J Neurogastroenterol Motil 2023; 29(2): 174-182  https://doi.org/10.5056/jnm22049
Distal Mean Nocturnal Baseline Impedance Predicts Pathological Reflux of Isolated Laryngopharyngeal Reflux Symptoms
Hua-Nong Luo,1 Chen-Chi Wang,2,3,4 Ying-Cheng Lin,1 Chun-Yi Chuang,5,6 Yung-An Tsou,7 Ja-Chih Fu,8 Sheng-Shun Yang,1,6,9 Chi-Sen Chang,1,6 and Han-Chung Lien1,3,10*
1Division of Gastroenterology, Taichung Veterans General Hospital, Taichung, Taiwan; 2Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan; 3School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 4School of Speech Language Pathology and Audiology, Chung Shan Medical University, Taichung, Taiwan; 5Department of Otolaryngology, Chung Shan Medical University Hospital, Taichung, Taiwan; 6School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 7Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung, Taiwan; 8Computer Aided Measurement and Diagnostic Systems Laboratory, Department of Industrial Engineering and Management, National Yunlin University of Science and Technology, Yunlin, Taiwan; 9Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; and 10Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
Correspondence to: *Han-Chung Lien, MD, PhD
Division of Gastroenterology, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung 40705, Taiwan
Tel: +886-4-23592525 (ext. 3315), Fax: +886-4-23741331, E-mail: lhc@vghtc.gov.tw
Received: March 25, 2022; Accepted: August 6, 2022; Published online: April 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.
Abstract
Background/Aims
Diagnosis of isolated laryngopharyngeal reflux symptoms (ILPRS), ie, without concomitant typical reflux symptoms (CTRS), remains difficult. Mean nocturnal baseline impedance (MNBI) reflects impaired mucosal integrity. We determined whether esophageal MNBI could predict pathological esophagopharyngeal reflux (pH+) in patients with ILPRS.
Methods
In this cross-sectional study conducted in Taiwan, non-erosive or low-grade esophagitis patients with predominant laryngopharyngeal reflux symptoms underwent combined hypopharyngeal multichannel intraluminal impedance-pH monitoring when off acid suppressants. Participants were divided into the ILPRS (n = 94) and CTRS (n = 63) groups. Asymptomatic subjects without esophagitis (n = 25) served as healthy controls. The MNBI values at 3 cm and 5 cm above the lower esophageal sphincter (LES) and the proximal esophagus were measured.
Results
Distal but not proximal esophageal median MNBI values were significantly lower in patients with pH+ than in those with pH– (ILPRS in pH+ vs pH–: 1607 Ω vs 2709 Ω and 1885 Ω vs 2563 Ω at 3 cm and 5 cm above LES, respectively; CTRS in pH+ vs pH–: 1476 vs 2307 Ω and 1500 vs 2301 Ω at 3 cm and 5 cm above LES, respectively, P < 0.05 for all). No significant differences of any MNBI exist between any pH– subgroups and healthy controls. The areas under the receiver operating characteristic curve in the ILPRS group were 0.75 and 0.80, compared to the pH– subgroup and healthy controls (P < 0.001 for both), respectively. Interobserver reproducibility was good (Spearman correlation 0.93, P < 0.0001).
Conclusion
Distal esophageal MNBI predicts pathological reflux in patients with ILPRS.
Keywords: Diagnosis; Esophageal pH monitoring; Gastroesophageal reflux; Laryngopharyngeal reflux
Introduction

Laryngopharynx reflux (LPR) is an extraesophageal manifestation of gastroesophageal reflux disease (GERD), involving excessive backflow of gastric content into the laryngopharynx.1 Diagnosis of LPR is challenging, particularly for those with isolated LPR symptoms (ILRPS), ie, without concomitant typical reflux symptoms (CTRS), due to protean and non-specific laryngeal symptoms/signs2 and normal esophageal mucosa in the majority of patients.3

