Normative Ambulatory Reflux Monitoring Metrics for Laryngopharyngeal Reflux: A Systematic Review of 720 Healthy Individuals

Abstract

Objectives

To review the normative data for acid, weakly acid, and nonacid proximal esophageal (PRE) and hypopharyngeal reflux (HRE) events in diagnosing laryngopharyngeal reflux (LPR) using ambulatory reflux monitoring.

Data Sources

PubMed, Cochrane Library, and Scopus.

Review Methods

A literature search was conducted about the normative data for PRE and HRE on multichannel intraluminal impedance–pH monitoring (MII-pH), hypopharyngeal-esophageal MII-pH (HEMII-pH), or oropharyngeal pH monitoring using PICOTS (population, intervention, comparison, outcome, timing, and setting) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statements. Outcomes reviewed included device characteristics, impedance/pH sensor placements, study duration, number/average and percentiles of PRE or HRE occurrence, and the event characteristics (pH, composition, and position).

Results

Of 154 identified studies, 18 met criteria for analysis, including 720 healthy individuals. HEMII-pH, MII-pH, and oropharyngeal pH monitoring were used in 7, 6, and 5 studies, respectively. The definition and inclusion/exclusion criteria of healthy individuals varied substantially across studies, with 6 studies considering only digestive symptoms to exclude potential LPR patients. Substantial heterogeneity across studies was noted, including impedance/pH sensor placements/configurations and definitions of composition (liquid, gas, mixed) and type (acid, weakly acid, nonacid) of PRE/HRE. The 95th percentile thresholds were 10 to 73 events for PRE, 0 to 10 events for HRE on HEMII-pH, and 40 to 128 for events with pH <6.0 on oropharyngeal pH monitoring. Most HREs were nonacid and occurred upright. The mean HRE among healthy individuals was 1.

Conclusion

The low number of studies and the heterogeneity in inclusion criteria, definitions, and characterization of PRE and HRE limit the establishment of consensual normative criteria for LPR on ambulatory reflux monitoring. Future large multicenter studies are needed.

Keywords

reflux laryngopharyngeal gastroesophageal normative threshold impedance pH monitoring metry

Laryngopharyngeal reflux (LPR) is an inflammatory condition of the upper aerodigestive tract tissues related to direct and indirect effect of gastroduodenal content reflux, which induces morphological changes in the upper aerodigestive tract.¹ LPR-related symptoms are found in 10% to 30% of outpatients consulting in the otolaryngology department^2,3 and up to 50% of patients with dysphonia.⁴ Symptoms and signs associated with LPR are nonspecific and may be encountered in many other otolaryngological conditions, including primary voice disorders, chronic rhinosinusitis, allergy, or chronic laryngopharyngitis due to tobacco or alcohol.^1,5,6 The poor specificity of both symptoms and laryngoscopic findings for LPR highlights the important role of objective reflux assessments in the diagnosis of LPR, such as ambulatory reflux monitoring. Over the years, several types of ambulatory reflux monitoring modalities have been developed for the diagnosis of gastroesophageal reflux, including pH testing and multichannel intraluminal impedance (MII) measurements, as well as devices that allow analyses at various anatomic locations. Of these, the combined hypopharyngeal-esophageal MII–pH monitoring (HEMII-pH) and oropharyngeal pH study (Restech) were 2 technologies specifically designed for the diagnosis of LPR.¹ Although these approaches are recognized as the primary ways to objectively measure LPR and support the diagnosis, there are, to date, no consensus criteria regarding the thresholds of esophago-hypopharyngeal reflux episodes to define LPR.

Given the significant heterogeneity in technologies used, study protocols employed, and cohort inclusion and exclusion criteria, we hypothesized that a universal, gold-standard normative value for LPR across diagnostic modalities may be elusive under the currently available data in the literature. However, a careful analysis of the aggregate data to date would allow better insight into the current understanding of LPR diagnostic challenges and future research needs. The aim of this study was to systematically review the current literature regarding the normative ambulatory reflux monitoring data for LPR events using HEMII-pH, MII-pH, and oropharyngeal pH study.

Materials and Methods

Search Strategy

Three independent authors (J.R.L., F.B., C.M.C.-E.) conducted an electronic search using PubMed, Cochrane Library, and Scopus to identify studies investigating the normative data for LPR events on ambulatory reflux monitoring. The following search terms were used as both keywords and medical subject heading terms, where applicable: reflux, laryngitis, laryngopharyngeal, gastroesophageal, silent reflux, pH study, impedance, monitoring, normative, healthy, criteria, diagnosis, and data. Studies were considered if they had database abstracts, available full texts, or titles containing the search terms. Results of the search strategy were reviewed for relevance, and the reference lists of these articles were examined for additional pertinent studies.

Study Selection and Data Synthesis

The criteria for consideration of study inclusion for the systematic review were based on the population, intervention, comparison, outcome, timing, and setting (PICOTS) framework.⁷ The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for systematic reviews.⁸ For each included study, 2 authors independently reviewed and extracted the data. Any discrepancies in synthesized data were discussed and resolved by the remaining coauthors.

Types of studies

Studies were included if they investigated the ambulatory reflux monitoring findings in healthy, asymptomatic adults with no LPR or esophageal symptoms, through retrospective or prospective, controlled or uncontrolled studies. All studies evaluating these approaches were included in the review: HEMII-pH, MII-pH, and oropharyngeal pH study (Restech). The studies had to be published in English or French peer-reviewed journals. Only studies reporting data for more than 10 individuals were considered.

