
2023 Impact Factor
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.
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.
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.
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.
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.
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.
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).
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.
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 (–) (
Table 1 . Demographic Data and Clinical Features of the Study Population
Demographic and clinical features | CTRSa | ILPRSb | Healthy 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 gender | 12/23 (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)j | 22.6 (21.4, 24.6) | 24 (20.5, 25.7) | 23.1 (21.6, 24.8) | 22.2 (20.8, 23.2)g | |
ENT first visit | 17/23 (73.9) | 28/40 (70.0) | 28/31 (90.3) | 57/63 (90.4) | - | |
Clinical presentations | ||||||
Major laryngeal symptom | ||||||
Globus sensation | 5/23 (21.7) | 11/40 (27.5) | 6/31 (19.3) | 15/63 (23.8) | - | |
Throat pain | 8/23 (34.7) | 11/40 (27.5) | 7/31 (22.5) | 13/63 (20.6) | - | |
Hoarseness | 5/23 (21.7) | 11/40 (27.5) | 10/31 (32.2) | 22/63 (34.9) | - | |
Cough | 3/23 (13.0) | 6/40 (15.0) | 6/31 (19.3) | 9/63 (14.2) | - | |
Throat clearing | 2/23 (8.7) | 1/40 (2.5) | 2/31 (6.5) | 4/63 (6.3) | - | |
Typical GERD symptoms | 23/23 (100.0) | 40/40 (100.0) | 0/31 (0.0) | 0/63 (0.0) | - | |
Symptom duration, month | 24 (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 response | 4/18 (22.2) | 12/33 (36.3) | 6/14 (42.8) | 10/31 (32.2) | - | |
Diabetes mellitus | 1/23 (4.3) | 1/40 (2.5) | 1/31 (3.2) | 3/63 (4.8) | 0/25 (0.0) | |
Hypertension | 5/18 (27.7) | 7/40 (17.5) | 5/31 (16.1) | 13/63 (20.6) | 1/25 (4.0) | |
Endoscopic findings | ||||||
Erosion esophagitis | ||||||
No esophagitis | 3/23 (13.0) | 10/40 (25.0) | 4/31 (12.9) | 10/63 (15.8) | 25/25 (100.0) | |
Esophagitis grade A | 18/23 (78.2) | 25/40 (62.5) | 23/31 (74.1) | 49/63 (77.7) | 0/25 (0.0) | |
Esophagitis grade B | 2/23 (8.7) | 5/40 (12.5) | 4/31 (12.9) | 4/63 (6.3) | 0/25 (0.0) | |
Hiatus hernia | 1/23 (4.3) | 2/40 (5.0) | 2/31 (6.5) | 3/63 (4.8) | 0/25 (0.0) | |
Peptic ulcer | 2/23 (8.7) | 4/40 (10.0) | 3/31 (9.7) | 9/63 (14.2) | 3/25 (12.0) | |
6/19 (31.5) | 7/36 (19.4) | 7/28 (25.0) | 12/56 (21.4) | 7/24 (29.1) | ||
Reflux Finding Scored | 8 (5, 11) | 6 (4, 9) | 7 (3, 9) | 7 (5, 10) | - | |
Patient report outcome | ||||||
Reflux Symptom Index total scoree | 19 (14, 23) | 18 (11, 23) | 13 (8, 18) | 11 (6, 16) | 0 (0, 2) | |
Heartburn, frequencyf | 3 (2, 5) | 3 (1, 4) | 0 (0, 2) | 0 (0, 1) | - | |
Heartburn, severityf | 3 (2, 3) | 2 (0, 3) | 0 (0, 2) | 0 (0, 1) | - | |
Acid regurgitation, frequencyf | 3 (2, 4) | 3 (3, 4) | 1 (0, 3)j | 0 (0, 1) | - | |
Acid regurgitation, severityf | 3 (2, 3) | 3 (2, 4) | 1 (0, 2)j | 0 (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.
g
h
i
j
BMI, body mass index; ENT, ear, nose, and throat.
Pearson χ2 tests were used for dichotomous variables, whereas Mann–Whitney
Data are expressed as median (interquartile range) or n (%).
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,
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 parameters | CTRSa | ILPRSb | Healthy 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)d | 0.7 (0.1, 1.3) | 4.6 (3.1, 9.2)d | 0.2 (0.1, 1) | 0.3 (0.1, 0.9)e,f | |
Excessive distal esophageal acid reflux | 19/23 (82.6)d | 0/40 (0) | 27/31 (87.0)d | 0/63 (0) | 0/25 (0.0)e,f | |
Pharyngeal acid reflux events | 1 (0, 6)d | 0 (0, 0) | 0 (0, 2)d | 0 (0, 0) | 0 (0, 0)e,f | |
Excessive pharyngeal acid reflux | 11/23 (47.8)d | 0/40 (0) | 8/31 (25.8)d | 0/63 (0) | 0/25 (0.0)e,f | |
Number of reflux events | ||||||
Proximal esophagus | ||||||
Acid reflux events | 14 (7, 24)d | 4 (1, 7) | 13 (6, 20)d | 2 (1, 5) | 7 (4, 10)e,f,g | |
Total events | 25 (15, 32)d | 10 (7, 18) | 23 (12, 31)d | 9 (5, 17) | 30 (20, 45)e,f | |
Distal esophagus | ||||||
Acid reflux events | 25 (17, 36)d | 10 (4, 17) | 26 (15, 34)d | 8 (2, 16) | 2 (0, 3)e,f | |
Total events | 45 (31, 71)d | 32 (23, 43) | 50 (29, 54)d | 30 (17, 43) | 10 (7, 14)e,f | |
MNBI value | ||||||
Proximal esophagus | 2730 (2205, 3213) | 2873 (2144, 3391) | 2835 (2113, 3565) | 2616 (2173, 3168) | 2885 (2481, 2972) | |
Distal esophagus | ||||||
5 cm | 1500 (609, 2630)d | 2301 (1664, 3002) | 1885 (618, 2587)d | 2563 (1818, 3405) | 2690 (2183, 3032)e,f | |
3 cm | 1476 (920, 1848)d | 2307 (1920, 2894) | 1607 (1049, 2441)d | 2709 (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.
d
e
f
g
Data are expressed as median (interquartile range) or n (%).
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 groups | AUC | Cut-point | Sensitivity | Specificity | Relative risk (95% CI) |
---|---|---|---|---|---|
Patients pH (+) vs pH (–) | |||||
CTRSa + ILPRSb | 0.77 | 2059 | 0.72 | 0.71 | 6.3 (3.0-13.1) |
CTRSa | 0.81 | 1864 | 0.78 | 0.78 | 12.4 (3.6-42.8) |
ILPRSb | 0.75 | 2059 | 0.65 | 0.71 | 15.0 (3.3-68.1) |
Patients pH (+) vs healthy controls | |||||
CTRSa + ILPRSb | 0.83 | 2065 | 0.72 | 0.88 | 19.1 (5.0-73.2) |
CTRSa | 0.87 | 2038 | 0.83 | 0.88 | 34.8 (6.9-175.6) |
ILPRSb | 0.80 | 2065 | 0.65 | 0.88 | 13.3 (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.
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 (
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.
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.
None.
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.