Reflux theory (direct damage of laryngeal mucosal surface by refluxate exposure) and reflex theory (indirect vagal reflex arc between the esophagus and airway triggered by acid reflux) have been proposed as mechanisms of LPR symptom generation.4 However, little is known about the mechanism of absent esophageal symptoms and physiological characteristics in patients with ILPRS. Recently, Lien et al5 used 24-hour combined hypopharyngeal multichannel intraluminal impedance-pH (HMII-pH) to define pathological esophagopharyngeal reflux, ie, excessive acid exposure time in the distal esophagus, and/or pharyngeal acid reflux episodes ≥ 2/day. They found that both ILPRS and CTRS groups (63% and 57%) with pathological esophagopharyngeal reflux responded equally well to proton pump inhibitors (PPIs) therapy, compared to the non-refluxers (32%).5 In addition, patients with ILPRS were less likely to respond to the esophageal acid perfusion test, and had fewer pharyngeal pathological reflux episodes compared to its counterpart. These findings imply that the generation of symptoms in patients with ILPRS may involve a vago-vagal-mediated “reflex” or central sensitization, rather than “reflux” mechanism.6 In the recent America Collage of Gastroenterology guidelines for GERD, up-front reflux monitoring is recommended in patients with ILPRS before PPIs therapy.7 Given the absence of concomitant esophageal symptoms, obtaining evidence of reflux in this challenging subset of patients is of paramount importance in the clinical setting.1

Mean nocturnal baseline impedance (MNBI) is an impedance-pH metric assessing impaired mucosal integrity of the esophagus owing to chronic reflux, and has been proposed to segregate GERD patients from healthy controls.8 Low MNBI (< 2292 Ω) in the distal esophagus predicts the response to anti-reflux therapy and is also considered to be an adjunctive diagnosis of GERD according to the Lyon Consensus.9 In contrast, data on MNBI in patients with LPR are limited. Kavitt et al10 conducted a case-control study to measure mucosal impedance (MI) in patients with LPR symptoms during endoscopy. They found that patients with pathological reflux in the distal esophagus detected by wireless pH monitoring have a lower MI than those without.10 However, data in patients with ILPRS remain unknown, and the diagnostic ability of MI, including sensitivity and specificity, was not evaluated in that study.

In this study, we hypothesized that distal esophageal MNBI values in non-erosive or low-grade esophagitis patients with ILPRS may predict pathological esophagopharyngeal reflux. Based on the 2 distinct phenotypes, ie, CTRS and ILPRS, we compared MNBI values in both distal and proximal esophagus between patients with and without pathological esophagopharyngeal reflux. We also evaluated the diagnostic ability of MNBI and determined the best cutoff values for separating patients with pathological reflux from those with physiological reflux and from healthy controls.

Materials and Methods

This was prospective multicenter cohort study evaluating referral patients with LPR symptoms. The Institutional Review Board of Taichung Veterans General Hospital approved the protocol (#CF16150B) in accordance with the Declaration of Helsinki and Good Clinical Practice. All participants signed an informed consent form prior to undergoing the investigations.

Patient Population

Patients with suspected LPR symptoms referred from otolaryngologic outpatient clinics in tertiary medical centers were prospectively enrolled during the period from June 2016 to June 2019.

Patients (aged > 20 years) with a chief complaint of chronic laryngitis symptoms for more than 3 months, such as hoarseness, cough, throat clearing, or globus (at least moderate severity) were evaluated for eligibility, which included comprehensive history taking, laryngoscopic signs based on the Reflux Finding Score,11 and an upper gastrointestinal endoscopy. Participants also filled out a LPR-specific questionnaire, the Chinese version Reflux Symptoms Index to evaluate the symptom severity.12,13

Participants were excluded if there was any evidence of the following conditions: severe esophagitis (Los Angeles classification Grade C or D), Barrett’s esophagus, or any common non-reflux etiologies of chronic laryngitis, as stated previously.5 Healthy subjects recruited from flyers served as controls. To obtain the norms of MNBI, patients were excluded from the study if they had airway or reflux symptoms, were taking acid suppressive therapy, had any grade esophagitis or endoscopic suspected esophageal metaplasia, or had evidence of pathological reflux on the HMII-pH test.

Study Design

Eligible participants underwent 24-hour combined hypopharyngeal multichannel intraluminal impedance-pH (HMII-pH) monitoring. The catheter was composed of 2 pH sensors (hypopharynx and distal esophagus) and 6 pairs of impedance electrodes (catheter models ZAI-BL-54, -55, and -56; Sandhill Scientific, Highlands Ranch, CO, USA). We selected catheters according to subjects’ esophageal length. The proximal pH probe was positioned 1 cm above the proximal margin of the upper esophageal sphincter (UES) and the distal pH probe was placed at 5 cm (± 1 cm) above the proximal margin of the lower esophageal sphincter (LES), determined by high resolution manometry (SOLAR GI HRIM, MMS, Enschede, Netherlands). There were 6 impedance pairs, with 2 located at the hypopharynx, 2 at the proximal esophagus (2 ± 1 cm and 4 ± 1 cm below the UES), and 2 at the distal esophagus (3 ± 1 cm and 5 ± 1 cm above LES), respectively. Participants recorded their meals, supine or upright position, and symptom events throughout the period of data acquisition while off PPI for at least 7 days. After recording, the impedance pH data were uploaded and analyzed using Bioview Analysis software (Sandhill Scientific, Highlands Ranch, CO), which calculated acid exposure time (AET%) in the distal esophagus automatically.