Populations, inclusion/exclusion criteria

Eligible studies should include healthy adults without symptoms and signs of LPR. Studies were only included if the authors clearly provided the inclusion and exclusion criteria used. Controlled, comparative studies were eligible as long as the study cohorts contained an arm of healthy, asymptomatic individuals. Studies investigating normative data for gastroesophageal reflux disease (GERD) without proximal esophageal/hypopharyngeal findings were not considered.

Among controlled studies, the criteria for LPR diagnosis were analyzed. Patients with esophago-hypopharyngeal reflux episodes detected by HEMII-pH, MII-pH, or oropharyngeal pH study were considered LPR patients. Patients with reflux esophagitis or positive DeMeester score and increased reflux burden, ambulatory reflux monitoring, but no hypopharyngeal reflux episodes were considered GERD, but not LPR, patients. Subjects with only a clinical diagnosis of LPR without objective testing were considered “suspected LPR patients.”

Outcomes

The following outcomes were reviewed: testing modality used (HEMII-pH, MII-pH, or oropharyngeal pH study); probe placement; placement and number of impedance segments and pH electrodes; definitions of proximal (PRE) or hypopharyngeal (HRE) reflux episodes and liquid, gas, or mixed events; definitions of acidic, weakly acidic, mixed, nonacidic, and variant reflux episodes; and time of recording. Moreover, the following characteristics of the included studies were also collected: number of subjects, age, sex, inclusion/exclusion criteria for healthy individuals, and, in controlled studies, potential LPR patients and the method/criteria used for the reflux diagnosis.

The Tool to Assess Risk of Bias in Cohort Studies developed by the Clarity Group and Evidence Partners was used by 2 authors (J.R.L. and C.M.C.-E.) for the bias/heterogeneity analyses of the included studies.⁹

Intervention and comparison

Because the objective of this systematic review is to analyze the normative data for LPR events, the included studies did not have to detail treatment approaches or response.

Timing and setting

As this was an analysis of normative data in healthy individuals, there were no criteria for specific stage or timing in the “disease process” of the study population.

Results

A total of 154 articles were identified and 18 studies met our inclusion criteria ( Figure 1 ).^10-26 MII-pH and HEMII-pH were used in 13 studies ( Table 1 )^{10-12,14-17,19-23} while oropharyngeal pH monitoring was used in 5 studies ( Table 2 ).^13,18,24-27 There were 16 prospective controlled (n = 6) or uncontrolled (n = 10) studies and 2 retrospective cohorts. Two studies were excluded due to patient overlap²⁸ and the inclusion of patients with nonerosive reflux disease as “healthy” controls.²⁹ A meta-analysis was found that specifically focused on normative criteria for acidic LPR using findings from dual- or triple-channel esophageal pH monitoring, without inclusion of impedance data.³⁰

Figure 1.

Flowchart. (HE)MII-pH, (hypopharyngeal-esophageal) multichannel intraluminal impedance pH monitoring.

Table 1.

Features of Included Studies Using Multichannel Intraluminal Impedance pH Monitoring.

First author	Design	EL	System	Sample features	Outcomes	Results	Main findings
Shay, 2004¹⁰	Prospective	C	24-h MII-pH (M = Sanhill)	N = 60 healthy subjects	PRE (md, 25-75-95th percentile)	8, 4-21-31	1. The median and 95th percentile of PREs were 8 and 31 in healthy individuals.
	Uncontrolled		pH probe level: 15 cm above LES	Sex: 30 M/30 F	Upright PRE	7, 4-19-29
			Probe placement: manometry	Age: 39 y	Recumbent PRE	0, 0-1-3	2. The majority of PREs occurred upright.
			IE: 6 esophageal	BMI: NA	Acid/weakly acid	5, 2-14-28/2, 1-5-12
			pH electrodes: 1 lower esophageal	Day diet: NA	Nonacid/superimposed acid	0, 0-0-1/0, 0-0-2
			Duration: 24 h
Zentilin, 2006¹¹	Prospective	C	24-h MII-pH (M = Sandhill)	N = 25 healthy subjects	PRE (md, 25-75-95th percentile) male/female	22, 6-41-70/10, 9-17-34	1. The mean and the 95th percentile of PREs occurring in proximal esophagus varied between males and females.
	Uncontrolled		pH probe level: 6 cm above LES	Sex: 13 M/12 F	% of distal events in PE
			Probe placement: manometry	Age: 29 y	Upright/supine ratio	94%	2. PREs were cleared very quickly in healthy subjects.
			IE: 6 esophageal	BMI: NA	Difference acid vs weakly acid	NS	3. Males had a higher number of PREs than females.
			pH electrodes: 1 esophageal	Day diet: specified	Proximal liquid events	Acid > weakly acid	4. The majority of PREs occurred upright.
			Duration: 23 h	Mediterranean diet
Xiao, 2009¹²	Prospective	C	24-h MII-pH (M = Sandhill)	N = 70 healthy subjects	PRE (md, 25-75-95th percentile)	8, 3-16-32	1. The 95th percentile of PREs in healthy individuals was 8.
	Uncontrolled		pH probe level: 5 cm above LES	Sex: 33 M/37 F	Acid	6, 1-11-27
			Probe placement: manometry	Age: 27 y	Weakly acid	2, 1-5-13	2. The majority of PREs were acid.
			IE: 8 esophageal	BMI: NA	Alkaline	0, 0-0-0	3. The majority of PREs occurred upright.
			pH electrodes: 1 esophageal	Day diet: normal	Upright PRE	8, 3-15-32
			Duration: 24 h		Recumbent PRE	0, 0-0-1
Wang, 2011¹⁴	Prospective	C	24-h MII-pH (M = Sanhill)	N = 37 healthy subjects	No. of subjects with ≥1 HRE	n = 6/37	1. PREs were acid (74.2%) or weakly acid (25.8%).
	Uncontrolled		pH probe level: 0.5 cm above UES	Sex: 17 M/20 F	Acid/nonacid HRE	12.5/87.5%	2. Mixed and liquid PREs accounted for 41% and 59% and occurred upright in 97.4% of cases.
			5 cm above LES	Age: 38 y (15.2)	PRE (md, 25-75-95th percentile)	6, 2-8-10
			Probe placement: manometry	BMI: 20.7 (2.0)	Acid/weakly acid/alkaline	1, 0-3-4/0, 0-0-0/3, 1-4-8	3. Of subjects, 16.2% had ≥1 HREs. HRE accounted for 0.5% of PREs.
			IE: 6 esophagus and 3 pharynx	Day diet: normal	Liquid/mixed	2, 1-3-5/0, 0-0-0
			pH electrodes: 1 esophagus and 1 pharynx		Upright/recumbent	6, 2-8-10/0, 0-0-1	4. HREs were associated with shorter bolus and acid clearance times. Bolus and acid exposures (%) became smaller.
			Duration: 24 h		HRE (md, 25-75-95th percentile)	0, 0-0-2
					Acid/weakly acid/alkaline	0, 0-0-0/0, 0-0-0/0, 0-0-2
					Liquid/mixed	0, 0-0-1/0, 0-0-0
					Upright/recumbent	0, 0-0-2/0, 0-0-0
Xiao, 2012 ¹⁵	Prospective	B	24-h MII-pH (M = Sanhill)	N = 20 healthy subjects	No. of subjects with ≥1 HRE	n = 7/20	1. Healthy individuals had not more than 1 HRE.
	Controlled		pH probe level: 0.5 cm above UES	Sex: 10 M/10 F	HRE (md, 25-75th percentile)	0, 0-1	2. Patients with obstructive apnea syndrome had more HREs than healthy subjects.
			5 cm above LES	Age: 39 y
			Probe placement: NA	BMI: 21.7
			IE: 6 esophagus and 2 pharynx	Day diet: normal
			pH electrodes: 1 esophagus and 1 pharynx
			Duration: 24 h

