic patients reported higher symptom burden on items including “heartburn”, “regurgitation,” “trouble sleeping”, and “need for over-the-counter medicine”. There were no significant differences in either total score or on any of the subscales on the PAGI-SYM.

Objective evaluation of gastroesophageal characteristics

Endoscopy showed no significant differences in the prevalence of EE and hiatal hernia (P = 0.701) between the 2 groups (Table 3). On pH-impedance monitoring, none of the parameters including AET (P = 0.522), acid reflux (P = 0.551), and non-acidic reflux (P = 0.129) differed between the 2 groups. The prevalence of abnormal AET overall and in upright position were similar. On HRIM, there were also no significant differences in key parameters including LES IRP-4s, failed peristalsis, and ineffective esophageal motility.

Psychological characteristics and sleep quality

Overall, the scores of BSRS-5 and PSQI were high in all patients (Table 4). The total BSRS-5 score and the prevalence of psychiatric comorbidity were similar between the laryngeal symptoms alone and the Laryngeal-GERD symptomatic patient groups (Table 5). However, Laryngeal-GERD symptomatic patients reported a significantly higher score on “trouble falling asleep” on the BSRS-5 (2.17 ± 1.35 vs 1.54 ± 1.19, P = 0.020). Moreover, Laryngeal-GERD symptomatic patients reported an even higher total PSQI score and higher prevalence of sleep disturbance (11.50 ± 4.63 vs 8.79 ± 4.01, P < 0.001 and 89.7% vs 71.8%, P < 0.001, respectively).

Table 5 . Comparison of Psychological Characteristics and Sleep Quality Between Patients With Laryngeal Symptoms Alone and Those With Concurrent Gastroesophageal Reflux Disease Symptoms

Characteristics Laryngeal symptoms alone (n = 39)Concurrent laryngeal and GERD symptoms (n = 58)P-value
Age (yr)46.62 ± 14.1451.10 ± 12.820.109
Female21 (53.8)35 (60.3)0.538
Trouble falling asleep1.54 ± 1.192.17 ± 1.350.020
Feeling tense or keyed up1.56 ± 1.121.48 ± 1.410.763
Feeling easily annoyed or irritated1.38 ± 1.251.41 ± 1.360.915
Feeling depressed1.18 ± 1.071.29 ± 1.280.650
Feeling inferior to others0.38 ± 0.780.47 ± 1.000.671
Total scores6.05 ± 4.086.83 ± 4.850.413
Psychiatric comorbidity19 (48.7)32 (55.2)0.543
Sleep duration1.03 ± 0.781.22 ± 1.940.545
Sleep latency1.10 ± 1.051.57 ± 1.080.037
Habitual sleep efficiency1.05 ± 0.941.53 ± 1.100.027
Sleep disturbances2.13 ± 1.172.67 ± 0.740.006
Subjective sleep quality1.72 ± 0.691.97 ± 0.750.102
Use of sleeping medication0.87 ± 1.341.33 ± 1.390.112
Daytime dysfunction0.90 ± 1.101.21 ± 1.270.217
Total scores8.79 ± 4.0111.50 ± 4.630.004
Sleep disturbance28 (71.8)52 (89.7)0.030

Psychiatric comorbidity indicates a 5-item brief symptom rating scale (BSRS-5) total score ≥ 6.

Sleep disturbance indicates a Pittsburgh sleep quality index (PSQI) score > 5.

GERD, gastroesophageal reflux disease.

Data are presented as mean ± SD or n (%).


In the present study, patients with PPI-refractory laryngeal symptoms had markedly higher prevalence of psychological distress and sleep disturbance when compared to the healthy volunteers. The prevalence of EE and motility characteristics on HRIM were similar to the normal population.26,28,29 Compared to patients with laryngeal symptoms alone, those with concurrent GERD symptoms had even more prominent sleep disturbances but presented with similar reflux profiles and esophageal motility.