Measurements and Data Analysis

Pathological esophagopharyngeal acidic reflux, or pH (+) was defined as: 1) ≥ 2 pharyngeal acid reflux episodes; and/or 2) excessive distal esophageal acid reflux, ie, the percent time with pH < 4 at 5 cm above the LES (total > 4.2%, or upright > 6.3%, or supine > 1.2%) during the 24-hour recording period.5,14 Patients with suspected LPR were divided into 2 groups based on the presence or absence of concomitant typical reflux symptoms, ie, CTRS or ILPRS, respectively. CTRS was defined as the presence of heartburn or regurgitation at least twice per week with mild symptoms, or once per week with moderate to severe symptoms. Each group was further divided into pH (+) and pH (–) groups.

MNBI values were determined by averaging 3 nocturnal 10-minute periods (at 1:00 AM, 2:00 AM, and 3:00 AM) selected to avoid events such as reflux, swallows, and pH drops during the recumbent period, at 3 impedance electrodes (3 ± 1 cm and 5 ± 1 cm above LES and 4 ± 1 cm below the UES, or proximal esophagus).15 Two independent observers read the tracings manually to assess interobserver agreement of MNBI values.

Statistical Methods

Demographic data, clinical presentations, and impedance-pH values were compared between the pH (+) and pH (–) groups in both CTRS and ILPRS patients. Categorical variables were compared using Pearson chi-square tests. Continuous variables were compared using Kruskal-Wallis tests. P-value < 0.05 was considered significant. We also conducted receiver operating characteristic (ROC) analysis and calculated the area under the curve (AUC) for pairwise comparisons and evaluation of the diagnostic performance of MNBI for the prediction of pH (+). The sensitivity and specificity were calculated with best cutoff points of the MNBI normal threshold based on the maximal Youden index. Interobserver agreement of the MNBI readings and correlation between MNBI and AET% were evaluated by Spearman rank correlation test.

To determine the appropriate sample size, we used a conservative estimate of standard deviation of 1513 Ω,16 and assumed a difference of 1300 Ω and 1100 Ω in impedance values between pH (+) and pH (–) for the CTRS and ILPRS groups, respectively. Based on this model, 57 and 81 subjects with a pH (–) to pH (+) ratio of 2:1 in each corresponding groups may provide 80% power with a significant level of 0.025. (https://clincalc.com/Stats/SampleSize.aspx).

Results

Baseline Characteristics

A total of 157 subjects with suspected LPR completed impedance-pH tests, including 63 and 94 subjects in the CTRS and ILPRS group, respectively (Fig. 1). Among them, 23 (36%) and 31 (33%) subjects in the corresponding groups had pathologic reflux. Twenty-five healthy subjects were included in the control group.

Figure 1. Flow chart of study population. CTRS, concomitant typical reflux syndrome; ILPRS, isolated laryngopharyngeal reflux symptoms; COPD, chronic obstructive pulmonary disease.

The baseline characteristics are shown in Table 1. There was no significant differences in age, gender, or ENT first visit (consulting otolaryngologists first for their primary laryngeal symptoms) between the pH (+) and pH (–) groups in both CTRS and ILPRS groups. The healthy controls were slightly younger than those in the CTRS and ILPRS groups. In the CTRS group but not the ILPRS group, patients with pH (+) had higher body mass index than those with pH (–) (P < 0.05). Other clinical features including endoscopic findings, major laryngeal symptoms, symptom durations, comorbidities, and rates of previous use of suppressive agents were similar between the pH (+) and pH (–) groups in both CTRS and ILPRS patients.