Hoppo, 2012¹⁶	Prospective	B	24-h MII-pH (M = Sanhill)	Gr1: Healthy (N = 40)	No. of subjects with ≥1 HRE	n = 1/32	1. The normative value of HRE in healthy subjects was 0 (prototype HEMII-pH system).
	Controlled		pH probe level: 0.5 cm above UES	Gr2: LPR (N = 24)	HRE (md, 25-75-95th percentile)	0, 0-0-0
			5 cm above LES	Sex: 18 M/22 F			2. The normative value of PRE in healthy subjects was 4.
			Probe placement: transnasal esophagoscopy	Age: 33 y			2. The normative value of PRE in healthy subjects was 4.
			IE: 2 esophagus and 2 pharynx	BMI: 26.1			3. Hypopharyngeal acid exposure occurred upright.
			pH electrodes: 1 esophagus and 1 pharynx	Day diet: normal			4. Sixty percent of HREs were acid.
			Duration: 24 h				5. Thirty percent of nonacid HREs were acid in the esophagus.
Desjardin, 2013¹⁷	Prospective	C	24-h MII-pH (M = Sanhill)	N = 45 healthy subjects	PRE events pH <4	1	1. HREs occur once daily in healthy individuals.
	Uncontrolled		pH probe level: 0.5 cm above UES	Sex: 23 M/22 F	PRE events pH <5	1	2. Pharyngeal pH alone is not reliable for the detection because many pH <4 or 5 occurred during swallowing.
			5 cm above LES	Age: 46 y	HRE events pH <4	1
			Probe placement: manometry	BMI: 23.9	HRE events pH <5	1	3. The impedance patterns reporting the presence of HRE preceded by a distal event and PRE are the only reliable way to demonstrate the occurrence of HRE.
			IE: 4 esophagus and 2 pharynx	Day diet: NA
			pH electrodes: 1 esophagus and 1 pharynx
			Duration: 24 h
Jetté, 2014¹⁹	Prospective	B	24-h MII-pH (M = Sanhill)	N = 142 healthy subjects	Number PRE (mean, SD)	23.8 (14.0)	1. Based on the MII-pH findings defining LPR as >31 proximal reflux events, the prevalence of LPR in the healthy population was 31.0%.
	Controlled		pH probe level: 1 cm below UES	GERD/LPR: 38/44	Number of acid PRE (mean, SD)	14.7 (11.3)
			Probe placement: manometry	Sex: 64 M/78 F	Number of nonacid PRE (mean, SD)	9.0 (6.7)
			IE: 6 esophageal	Age: 43 y
			pH electrodes: 2 esophageal	BMI: NA
			Duration: 18-24 h	Day diet: normal
Kawamura, 2016²⁰	Prospective	C	24-h MII-pH (M = Sanhill)	N = 42 healthy subjects	PRE (md, 25-75-95th percentile)	36, 23-45-73	1. PRE events are mainly nonacid.
	Uncontrolled		pH probe level: 10 cm below LES	Sex: 25 M/17 F	Upright/supine	35, 23-44-73/0, 0-0-3	2. Nineteen percent of liquid and mixed reflux episodes reached the proximal esophagus.
			Probe placement: manometry	Age: 33 y	Acid/weakly acid	7, 3-13-34/8, 33-11-25
			IE: 6 esophageal	BMI: 21.7	Nonacid	17, 13-24-56	3. The 95th percentile of PRE was 73 events.
			pH electrodes: 2 esophageal	Day diet: normal	Liquid/mixed	2, 0-4-12/3, 0-9-19	4. The majority of PREs occurred upright.
			Duration: 24 h		Gas	26, 15-39-65
Hou, 2020 ²¹	Prospective	C	24-h MII-pH (M = NA)	N = 38 healthy subjects	Average (SD) of HRE	0 (0-0)	1. Acid HRE is almost undetectable in healthy subjects.
	Uncontrolled		pH probe level: 1 cm above UES	Sex: 20 M/18 F	Acid/nonacid	0 (0-0)/21 (14-28)	2. Healthy subjects had a mean of 21 nonacid HREs per 24 hours.
			Probe placement: manometry	Age: 46 y	Liquid: all—acid/nonacid	0 (0-0)–0 (0-0)/0 (0-0)
			IE: 2 pharynx and 4 esophageal	BMI: NA	Mixed: all—acid/nonacid	1 (0-2)–0 (0-0)/0 (0-0)
			pH electrodes: 1 pharynx and 1 esophageal	Day diet: normal without	Gas: all	20 (13-27)
			Duration: 24 h	Alcohol and smoking	Gas: acid/nonacid	0 (0-0)/20 (13-27)