Compared to normal pH-impedance monitoring data in the Chinese population, our laryngeal symptomatic patients had similar episodes of acid reflux, but their total and upright AETs were slightly higher.30,31 Compared to healthy volunteers, however, patients in this study were observed to have a significantly higher prevalence of psychiatric morbidity and sleep disturbance. Bradley et al32 found that chronic reflux patients with chronic anxiety were more likely to perceive low-intensity esophageal stimuli as painful reflux symptoms. A recent study further compared individuals with non-erosive reflux disease, reflux hypersensitivity, and functional heartburn to healthy controls, and found that all 3 of these groups had increased sensation to visceral stimuli based on the visceral sensitivity index.33 Similarly, many studies had reported the association between laryngeal symptoms and higher somatization symptoms,34,35 and between laryngeal symptoms and psychiatric morbidity.36-38 Furthermore, in cases of refractory laryngeal symptoms, 52.6% of our patients in the present study showed psychological symptoms on BSRS-5, while the prevalence of psychiatric morbidity was 27.2 % in a hospital-based general health screening.22 It seems that patients with PPI-refractory laryngeal symptoms presented with a high burden of psychological stress. Vertigan et al39 found significant sensory impairments in patients with chronic refractory cough and globus pharyngeus using quantitative sensory testing. Visceral hypersensitivity and psychological factors may also play an important role in the development of laryngeal symptoms and symptoms that appear refractory to first-line treatment.40,41

Extraesophageal reflux disease is usually multifactorial with GERD as one of the several potential aggravating cofactors.2 In the present study, about 60% of the subjects had GERD symptoms, as defined with a GerdQ score ≥ 8. Recently, a Taiwanese multi-center observational study also showed that among 106 patients with predominant laryngopharyngeal reflux symptoms, 66 (62.2%) had concomitant typical reflux symptoms, who had similar PPI-responsiveness and similar distal esophageal acid exposure time when compared to patients with isolated laryngeal symptoms.42 In present study, the clinical features of patients with PPI-refractory laryngeal symptoms were further investigated and classified according to the presence or absence of concurrent GERD symptoms. We showed that the reflux profile and esophageal motility were similar. Although all patients in the present study had a higher prevalence of psychiatric morbidity and sleep disturbance when compared to healthy volunteers, patients with concurrent GERD symptoms reported even higher scores with regards to sleep disturbance on the BSRS-5 and PSQI scores than patients with laryngeal symptoms alone. Similarly, higher psychological comorbidities had also been identified in patients with overlapping laryngeal and GERD symptoms.43 Poor sleep has been reported to be related to increased esophageal acid exposure and visceral hypersensitivity.44,45 It is estimated that up to 50% of patients with GERD remained symptomatic on standard PPI therapy.46,47 Poor medication compliance and adherence, differences in PPI metabolism, residual reflux (non-acidic, bile, or acidic), concomitant functional bowel disorders, psychological comorbidity, and delayed gastric emptying have been proposed as mechanisms of treatment failure.48 A prospective cohort study demonstrated that reflux characteristics, measured using impedance pH, were not significantly different between patients who responded to standard PPI therapy when compared to those who failed to do so.13 Their findings also supported the important role of esophageal hypersensitivity in this patient population. The authors concluded that patients who do not respond to PPI therapy may benefit from adding a neuromodulator and potentially from psychological intervention. Hyperalgesia, hypervigilance, and heightened anxiety are thought to be the most plausible candidates for the dominant determinants of PPI-refractory symptoms.49 Psychosocial factors influence physiological functioning of the GI tract via the brain–gut axis, are modulators of the patient’s pain experience and symptom behavior, and ultimately affect treatment selection and clinical outcome.50

Assessment of patients with laryngeal symptoms referred for reflux evaluation has remained challenging and treatment response has been less than satisfactory.6,51 Systemic assessment on clinical and physiologic characteristics of these patients has been demonstrated to be efficient in daily practice.52 Patients with proven pathological GERD would be the optimal candidates for an escalated anti-reflux therapy. On the other hand, patients with nonacid reflux events could be spared prolonged acid suppression and could be offered treatments addressed to associated mechanism such as alginates or antireflux surgery, which had been demonstrated to be more cost-saving.53 Finally, for those presenting laryngeal symptoms with reflux hypersensitivity, neuromodulation may be particularly beneficial.54