Table 1 . Demographic Data and Clinical Features of the Study Population

Demographic and clinical featuresCTRSaILPRSbHealthy controls
(n = 25)
pH (+)c
(n = 23)
pH (–)
(n = 40)
pH (+)c
(n = 31)
pH (–)
(n = 63)
Demography
Age (yr)57 (48, 63)53 (47, 61)56 (49, 62)56 (48, 64)40 (34, 56)g,h,i
Male gender12/23 (52.1)13/40 (32.5)22/31 (70.9)40/63 (63.4)6/25 (24.0)h,i
BMI (kg/m2)25.9 (24.4, 27)j22.6 (21.4, 24.6)24 (20.5, 25.7)23.1 (21.6, 24.8)22.2 (20.8, 23.2)g
ENT first visit17/23 (73.9)28/40 (70.0)28/31 (90.3)57/63 (90.4)-
Clinical presentations
Major laryngeal symptom
Globus sensation5/23 (21.7)11/40 (27.5)6/31 (19.3)15/63 (23.8)-
Throat pain8/23 (34.7)11/40 (27.5)7/31 (22.5)13/63 (20.6)-
Hoarseness5/23 (21.7)11/40 (27.5)10/31 (32.2)22/63 (34.9)-
Cough3/23 (13.0)6/40 (15.0)6/31 (19.3)9/63 (14.2)-
Throat clearing2/23 (8.7)1/40 (2.5)2/31 (6.5)4/63 (6.3)-
Typical GERD symptoms23/23 (100.0)40/40 (100.0)0/31 (0.0)0/63 (0.0)-
Symptom duration, month24 (12, 54)24 (12, 42)18 (6, 36)12 (6, 36)-
Previous acid suppressive therapy use (%)18/23 (78.2)34/40 (85)14/31 (45.1)33/63 (52.3)-
Anti-reflux medication response4/18 (22.2)12/33 (36.3)6/14 (42.8)10/31 (32.2)-
Diabetes mellitus1/23 (4.3)1/40 (2.5)1/31 (3.2)3/63 (4.8)0/25 (0.0)
Hypertension5/18 (27.7)7/40 (17.5)5/31 (16.1)13/63 (20.6)1/25 (4.0)
Endoscopic findings
Erosion esophagitis
No esophagitis3/23 (13.0)10/40 (25.0)4/31 (12.9)10/63 (15.8)25/25 (100.0)
Esophagitis grade A18/23 (78.2)25/40 (62.5)23/31 (74.1)49/63 (77.7)0/25 (0.0)
Esophagitis grade B2/23 (8.7)5/40 (12.5)4/31 (12.9)4/63 (6.3)0/25 (0.0)
Hiatus hernia1/23 (4.3)2/40 (5.0)2/31 (6.5)3/63 (4.8)0/25 (0.0)
Peptic ulcer2/23 (8.7)4/40 (10.0)3/31 (9.7)9/63 (14.2)3/25 (12.0)
Helicobacter pylori6/19 (31.5)7/36 (19.4)7/28 (25.0)12/56 (21.4)7/24 (29.1)
Reflux Finding Scored8 (5, 11)6 (4, 9)7 (3, 9)7 (5, 10)-
Patient report outcome
Reflux Symptom Index total scoree19 (14, 23)18 (11, 23)13 (8, 18)11 (6, 16)0 (0, 2)
Heartburn, frequencyf3 (2, 5)3 (1, 4)0 (0, 2)0 (0, 1)-
Heartburn, severityf3 (2, 3)2 (0, 3)0 (0, 2)0 (0, 1)-
Acid regurgitation, frequencyf3 (2, 4)3 (3, 4)1 (0, 3)j0 (0, 1)-
Acid regurgitation, severityf3 (2, 3)3 (2, 4)1 (0, 2)j0 (0, 1)-

aConcomitant typical reflux syndrome (CTRS) is defined as regurgitation or heartburn at least twice a week with mild symptom, or once a week with moderate/severe symptom.

bIsolated laryngopharyngeal reflux symptoms (ILPRS) is defined as patients with laryngopharynx reflux (LPR) without CTRS.

cpH (+), pathological esophagopharyngeal reflux, is defined as the presence of (1) excessive pharyngeal acid reflux (PAR), ie, ≥ 2 episodes of PAR; and/or (2) excessive distal esophageal acid reflux, ie, ≥ 4.2% of 24-hr, or ≥ 6.3% of upright position, or ≥ 1.2% of supine position.

dScore range from 0 to 26, with higher scores suggesting more severe laryngitis.

eScore range from 0 to 45, with higher scores indicating more severe symptoms.

fScore range from 0 to 5 for symptom frequency or severity, with higher scores suggesting worse quality of life.

gP < 0.05 for CTRS pH (+) vs healthy controls.

hP < 0.05 for ILPRS pH (+) vs healthy controls.

iP < 0.05 for ILPRS pH (–) vs healthy controls.

jP < 0.05 for pH (+) vs pH (–).