Chen, 2020 ²²	Retrospective	D	24-h MII-pH (M = Sandhill)	Gr1 = 59 LPR-symptoms	Acid PRE	Gr2 > Gr4	1. Patients with LPR and GERD symptoms had more acid PRE than healthy individuals.
			pH probe level: 5 cm above LES	Gr2 = 114 LPR/GERD symptoms	Basal UES pressure	Gr1-3 > Gr4
			Probe placement: manometry	Gr3 = 44 GERD symptoms			2. The baseline UES pressure of healthy individuals was significantly lower than other groups.
			IE: 6 esophageal	Gr4 = 25 healthy controls
			pH electrodes: 1 esophageal	Sex: 121 M/121 F			*This study mainly investigated UES pressure and baseline impedance of proximal esophagus in LPR and CT subjects.
			Duration: 24 h	Age (md): 41 y (25 healthy)
				BMI: NA
				Day diet: normal
Doo, 2020²³	Retrospective	D	24-h MII-pH (M = Sandhill)	Gr1 = 63 confirmed LPR	Basal impedance level (PRE)	Gr2 = Gr3	1. Pharyngeal intraluminal baseline impedance was higher in patients with or without confirmed LPR compared with healthy controls.
			pH probe level: 1 cm above UES	Gr2 = 51 LPR symptoms	Basal impedance level (HRE)	Gr1/2 > Gr3
			Probe placement: fiber-optic control	Gr3 = 21 healthy subjects
			IE: 6 esophageal (1-2 hypopharynx)	Sex: 4 M/17 F			(LPR was based on the occurrence of ≥1 HRE.)
			pH electrodes: 1 pharynx and 1 esophageal	Age: 44 y
			Duration: 24 h	BMI: NA
				Day diet: normal without
				Alcohol and caffeine
Doo, 2020 ²³	Retrospective	D	24-h MII-pH (M = Sandhill)	Gr1 = 63 confirmed LPR	Basal impedance level (PRE)	Gr2 = Gr3	1. Pharyngeal intraluminal baseline impedance was higher in patients with or without confirmed LPR compared with healthy controls.
			pH probe level: 1 cm above UES	Gr2 = 51 LPR symptoms	Basal impedance level (HRE)	Gr1/2 > Gr3
			Probe placement: fiber-optic control	Gr3 = 21 healthy subjects
			IE: 6 esophageal (1-2 hypopharynx)	Sex: 4 M/17 F			(LPR was based on the occurrence of ≥1 HRE.)
			pH electrodes: 1 pharynx and 1 esophageal	Age: 44 y
			Duration: 24 h	BMI: NA
				Day diet: normal without
				Alcohol and caffeine
Klimara, 2020²⁷	Prospective	B	24-h MII-pH (M = Diversatek)	N = 13 healthy subjects	Healthy: positive LPR (MII-pH)	n = 4 (31%)	1. Thirty-one percent of healthy subjects had LPR regarding HEMII-pH. None of these individuals had pepsin in the saliva.
	Controlled		pH probe level: just above UES	Sex: 4 M/9 F	Pepsin positive (healthy)	n = 0 (0%)
			Probe placement: fibroscopy	Age: 34 y
			IE: NA	BMI: NA
			pH electrodes: 1 pharynx and 1 esophageal	Day diet: normal
			Duration: 24 h

Abbreviations: BMI, body mass index; EL, evidence level; GERD, gastroesophageal reflux disease; Gr, grade; HEMII-pH, hypopharyngeal-esophageal multichannel intraluminal impedance–pH monitoring; HRE, hypopharyngeal reflux episodes; IE, impedance electrodes; LES, lower esophageal sphincter; LPR, laryngopharyngeal reflux; M, manufacturer; md, median; MII-pH, multichannel intraluminal impedance–pH monitoring; NA, not available; NS, nonsignificant; PE, proximal esophagus; PRE, proximal esophageal reflux episodes; UES, upper esophageal sphincter.

Table 2.

Features of Included Studies Using Oropharyngeal pH Study.