The strengths of the current study include its prospective study design and its inclusion of objective multidisciplinary evaluation modalities, as well as patient-reported questionnaires. There are however some limitations. Firstly, we used only 1 pH sensor at the lower esophagus and could not confirm the presence of a proximal esophageal acid reflux event reaching the hypopharynx. To deal with this limitation, we reported the proximal extent of reflux episodes on impedance monitoring, and focused on patients whose symptoms persisted after a PPI trial, with the MII-pH monitoring being performed during off PPI period. Incorporating hypopharyngeal-esophageal MII-pH may provide additional understanding of the nature of laryngeal symptoms in laryngopharyngeal reflux55 and should be considered in future studies. On the other hand, pathological reflux to the hypopharynx could not solely explain the pathophysiology of laryngeal symptoms, as the neurally mediated vagal reflex has also been proposed as part of the pathogenesis of atypical GERD symptoms.56 Secondly, there were no differences in the endoscopic findings and pH monitoring results between patients with laryngeal symptoms alone and concurrent GERD symptoms, except for significantly higher sleep disturbance in Laryngeal-GERD symptomatic patients. Although there were numerically higher percentage of patients having AET at upright, higher number of symptoms, positive symptom association probability, and higher number of reflux episode on impedance (especially acidic and weakly acidic reflux) in patients with concurrent GERD symptoms, none of these parameters achieves statistical significance. Future studies with a larger sample size could be helpful to clarify or confirm the clinical significance of these findings. Thirdly, in the employed study protocol, the prevalence and severity of psychological distress or sleep disturbance were investigated with validated questionnaires. However, the psychiatric medication or insomnia medication were not specifically recorded. In addition, we did not routinely refer our patients for psychiatric consultation. Although our study has demonstrated close association between psychological stress and these bothersome laryngeal symptoms, the cause-effect relationship remained undetermined. Therefore, considering the high prevalence of psychiatric comorbidities shown in patients with refractory laryngeal symptoms, future studies incorporating psychiatric specialists in the multidisciplinary team would help clarify the complex relationship between psychological distress and PPI-refractory laryngeal symptoms and tailor further treatment plans.

In conclusion, a multidisciplinary evaluation should be performed in patients whose troublesome laryngeal symptoms do not respond to a PPI trial.5 We investigated patients’ anatomical, physiological, and psychological characteristics using validated questionnaires, EGD, MII-pH monitoring, and HRIM. The present study confirmed the hypothesis that PPI-refractory laryngeal symptoms are more associated with psychological comorbidities and sleep disturbances rather than reflux-related. In addition to providing careful physical examination, physicians should also address these psychosocial factors. Our study suggests that meticulous recognition of psychological comorbidities appears to be clinically meaningful in the management of patients whose laryngeal symptoms persist after PPI therapy.


The authors would also like to thank Unit-Edit (www.uni-edit.net) for editing and proofreading this manuscript.

Financial support

This study was supported by research grants from the National Taiwan University Hospital (NTUH 110-005025) and the Ministry of Science and Technology (109-2628-B-002-036 and 110-2628-B-002-048). The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest


Author contributions

Ping-Huei Tseng: guarantor of the article who was also in charge of study design, performing the study, data acquisition, interpretation, and manuscript revision; Wen-Hsuan Tseng: drafted manuscript, acquisition of data, and interpretation and analysis of data; Wei-Chung Hsu, Jia-Feng Wu, and Hui-Chuan Lee: study design, interpretation, and acquisition of data; and Tsung-Lin Yang, Tzu-Yu Hsiao, Hsiu-Po Wang, and Ming-Shiang Wu: study design and interpretation. All authors have approved the final version of the manuscript.