BMI, body mass index; ENT, ear, nose, and throat.

Pearson χ2 tests were used for dichotomous variables, whereas Mann–Whitney U tests were used for continuous variables.

Data are expressed as median (interquartile range) or n (%).



Mean Nocturnal Baseline Impedance

In the CTRS group, median (interquartile range) MNBI values at 3 cm above LES were significantly lower in those with pH (+) (1476 Ω; 920-1848 Ω) than in those with pH (–) (2307 Ω; 1920-2894 Ω, P < 0.001) and healthy controls (2639 Ω; 2342-2846 Ω, P < 0.0001). A similar trend was found at 5 cm above LES (Fig. 2 and Table 2). In the ILPRS group, significant differences, though to a lesser extent, were also found at 3 cm and 5 cm above LES between pH (+) and pH (–). In contrast, there were no differences among groups at the proximal esophagus. There were also no differences in the MNBI values at 3 cm and 5 cm between healthy controls and participants with pH (–) in both CTRS and ILPRS groups. The MNBI values at 3 cm above LES negatively correlated with AET% (r = –0.55, P < 0.0001 and –0.41, P < 0.0001 in the CTRS and ILPRS groups, respectively). The Spearman rank correlation coefficient for interobserver agreement of MNBI values at 3 cm above LES was 0.93 (P < 0.0001).

Table 2 . Comparison of Acid Exposure Time, Acidic Reflux Episodes, and Mean Nocturnal Baseline Impedance Values of 24-Hour pH-impedance Between Patients With and Without Pathological Esophagopharyngeal Reflux in the Concomitant Typical Reflux Syndrome, Isolated Laryngopharyngeal Reflux Symptoms Groups, and Healthy Controls

Reflux parametersCTRSaILPRSbHealthy controls
(n = 25)
pH (+)c
(n = 23)
pH (–)
(n = 40)
pH (+)c
(n = 31)
pH (–)
(n = 63)
24-hr pH test finding
Distal esophageal acid exposure (%)4.6 (2.3, 7.4)d0.7 (0.1, 1.3)4.6 (3.1, 9.2)d0.2 (0.1, 1)0.3 (0.1, 0.9)e,f
Excessive distal esophageal acid reflux19/23 (82.6)d0/40 (0)27/31 (87.0)d0/63 (0)0/25 (0.0)e,f
Pharyngeal acid reflux events1 (0, 6)d0 (0, 0)0 (0, 2)d0 (0, 0)0 (0, 0)e,f
Excessive pharyngeal acid reflux11/23 (47.8)d0/40 (0)8/31 (25.8)d0/63 (0)0/25 (0.0)e,f
Number of reflux events
Proximal esophagus
Acid reflux events14 (7, 24)d4 (1, 7)13 (6, 20)d2 (1, 5)7 (4, 10)e,f,g
Total events25 (15, 32)d10 (7, 18)23 (12, 31)d9 (5, 17)30 (20, 45)e,f
Distal esophagus
Acid reflux events25 (17, 36)d10 (4, 17)26 (15, 34)d8 (2, 16)2 (0, 3)e,f
Total events45 (31, 71)d32 (23, 43)50 (29, 54)d30 (17, 43)10 (7, 14)e,f
MNBI value
Proximal esophagus2730 (2205, 3213)2873 (2144, 3391)2835 (2113, 3565)2616 (2173, 3168)2885 (2481, 2972)
Distal esophagus
5 cm1500 (609, 2630)d2301 (1664, 3002)1885 (618, 2587)d2563 (1818, 3405)2690 (2183, 3032)e,f
3 cm1476 (920, 1848)d2307 (1920, 2894)1607 (1049, 2441)d2709 (1796, 3360)2639 (2342, 2846)e,f

aConcomitant typical reflux syndrome (CTRS) is defined as regurgitation or heartburn at least twice a week with mild symptom, or once a week with moderate/severe symptom.

bIsolated laryngopharyngeal reflux symptoms (ILPRS) is defined as patients with laryngopharynx reflux (LPR) without CTRS.

cpH (+), pathological esophagopharyngeal reflux, is defined as the presence of (1) excessive pharyngeal acid reflux (PAR), ie, ≥ 2 episodes of PAR; and/or (2) excessive distal esophageal acid reflux, ie, ≥ 4.2% of 24-hr, or ≥ 6.3% of upright position, or ≥ 1.2% of supine position.

dP < 0.05 for pH (+) vs pH (–).

eP < 0.05 for CTRS pH (+) vs healthy controls.

fP < 0.05 for ILPRS pH (+) vs healthy controls.

gP < 0.05 for CTRS pH (–) vs healthy controls.