First author	Design	EL	System	Sample features	Outcomes	Results	Main findings
Sun, 2009¹³	Prospective	C	Oropharyngeal pH metry (Restect)	N = 20 healthy subjects	HRE-pH <4 (md, 25-75-95th percentile)	0, 0-0-1	1. Healthy subjects infrequently had oropharyngeal acid episodes regarding oropharyngeal pH metry. Note that a custom made longer catheter was used to assess distal esophageal pH.
	Uncontrolled		pH probe level: oropharyngeal	Sex: 8 M/12 F	Upright/recumbent HRE	0, 0-0-1/0, 0-0-0
			Probe placement: manometry	Age: 31 y	HRE-pH <5 (md, 25-75-95th percentile)	0, 0-0-8
			IE: —	BMI: NA	Upright/recumbent HRE	0, 0-0-8/0, 0-0-0
			pH electrodes: 1 esophagus and 1 pharynx	Day diet: NA	HRE-pH <6 (md, 25-75-95th percentile)	7, 0-35-128	Note that the pH study system was hybrid with 1 esophagus and 1 pharyngeal probe.
			Duration: 20 h (14-24)		Upright/recumbent HRE	1, 0-10-30/3, 0-12-116
Ayazi, 2009²⁵	Prospective	C	Oropharyngeal pH metry (Restect)	N = 55 healthy subjects	HRE (md, 25-75-95th percentile)		1. A pharyngeal composite score overcoming artifacts was developed. The 95th percentile values for the composite score were 9.4 (upright) and 6.8 (supine).
	Uncontrolled		pH probe level: oropharyngeal	Sex: 28 M/27 F	pH <4.0 (mean % time)	0, 0-0-0 (0)
			Probe placement: visual control	Age: 28 y	pH <5.0 mean (% time)	0, 0-0-0 (0)
			IE: —	BMI: NA	pH <5.5 (mean % time)	0, 0-0-1 (0.1)
			pH electrodes: oropharyngeal	Day diet: Normal	pH <6.0 (mean % time)	1, 0-5-40 (0.8)	2. The calculated discriminatory pH threshold was 5.5 for upright and 5.0 for supine periods.
			Duration: 24 h		pH <6.5 (mean % time)	10, 2-43-154 (6.5)
Chheda, 2009²⁶	Prospective	C	Oropharyngeal pH metry (Restect)	N = 20 healthy subjects	HRE (md, 95th percentile)		1. The 95th percentiles for the event number pH <5.5, 5.0, 4.5, and 4.0 were 16.6, 10.7, 7.4, and 0.2, respectively.
	Uncontrolled		pH probe level: oropharyngeal and just above UES and esophageal	Sex: 7 M/13 F	pH <4.0 all (upright, supine)	0, 0.2 (0, 0.2-0, 0)
				Age: 35 y	pH <4.5 all (upright, supine)	0, 7.4 (0, 7.4-0, 0)	2. The 95th percentiles for acid exposure time pH <5.5, 5.0, 4.5, and 4.0 were 820, 385, 75, and 3 seconds.
			Probe placement: visual control	BMI: NA	pH <5.0 all (upright, supine)	0, 10.7 (0, 10.7-0, 1.1)
			IE: —	Day diet: normal	pH <5.5 all (upright, supine)	1, 16.6 (0, 16.5-0, 2.1)
			pH electrodes: hypo/oropharyngeal
			Duration: 24 h
Feng, 2014¹⁸	Prospective	C	Oropharyngeal pH metry (Restect)	N = 29 healthy subjects	95th percentile for % total time:		1. LPR maybe considered if the oropharyngeal percent time at pH <4.5 is no more than 1%.
	Uncontrolled		pH probe level: oropharyngeal	Sex: 20 M/9 F	pH <4, pH <4.5, pH <5, pH <5.5	0.6%, 1.01%, 7.23%, 27.3%
			Probe placement: visual control	Age: 23 y	95th percentile number of HRE		2. The majority of HRE occured upright.
			IE: —	BMI: NA	pH <4, 4.5, 5, 5.5	2.5, 18.0, 107.5, 284.5
			pH electrodes: 1 pharynx	Day diet: normal	Upright (pH <4, 4.5, 5, 5.5)	2.0, 5.5, 28.0, 207.0
			Duration: 22-24 h		Supine (pH <4, 4.5, 5, 5.5)	0.5, 15.5, 88.0, 116.0
Yadlapati, 2016²⁴	Prospective	B	Oropharyngeal pH metry (Restect)	Gr1 = 18 suspected LPR	Abnormal % time pH <5.0, mean (SD)	0 (0)	1. There was no significant difference between groups regarding the % spent below pH 4.0, 5.0, 5.5, or 6.0.
	Controlled		pH probe level: oropharyngeal	Gr2 = 17 suspected LPR and GERD	Abnormal % time pH <5.5, mean (SD)	3 (16.7)
			Probe placement: visual control	Gr3 = 18 healthy subjects	Gr1 vs Gr2 vs Gr3	NS	2. Percent time pH <5.0 and 5.5 was higher supine vs upright.
			IE: —	Sex: 8 M/10 F
			pH electrodes: oropharyngeal	Age: 28 y
			Duration: 24 h	BMI: 23
				Day diet: normal

Abbreviations: BMI, body mass index; EL, evidence level; GERD, gastroesophageal reflux disease; Gr, grade; HRE, hypopharyngeal reflux episodes; IE, impedance electrodes; LPR, laryngopharyngeal reflux; md, median; NA, not available; NS, nonsignificant; —, no information available.

The included studies comprised a total of 720 healthy individuals, with 363 (50.4%) women and a mean age of 35.7 years. The mean body mass index, which was provided in 6 studies,^14-17,20,24 was 22.8 kg/m². The inclusion and exclusion criteria substantially varied among studies ( Table 3 ). Six studies based the inclusion of healthy individuals on the lack of gastroesophageal reflux symptoms without consideration for laryngopharyngeal reflux symptoms.^{10-12,15,20,25} LPR symptoms were considered in 11 studies.* The inclusion criteria of healthy subjects were not provided in 1 study.²² Heterogeneity among included articles in inclusion/exclusion criteria, ambulatory reflux monitoring characteristics, and outcomes measures, as well as the nonnormal distribution of measured outcomes, precluded statistically pooling the data into a formal meta-analysis, thereby limiting the analysis to a qualitative rather than quantitative summary of the available information.