  1. Klauser AG, Schindlbeck NE, Müller-Lissner SA. Symptoms in gastro-oesophageal reflux disease. Lancet (London, England) 1990;335:205-208.
  2. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900-1920.
    Pubmed CrossRef
  3. Poelmans J, Tack J. Extraoesophageal manifestations of gastro-oesophageal reflux. Gut 2005;54:1492-1499.
    Pubmed KoreaMed CrossRef
  4. Vaezi MF. Editorial: reflux and laryngeal symptoms: a sea of confusion. Am J Gastroenterol 2016;111:1525-1527.
    Pubmed CrossRef
  5. Lechien JR, Akst LM, Hamdan AL, et al. Evaluation and management of laryngopharyngeal reflux disease: state of the art review. Otolaryngol Head Neck Surg 2019;160:762-782.
    Pubmed CrossRef
  6. Barrett CM, Patel D, Vaezi MF. Laryngopharyngeal reflux and atypical gastroesophageal reflux disease. Gastrointest Endosc Clin N Am 2020;30:361-376.
    Pubmed CrossRef
  7. de Bortoli N, Nacci A, Savarino E, et al. How many cases of laryngopharyngeal reflux suspected by laryngoscopy are gastroesophageal reflux disease-related? World J Gastroenterol 2012;18:4363-4370.
    Pubmed KoreaMed CrossRef
  8. Bajbouj M, Becker V, Neuber M, Schmid RM, Meining A. Combined pH-metry/impedance monitoring increases the diagnostic yield in patients with atypical gastroesophageal reflux symptoms. Digestion 2007;76:223-228.
    Pubmed CrossRef
  9. Roman S, Kahrilas PJ. Challenges in the swallowing mechanism: nonobstructive dysphagia in the era of high-resolution manometry and impedance. Gastroenterol Clin North Am 2011;40:823-835, ix-x.
    Pubmed KoreaMed CrossRef
  10. Lee BE, Kim GH. Globus pharyngeus: a review of its etiology, diagnosis and treatment. World J Gastroenterol 2012;18:2462-2471.
    Pubmed KoreaMed CrossRef
  11. Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Functional esophageal disorders. Gastroenterology 2016;150:1368-1379.
    Pubmed CrossRef
  12. Yadlapati R, DeLay K. Proton pump inhibitor-refractory gastroesophageal reflux disease. Med Clin North Am 2019;103:15-27.
    Pubmed KoreaMed CrossRef
  13. Fass OZ, Fass R. Overlap between GERD and functional esophageal disorders-a pivotal mechanism for treatment failure. Curr Treat Options Gastroenterol 2019;17:161-164.
    Pubmed CrossRef
  14. Katz PO, Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2022;117:27-56.
    Pubmed KoreaMed CrossRef
  15. Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the Llon consensus. Gut 2018;67:1351-1362.
    Pubmed KoreaMed CrossRef
  16. Ghisa M, Barberio B, Savarino V, et al. The lyon consensus: does it differ from the previous ones? J Neurogastroenterol Motil 2020;26:311-321.
    Pubmed KoreaMed CrossRef
  17. Tseng PH, Chen CC, Chiu HM, et al. Performance of narrow band imaging and magnification endoscopy in the prediction of therapeutic response in patients with gastroesophageal reflux disease. J Clin Gastroenterol 2011;45:501-506.
    Pubmed CrossRef
  18. Wang CH, Lee YC, Wang CP, et al. Use of transnasal endoscopy for screening of esophageal squamous cell carcinoma in high-risk patients: yield rate, completion rate, and safety. Dig Endosc 2014;26:24-31.
    Pubmed CrossRef
  19. Jonasson C, Wernersson B, Hoff DA, Hatlebakk JG. Validation of the GerdQ questionnaire for the diagnosis of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2013;37:564-572.
    Pubmed CrossRef
  20. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice 2002;16:274-277.
    Pubmed CrossRef
  21. Kindt S, Dubois D, Van Oudenhove L, et al. Relationship between symptom pattern, assessed by the PAGI-SYM questionnaire, and gastric sensorimotor dysfunction in functional dyspepsia. Neurogastroenterol Motil 2009;21:1183-e105.