Data are expressed as median (interquartile range) or n (%).


Figure 2. The median mean nocturnal baseline impedance (MNBI) measurements for the study groups at each of the measured sites (3 cm and 5 cm above the lower esophageal sphincter (LES) and proximal esophagus) in the concomitant typical reflux syndrome (CTRS) (Fig. 2A) and isolated laryngopharyngeal reflux symptoms (ILPRS) groups (Fig. 2B). MNBI values were lower in patients with pH (+) than those with pH (–) and healthy controls at 3 cm and 5 cm above LES in both the CTRS and ILPRS groups. However, MNBI values were similar over the proximal esophagus among all groups.

Diagnostic Efficacy of Mean Nocturnal Baseline Impedance

For the ILRPS group, ROC analysis revealed AUC of 0.75 and 0.80 when compared to the pH (–) group and healthy controls, respectively, for the diagnosis of pH (+). The sensitivity and specificity were respectively 0.65 and 0.71 when compared with the pH (–) group, and 0.65 and 0.88 when compared to healthy controls (Fig. 3 and Table 3).

Table 3 . Diagnostic Accuracy of Mean Nocturnal Baseline Impedance in Laryngopharyngeal Reflux Phenotypes

Comparison of MNBI between pH (+) and control groupsAUCCut-pointSensitivitySpecificityRelative risk (95% CI)
Patients pH (+) vs pH (–)
CTRSa + ILPRSb0.7720590.720.716.3 (3.0-13.1)
CTRSa0.8118640.780.7812.4 (3.6-42.8)
ILPRSb0.7520590.650.7115.0 (3.3-68.1)
Patients pH (+) vs healthy controls
CTRSa + ILPRSb0.8320650.720.8819.1 (5.0-73.2)
CTRSa0.8720380.830.8834.8 (6.9-175.6)
ILPRSb0.8020650.650.8813.3 (3.2-54.8)

aConcomitant typical reflux syndrome (CTRS) is defined as regurgitation or heartburn at least twice a week with mild symptom, or once a week with moderate/severe symptom.

bIsolated laryngopharyngeal reflux symptoms (ILPRS) is defined as patients with laryngopharynx reflux (LPR) without CTRS.

MNBI, Mean nocturnal baseline impedance; AUC, area under the ROC curve.

Best cutoff points for MNBI at 3 cm above the LES were based on maximal Youden index.


Figure 3. Receiver operating characteristic (ROC) curves in the concomitant typical reflux syndrome (CTRS) (A) and isolated laryngopharyngeal reflux symptoms (ILPRS) (B) groups. AUC, area under the curve.
Discussion

In this study, we prospectively assessed the feasibility of MNBI in the prediction of pathologic reflux or pH (+) in patients with suspected ILPRS and mild esophagitis or normal esophageal mucosa. To this purpose, the relationship of MNBI values and pH (+) in patients with the presence of CTRS and in healthy controls was also evaluated. We found that distal MNBI values were significantly lower in patients with pH (+) than those in patients with pH (–), for both ILPRS and CTRS groups. In addition, distal MNBI may also predict pH (+) in both groups. In contrast, proximal MNBI values were comparable among groups. There were no differences of MNBI between patients with pH (–) and healthy controls for both ILPRS and CTRS groups, regardless of proximal or distal esophagus.

In line with the findings of Kavitt et al,10 we found that distal MNBI differentiated patients with pH (+) from those with pH (–) or healthy controls.10 Similarly, in a large-scale (n = 239) retrospective cohort study, Ribolsi et al17 found that patients with suspected LPR and pathological MNBI (< 2292 Ω) in the distal esophagus may predict PPI-responsiveness with a sensitivity of 71% and a specificity of 57%.