Table 3.

Inclusion or Exclusion Criteria of Healthy Individuals.

First author	Inclusion criteria	Exclusion criteria
Shay, 2004¹⁰	Individuals without GER symptoms	Previous esophageal or gastric surgery
Zentilin, 2006¹¹	Individuals without GER symptoms	Previous esophageal or gastric surgery
Zentilin, 2006¹¹	Individuals without GER symptoms	GI or systemic diseases
Xiao, 2009¹²	Individuals without GI symptoms	GER symptoms, asthma, or wheezing
		Acid-suppressive medications
		Individuals without chronic GI disease
Sun, 2009¹³	Individuals without GER/LPR symptoms	Acid-suppressive medications
		Esophageal motility abnormalities
		Alcohol or tobacco use
		Nasal surgery or obstruction
		Neuropsychiatric disabilities
		Pregnancy
Ayazi, 2009²⁵	Individuals without GER symptoms	GI dysmotility disease
		Nasal obstruction/surgery (recent)
		Alcohol or tobacco use/anticoagulation
		Pregnancy
Chheda, 2009²⁶	RSI <10 and RFS <6	Head and neck cancer, pacemaker
		Nursing
		Esophageal motility abnormalities
		Antireflux treatment
		Pregnancy
Wang, 2011¹⁴	Individuals without GER/airway symptoms	Esophageal motility abnormalities
		Chronic GI disease or HP infection
		Laryngopharyngeal/respiratory illness
Xiao, 2012¹⁵	Individuals without GER/snoring symptoms	NA
Hoppo, 2012¹⁶	GERD-HRQoL and RSI = 0	Esophageal disease (esophagitis, hiatal hernia (III-IV), inlet patch, diverticulum
		Positive DeMeester score/GER history
		Antireflux surgery
		LPR symptoms or epistaxis
		Pregnancy
Desjardin, 2013¹⁷	Individuals without GER/LPR symptoms	History of thoracic or digestive surgery
		Alcohol consumption >40 g/d
		Smoking >10 cigarettes/d
		Antireflux drug allergy/GI medications
Feng, 2014¹⁸	Individuals without GER/LPR symptoms	≥1 laryngeal RFS finding(s)
Jetté, 2014¹⁹	Individuals without LPR symptoms	History of head and neck radiation/cancer
		Esophageal or lung surgery
		Rhinitis or chronic rhinosinusitis
		Laryngeal trauma (last year)/surgery
		Alcohol or tobacco abuse
		Infectious laryngitis (last 3 months)
		Antireflux medication
		Pregnancy/lactating
Kawamura, 2016²⁰	Individuals without GER symptoms	History of chest or digestive surgery
		Esophageal dysmotility or hiatal hernia
		Gastroduodenal disorder (HP)
		Pregnancy
Yadlapati, 2016²⁴	RSI <13 and GERDQ <8	Unable to discontinue 5-day PPIs
		Significant comorbidities (GI dysmotility)
		Pregnancy
Hou, 2020²¹	Individuals without GER/LPR symptoms	History of GI disease
	RSI <13 and RFS <7	Laryngopharyngeal organic lesions
		GI organic disease (ulcer, HP, etc)
		Acute tonsillitis, otitis, rhinosinusitis
		Serious organ/systemic diseases
		Smoker or alcoholic
		Antireflux medication
		Neuropsychiatric disabilities
		Pregnancy/lactating
Chen, 2020²²	NA	NA
Doo, 2020²³	Individuals without LPR symptoms	RFS <7
Klimara, 2019²⁷	Individuals without LPR symptoms	Antireflux medication

Abbreviations: GER, gastroesophageal reflux; GERD-HRQoL, gastroesophageal reflux disease–high related quality of life; GERDQ, gastroesophageal reflux disease questionnaire; GI, gastrointestinal; HP, Helicobacter pylori; LPR, laryngopharyngeal reflux; NA, not available; PPI, proton pump inhibitor; RFS, reflux finding score; RSI, reflux symptom score.

Study Characteristics and Level of Evidence

There were 4 prospective controlled studies (evidence level [EL] = B), 9 prospective uncontrolled studies (EL = C), and 2 retrospective chart reviews (EL = D). One controlled study compared healthy individuals with patients with LPR or chronic rhinosinusitis.²⁷ There was an important heterogeneity between studies regarding the inclusion and exclusion criteria used to include healthy individuals. Among the controlled studies, the LPR diagnosis substantially varied. In the study by Xiao et al,¹⁵ LPR diagnosis was defined as a percentage of total time for which the pH value below 4, detected 5 cm above the lower esophageal sphincter (LES), was >4.2%. Jetté et al¹⁹ considered LPR in patients with >31 PRE, while Hoppo et al¹⁶ made the diagnosis in individuals with ≥1 HRE. In these 3 controlled studies, the mean age of healthy controls was significantly lower than the mean age of LPR patients. The bias analysis is available in Appendix 1 (in the online version of the article). The inclusion and exclusion criteria were evaluated as highly reliable in 4 studies.