    Pubmed CrossRef
  22. Chen HC, Wu CH, Lee YJ, Liao SC, Lee MB. Validity of the five-item brief symptom rating scale among subjects admitted for general health screening. J Formos Med Assoc 2005;104:824-829.
  23. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193-213.
    Pubmed CrossRef
  24. Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004;53:1024-1031.
    Pubmed KoreaMed CrossRef
  25. Liu YW, Wu JF, Chen HL, et al. The correlation between endoscopic reflux esophagitis and combined multichannel intraluminal impedance-pH monitoring in children. Pediatr Neonatol 2016;57:385-389.
    Pubmed CrossRef
  26. Tseng PH, Wong RKM, Wu JF, et al. Normative values and factors affecting water-perfused esophageal high-resolution impedance manometry for a Chinese population. Neurogastroenterol Motil 2018;30:e13265.
    Pubmed CrossRef
  27. Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil 2015;27:160-174.
    Pubmed KoreaMed CrossRef
  28. Tseng PH, Lee YC, Chiu HM, et al. Prevalence and clinical characteristics of barrett's esophagus in a Chinese general population. J Clin Gastroenterol 2008;42:1074-1079.
    Pubmed CrossRef
  29. Tseng PH, Lee YC, Chiu HM, et al. Association of diabetes and HbA1c levels with gastrointestinal manifestations. Diabetes Care 2012;35:1053-1060.
    Pubmed KoreaMed CrossRef
  30. Xiao YL, Lin JK, Cheung TK, et al. Normal values of 24-hour combined esophageal multichannel intraluminal impedance and pH monitoring in the Chinese population. Digestion 2009;79:109-114.
    Pubmed CrossRef
  31. Wang AJ, Liang MJ, Jiang AY, et al. Gastroesophageal and laryngopharyngeal reflux detected by 24-hour combined impedance and pH monitoring in healthy Chinese volunteers. J Dig Dis 2011;12:173-180.
    Pubmed CrossRef
  32. Bradley LA, Richter JE, Pulliam TJ, et al. The relationship between stress and symptoms of gastroesophageal reflux: the influence of psychological factors. Am J Gastroenterol 1993;88:11-19.
  33. Losa M, Manz SM, Schindler V, Savarino E, Pohl Daniel. Increased visceral sensitivity, elevated anxiety, and depression levels in patients with functional esophageal disorders and non-erosive reflux disease. Neurogastroenterol Motil 2021;33:e14177.
    Pubmed CrossRef
  34. Shin KS, Tae K, Jeong JH, et al. The role of psychological distress in laryngopharyngeal reflux patients: a prospective questionnaire study. Clin Otolaryngol 2010;35:25-30.
    Pubmed CrossRef
  35. Park KH, Choi SM, Kwon SU, Yoon SW, Kim SU. Diagnosis of laryngopharyngeal reflux among globus patients. Otolaryngol Head Neck Surg 2006;134:81-85.
    Pubmed CrossRef
  36. Joo YH, Song YS, Pae CU. Relationship between depression and laryngopharyngeal reflux. Psychiatry Investig 2017;14:226-229.
    Pubmed KoreaMed CrossRef
  37. Cheung TK, Lam PK, Wei WI, et al. Quality of life in patients with laryngopharyngeal reflux. Digestion 2009;79:52-57.
    Pubmed CrossRef
  38. Siupsinskiene N, Adamonis K, Toohill RJ. Quality of life in laryngopharyngeal reflux patients. Laryngoscope 2007;117:480-484.
    Pubmed CrossRef
  39. Vertigan AE, Bone SL, Gibson PG. Laryngeal sensory dysfunction in laryngeal hypersensitivity syndrome. Respirology 2013;18:948-956.
    Pubmed CrossRef
  40. Boeckxstaens G, Camilleri M, Sifrim D, et al. Fundamentals of neurogastroenterology: physiology/motility - sensation. Gastroenterology 2016;150:1292-1304, e2.
    Pubmed CrossRef