When combined the CTRS and ILPRS groups, our study found a sensitivity of 72% in the prediction of pathological esophagopharyngeal reflux, and a specificity of 71% and 88% when comparing to patients with pH (–) and healthy controls, respectively (Table 3). When divided into the CTRS and ILPRS groups, substantial differences were observed in our study. In the CTRS group, there was an area under the ROC curve of 0.81-0.87 and a moderately negative correlation coefficient of –0.55 (P < 0.0001) with AET%, suggest a comparable diagnostic accuracy compared with patients with typical GERD in the literature.15,18 However, a relatively lower area under the ROC curve of 0.75-0.80 and a lower correlation coefficient of –0.41 (P < 0.0001) with AET% found in the ILPRS group, seem to indicate a lower diagnostic accuracy of MNBI compared to its counterpart. In addition, the median distal MNBI value tends to be higher in the ILPRS group than that in the CTRS group (1607 vs 1476, Table 2), suggesting a possible link of mucosal integrity to the symptom perception in the distal esophagus despite similar AET% between them.19 These results also support the recent findings that patients with ILPRS and pathological reflux are relatively insensitive to acid in the distal esophagus despite similar AET% and PPI-responsiveness to those with CTRS.5

One may postulate a lower MNBI value in the proximal esophagus in patients with LPR. In a large-scale retrospective observational study (n = 242), Chen et al20 compared MNBI values among 4 groups defined by symptoms, ie, CTRS, ILPRS, GERD only, and healthy controls. They found decreased MNBI values in the proximal esophagus in patients with CTRS compared to the other 3 groups, suggesting a possible diagnostic role of proximal esophageal mucosal integrity. However, in their ILPRS group, both AET% and distal MNBI values were similar to those in the healthy controls. Although the reasons are unclear, defining patients with ILPRS by symptom alone may include patients without objective evidence of pathological reflux.

The merit of our studies is 2-fold. First, using the HMII-pH catheters to diagnose pathological esophagopharyngeal reflux in this study may be more reliable than using traditional dual pH-metry, because the configuration of HMII-pH incorporated 2 trans-upper esophageal sphincter impedance channels to trace the refluxate along the entire esophagus to the hypopharynx for the detection of pharyngeal acid reflux episodes.21 Second, the criteria of pathological esophagopharyngeal reflux in this study comprised of acid (pH < 4) and part of weakly acid (pH between 4 and 5) reflux episodes and pathological AET% in the distal esophagus have been shown to predict PPI responsiveness in patients with ILPRS.5 One of the potential contributions of our study is to support the future implications for the newly developed esophageal balloon-incorporated MI test performed via direct mucosal contact during endoscopy particularly in patients with suspected ILPRS.22

There were some limitations in this study. First, our patients were all ethnic Chinese and only recruited from tertiary centers. Some of them have been prescribed PPIs for variable durations despite suspending the medications for more than 1 week prior to the HMII-pH test. Thus, the sensitivity and specificity may not be applicable to other ethnicities, primary care settings, or PPI-naive patients. Second, PPI responsiveness was not evaluated in our study, as the primary interest in this study was the objective evidence of GERD test in patients with ILPRS.

In conclusion, distal esophageal MNBI measurement is valuable in the prediction of pathological esophagopharyngeal reflux in patients with suspected LPR, in both the CTRS and ILPRS groups. The diagnostic ability of distal MNBI in the CTRS group seems to be superior to that seen in the ILPRS group, although further studies assessing associations of treatment outcomes to MNBI values are warranted.

Financial support

This work was funded by Taichung Veterans General Hospital, Taichung, Taiwan (TCVGH-1093304C). This funding agency played no role in the analysis of the data or the preparation of this manuscript.

Conflicts of interest

None.

Author contributions

Han-Chung Lien and Chen-Chi Wang conceived and designed the experiments; Hua-Nong Luo, Chen-Chi Wang, Ying-Cheng Lin, Chun-Yi Chuang, Yung-An Tsou, Sheng-Shun Yang, Chi-Sen Chang, and Han-Chung Lien performed the experiments; Hua-Nong Luo, Han-Chung Lien, and Ja-Chih Fu analyzed the data; and Hua-Nong Luo and Han-Chung Lien wrote the manuscript and approval of the final version.