Note that the exclusion criteria were assessed through structured or unstructured questionnaire in all studies with the exception of the study by Ayazi et al,²⁵ which excluded gastrointestinal dysmotility and other esophageal diseases after dual-probe esophageal pH monitoring, video esophagram, and esophageal manometry. Based on the type of ambulatory reflux monitoring used, the assessment of normative data for HRE was performed in 8 studies.^13-18,21,23 Among them, the definition of HRE was clearly provided in 7 studies.^14-18,21,23 The classification of reflux events according to the pH level (acid, weakly acid, nonacid, superimposed acid, and acid-to-nonacid) was available in 7 studies.^{10-12,14-16,20} The composition of reflux events, including gas, liquid, and mixed compositions, was clearly provided/defined in 10 studies.^{10-12,14-17,20,21,23} Overall, comprehensive information inclusive of clear definitions of reflux events, acidity of episodes, and composition of PRE/HRE was fully available in 3 studies.^14-16

Device and Ambulatory Reflux Monitoring System

The following systems for ambulatory reflux monitoring were used in the included studies: MII-pH without hypopharyngeal impedance channels (n = 6),^{10-12,19,20,22} HEMII-pH (n = 7),^{14-17,21,23,27} and oropharyngeal pH study (n = 2).^13,18,24-26 In 2 studies, patients underwent simultaneous oropharyngeal and esophageal pH monitoring.^13,26 The placement of MII-pH or HEMII-pH probes was guided by esophageal manometry,^{10-14,17,19-22} transnasal esophagoscopy,¹⁶ or flexible laryngoscopy.^23,27 The placements of oropharyngeal pH study devices were confirmed visually.^18,24-26 Information on methodology of catheter placement was lacking in 1 study.¹⁵ The duration of ambulatory reflux monitoring ranged from 14 to 24 hours ( Tables 1 and 2 ). Among the 6 studies using MII-pH without hypopharyngeal pH or impedance sensors, pH monitoring was measured using 1 (n = 4)^10-12,22 or 2 (n = 2) esophageal sensors (n = 2).^19,20 The location and number of impedance electrodes used in MII-pH or HEMII-pH varied substantially among studies ( Table 1 ). Depending on the device, the hypopharyngeal pH sensor was located 0.5 to 1.0 cm above the upper esophageal sphincter (UES)^14-17,21,23 or in the oropharyngeal cavity.^13,18,24-26

Reflux Event Definition

The definitions of PRE or HRE were available in 11 studies using MII-pH or HEMII-pH ( Table 4 ). PRE was uniformly defined across studies. The definition of HRE significantly differed across studies ( Table 4 ). The definitions of the composition of reflux event (gas vs liquid vs mixed) were available in 11 studies ( Table 4 ). We found 2 different definitions of gas and liquid reflux events, although in both cases, 10 of 11 studies agreed on 1 of the 2 definitions ( Table 4 ). Mixed reflux events were defined in 3 different ways, with 7 studies using the definition of gaseous reflux episode occurring before or during a liquid reflux event ( Table 4 ). The types of reflux events (acid vs weakly acidic vs alkaline) were classified according to the pH level, as shown in Table 5 . In general, acid reflux events were defined by pH <4, while weakly acidic reflux comprised events with pH between 4 and 7. There was some heterogeneity among authors in the definition of weakly acidic vs nonacid or weakly alkaline PRE or HRE, namely, those events with pH >4. While some studies classified events with pH between 4 and 7 as weakly acidic events and those with pH >7 as weakly alkaline events, others summarily labeled all events with pH >4 as nonacidic.

Table 4.

Definitions of Proximal Esophageal and Hypopharyngeal Reflux Episodes According to Studies.

Outcomes	Definition and features	References
Proximal GER	1. Episode reaching proximally to 5.5 cm below the upper border of UES or in the impedance drop reached the 2 electrode pairs located in the proximal esophagus.	11, 12, 14, 17
LPR (HRE)	1. Episode reaching proximally to 1 cm above the upper border of UES (with decreased impedance).	14, 15
	2. Episode reaching proximally to 0.5 cm above the upper border of UES (with decreased impedance).	16
	3. Retrograde 50% drop in impedance starting distally (UES) and reaching the more proximal impedance site. HRE event was considered only if it was preceded by retrograde impedance drop both distally and proximally within the esophagus and if no swallow occurred during the pharyngeal impedance drop.	17
	4. Episode when the time of pH reaching to the lowest point was no more than 30 seconds (Restech).	18
	5. Reflux reaching Z1-Z2 (hypopharyngeal) impedance segment.	21, 23
	6. Episode reaching oropharyngeal sensor.	13, 24, 25, 26
Gas reflux	1. Simultaneous increase in impedance of >3000 W in any 2 consecutive impedance sites with 1 site having an absolute value >7000 W in the absence of swallowing.	10, 11, 12, 14-17, 19, 21, 23
	2. Abrupt increase of impedance by ≥50% in 2 adjacent channels with simultaneous or near-simultaneous propagation in the retrograde direction.	20
Liquid reflux	1. Retrograde 50% drop in impedance starting distally (LES) and propagating at least to the next 2 or more proximal impedance measuring segments.	10-12, 14-17, 20, 21, 23
	2. Retrograde-moving, 40% fall in impedance in 2 distal impedance sites.	19
Mixed reflux	1. Gas reflux occurring immediately before or during a liquid reflux.	10, 12, 14, 15, 16, 17, 23
	2. Combination of the gas reflux and liquid reflux patterns.	20, 21
	3. Fall in impedance to <50% of resting impedance (liquid) preceded or followed by an abrupt rise in impedance (gas).	11

Abbreviations: GER, gastroesophageal reflux; HRE, hypopharyngeal reflux episode(s); LES, lower esophageal sphincter; LPR, laryngopharyngeal reflux; UES, upper esophageal sphincter.

Table 5.

Definition of the Reflux Events According to pH.