  41. Hull JH, Backer V, Gibson PG, Fowler SJ. Laryngeal dysfunction: assessment and management for the clinician. Am J Respir Crit Care Med 2016;194:1062-1072.
    Pubmed CrossRef
  42. Lien HC, Wang CC, Kao JY, et al. Distinct physiological characteristics of isolated laryngopharyngeal reflux symptoms. Clin Gastroenterol Hepatol 2020;18:1466-1474, e4.
    Pubmed CrossRef
  43. Wong MW, Bair MJ, Chang WC, et al. Clinical and psychological characteristics in gastroesophageal reflux disease patients overlapping with laryngopharyngeal reflux symptoms. J Gastroenterol Hepatol 2019;34:1720-1726.
    Pubmed CrossRef
  44. Yaoita F, Muto M, Murakami H, et al. Involvement of peripheral alpha2A adrenoceptor in the acceleration of gastrointestinal transit and abdominal visceral pain induced by intermittent deprivation of REM sleep. Physiol Behav 2018;186:52-61.
    Pubmed CrossRef
  45. Yamasaki T, Quan SF, Fass R. The effect of sleep deficiency on esophageal acid exposure of healthy controls and patients with gastroesophageal reflux disease. Neurogastroenterol Motil 2019;31:e13705.
    Pubmed CrossRef
  46. El-Serag H, Becher A, Jones R. Systematic review: persistent reflux symptoms on proton pump inhibitor therapy in primary care and community studies. Aliment Pharmacol Ther 2010;32:720-737.
    Pubmed CrossRef
  47. Delshad SD, Almario CV, Chey WD, Spiegel BMR. Prevalence of gastroesophageal reflux disease and proton pump inhibitor-refractory symptoms. Gastroenterology 2020;158:1250-1261, e2.
    Pubmed KoreaMed CrossRef
  48. Dickman R, Boaz M, Aizic S, Beniashvili Z, Fass R, Niv Y. Comparison of clinical characteristics of patients with gastroesophageal reflux disease who failed proton pump inhibitor therapy versus those who fully responded. J Neurogastroenterol Motil 2011;17:387-394.
    Pubmed KoreaMed CrossRef
  49. Kahrilas PJ, Keefer L, Pandolfino JE. Patients with refractory reflux symptoms: what do they have and how should they be managed? Neurogastroenterol Motil 2015;27:1195-1201.
    Pubmed KoreaMed CrossRef
  50. Drossman DA. Functional gastrointestinal disorders: history, pathophysiology, clinical features and rome IV. Gastroenterology 2016;150:1262-1279, e2.
    Pubmed CrossRef
  51. Oridate N, Takeda H, Asaka M, et al. Acid-suppression therapy offers varied laryngopharyngeal and esophageal symptom relief in laryngopharyngeal reflux patients. Dig Dis Sci 2008;53:2033-2038.
    Pubmed CrossRef
  52. Yadlapati R, Kaizer AM, Sikavi DR, et al. Distinct clinical physiologic phenotypes of patients with laryngeal symptoms referred for reflux evaluation. Clin Gastroenterol Hepatol 2021;20:776-786, e1.
    Pubmed KoreaMed CrossRef
  53. Carroll TL, Werner A, Nahikian K, Dezube A, Roth DF. Rethinking the laryngopharyngeal reflux treatment algorithm: evaluating an alternate empiric dosing regimen and considering up-front, pH-impedance, and manometry testing to minimize cost in treating suspect laryngopharyngeal reflux disease. Laryngoscope 2017;127(suppl 6):S1-S13.
    Pubmed CrossRef
  54. Dong R, Xu X, Yu L, et al. Randomised clinical trial: gabapentin vs baclofen in the treatment of suspected refractory gastro-oesophageal reflux-induced chronic cough. Aliment Pharmacol Ther 2019;49:714-722.
    Pubmed CrossRef
  55. Lechien JR, Bobin F, Dapri G, et al. Hypopharyngeal-esophageal impedance-pH monitoring profiles of laryngopharyngeal reflux patients. The Laryngoscope 2021;131:268-276.
    Pubmed CrossRef
  56. Katz PO. Gastroesophageal reflux disease and extraesophageal disease. Rev Gastroenterol Disord 2005;5:S31-S38.

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Aims and Scope