References
  1. Koufman JA, Aviv JE, Casiano RR, Shaw GY. Laryngopharyngeal reflux: position statement of the committee on speech, voice, and swallowing disorders of the American academy of otolaryngology-head and neck surgery. Otolaryngol Head Neck Surg 2002;127:32-35.
    Pubmed CrossRef
  2. Vaezi MF. Gastroesophageal reflux-related chronic laryngitis: con. Arch Otolaryngol Head Neck Surg 2010;136:908-909.
    Pubmed CrossRef
  3. Fletcher KC, Goutte M, Slaughter JC, Garrett CG, Vaezi MF. Significance and degree of reflux in patients with primary extraesophageal symptoms. Laryngoscope 2011;121:2561-2565.
    Pubmed CrossRef
  4. Burton LK Jr, Murray JA, Thompson DM. Ear, nose, and throat manifestations of gastroesophageal reflux disease. Complaints can be telltale signs. Postgrad Med 2005;117:39-45.
    Pubmed CrossRef
  5. 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
  6. Smith JA, Decalmer S, Kelsall A, et al. Acoustic cough-reflux associations in chronic cough: potential triggers and mechanisms. Gastroenterology 2010;139:754-762.
    Pubmed CrossRef
  7. 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
  8. Patel A, Wang D, Sainani N, Sayuk GS, Gyawali CP. Distal mean nocturnal baseline impedance on pH-impedance monitoring predicts reflux burden and symptomatic outcome in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2016;44:890-898.
    Pubmed KoreaMed CrossRef
  9. Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the Lyon consensus. Gut 2018;67:1351-1362.
    Pubmed KoreaMed CrossRef
  10. Kavitt RT, Lal P, Saritas Yuksel E, et al. Esophageal mucosal impedance pattern is distinct in patients with extraesophageal reflux symptoms and pathologic acid reflux. J Voice 2017;31:347-351.
    Pubmed CrossRef
  11. Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope 2001;111:1313-1317.
    Pubmed CrossRef
  12. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of reflux symptom index (RSI). J Voice 2002;16:274-277.
    Pubmed CrossRef
  13. Lien HC, Wang CC, Lee SW, et al. Responder definition of a patient-reported outcome instrument for laryngopharyngeal reflux based on the US FDA guidance. Value Health 2015;18:396-403.
    Pubmed CrossRef
  14. Lien HC, Wang CC, Liang WM, et al. Composite pH predicts esomeprazole response in laryngopharyngeal reflux without typical reflux syndrome. Laryngoscope 2013;123:1483-1489.
    Pubmed CrossRef
  15. Martinucci I, de Bortoli N, Savarino E, et al. Esophageal baseline impedance levels in patients with pathophysiological characteristics of functional heartburn. Neurogastroenterol Motil 2014;26:546-555.
    Pubmed CrossRef
  16. Saritas Yuksel E, Higginbotham T, Slaughter JC, et al. Use of direct, endoscopic-guided measurements of mucosal impedance in diagnosis of gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2012;10:1110-1116.
    Pubmed CrossRef
  17. Ribolsi M, Guarino MPL, Tullio A, Cicala M. Post-reflux swallow-induced peristaltic wave index and mean nocturnal baseline impedance predict PPI response in GERD patients with extra esophageal symptoms. Dig Liver Dis 2020;52:173-177.
    Pubmed CrossRef
  18. Frazzoni M, Savarino E, de Bortoli N, et al. Analyses of the post-reflux swallow-induced peristaltic wave index and nocturnal baseline impedance parameters increase the diagnostic yield of impedance-pH monitoring of patients with reflux disease. Clin Gastroenterol Hepatol 2016;14:40-46.
    Pubmed CrossRef
  19. Woodland P, Al-Zinaty M, Yazaki E, Sifrim D. In vivo evaluation of acid induced changes in oesophageal mucosa integrity and sensitivity in non-erosive reflux disease. Gut 2013;62:1256-1261.
    Pubmed CrossRef
  20. Chen S, Liang M, Zhang M, et al. A study of proximal esophageal baseline impedance in identifying and predicting laryngopharyngeal reflux. J Gastroenterol Hepatol 2020;35:1509-1514.
    Pubmed CrossRef
  21. Hoppo T, Sanz AF, Nason KS, et al. How much pharyngeal exposure is "normal"? Normative data for laryngopharyngeal reflux events using hypopharyngeal multichannel intraluminal impedance (HMII). J Gastrointest Surg 2012;16:16-24; discussion 24-25.
    Pubmed KoreaMed CrossRef
  22. Patel DA, Higginbotham T, Slaughter JC, et al. Development and validation of a mucosal impedance contour analysis system to distinguish esophageal disorders. Gastroenterology 2019;156:1617-1626, e1.
    Pubmed KoreaMed CrossRef


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