Outcomes	Definition and features	References
Acid HRE/PRE	1. Hypopharyngeal or proximal esophageal event with pH <4	10, 14, 15, 21
	2. Hypopharyngeal and proximal esophageal events with pH <4	16
	3. Drop/event in pH <4 for at least 5 seconds in the proximal esophagus	19, 20
	4. Drop/event in pH <4.0 from a preevent pH >4.0 units lasting for >5 seconds	11, 12
Superimposed acid PRE	1. Reflux event while pH <4 during an acid clearing interval	10
	2. Liquid reflux monitored by impedance electrodes while esophageal pH is still <4.0	11, 12
Weakly acid HRE/PRE	1. Hypopharyngeal or proximal esophageal pH 4-7	10, 11, 12, 14, 15
	2. Hypopharyngeal and proximal esophageal pH >4	16
	3. Decrease of more than 1 pH unit with a nadir pH above 4	20
Nonacid HRE/PRE (weakly alkaline)	1. Hypopharyngeal or proximal esophageal pH >7	10, 14-16
Nonacid HRE/PRE (weakly alkaline)	2. No change of pH or a decrease of less than 1 pH unit	20
	3. Hypopharyngeal or proximal esophageal pH >4	21
	4. Hypopharyngeal or proximal esophageal pH ≥7.0	11, 12
Acid-to-nonacid HRE/PRE	1. Proximal esophageal pH >4 and hypopharyngeal pH >4	16

Abbreviations: HRE, hypopharyngeal reflux episode(s); PRE, proximal esophageal reflux episode(s).

No definitions of weakly acidic or nonacid pharyngeal events were provided in studies using oropharyngeal pH monitoring, as it is a pH-only technology where reflux events themselves are defined by pH value decrease.

Proximal Esophageal Reflux Episodes

The normative value for PRE was determined by the 95th percentile number of events among healthy individuals in most studies.^10-12,20 The following 95th percentile values for PRE were established: 10,¹⁴ 31,¹⁰ 32,¹² 34 (female) to 70 (male),¹¹ and 73.²⁰ Considering the acidity of the PRE, the 95th percentile number of acid (pH <4.0) PRE ranged from 4 to 34,^10,12,14,20 while the 95th percentile number of weakly acidic (pH 4.0 to 7.0) PRE ranged from 0 to 25.^10,12,14,20 For weakly alkaline events (pH >7), the 95th percentile value ranged from 0 to 56.^10,12,14 Desjardin et al¹⁷ reported their results in terms of mean number of events, with mean PRE pH <4 of 1 and mean PRE pH <5 of 1. In the study by Jetté et al,¹⁹ the mean number of PREs was 23.8 ± 14.0, with a higher number of acid (pH <4) events (14.7 ± 11.3) compared to nonacid (pH >4) events (9.0 ± 6.7). According to studies where the data were reported,^10-12,14 most PREs occurred during daytime and in the upright position, and they may be more frequently gaseous²⁰ ( Table 1 ). Acid PREs, but not nonacid PREs, were reported to be more frequent in LPR patients compared to healthy controls in 1 study.²¹

Hypo- and Oropharyngeal Reflux Episodes

Hypopharyngeal reflux event (HEMII-pH studies)

The 95th percentile values of HRE measured by HEMII-pH ranged from 0¹⁶ to 10.¹⁴ The 95th percentile values of acid, weakly acidic, and nonacid HRE were 0, 0, and 2, respectively, in the study by Wang et al,¹⁴ who were also the only authors assessing the 25th, 75th, and 95th percentiles of HRE and their pH compositions. Xiao et al¹⁵ only provided the 75th percentile of HRE, which was found to be 1 event. In this study, 7 individuals (35%) had ≥1 HRE, while in the study by Wang et al,¹⁴ there were 6 individuals (16.2%) with ≥1 HRE, with the majority of HREs being nonacidic. Hoppo et al¹⁶ identified HRE in only 1 individual (3.1%). Hou et al²¹ reported average and standard deviation of HRE in healthy controls, taking into account the pH composition of events. The average numbers of acid and nonacid HRE in healthy individuals were 0 ± 0 and 21 ± 7 (SD = 14-28), respectively.²¹ In the study by Desjardin et al,¹⁷ the mean values of HRE with pH <4 and with pH <5 were both 1.

Most HREs were gaseous²¹ and occurred during daytime and in the upright position ( Table 1 ).^14,18 In 1 study assessing mean nocturnal baseline impedance (MNBI), the pharyngeal baseline impedance was found to be higher among LPR patients compared to healthy controls.²³

Oropharyngeal reflux event (Restech)

The 95th percentiles of oropharyngeal events according to the pH thresholds measured on oropharyngeal pH monitoring are described in Table 2 . Overall, the 95th percentiles of oropharyngeal events at thresholds of pH <4, pH <5, and pH <6.0 ranged from 0 to 2.5, 0 to 107.5, and 40 to 128, respectively.^12,18 The data were significantly different within studies depending on patient positions (upright vs supine).^13,18,26 The mean percentage time with pH <4 was 0% in the study by Ayazi et al,²⁵ while it ranged from 0% to 16.7% with a threshold of pH <5.5.²⁴ Similar to studies using HEMII-pH or MII-pH, the presentation of results of studies using oropharyngeal pH monitoring varied significantly among studies.

Discussion

To date, there are no international consensus guidelines or gold standard for the diagnosis of LPR through objective assessments.¹ The HEMII-pH or MII-pH and oropharyngeal pH monitoring have been recognized as the more reliable approaches, as they provide objective data about the occurrence of reflux events in the upper aerodigestive tract of patients with LPR-associated symptoms or findings.³¹ In this systematic review, we tried to analyze the current evidence regarding normative data of both HEMII-pH or MII-pH and oropharyngeal pH monitoring in order to propose agreeable thresholds. However, upon detailed review and analyses of the literature to date, we were unable to determine common thresholds for PRE or HRE across studies for several methodological reasons, chiefly the significant heterogeneity in inclusion criteria, definitions, and study protocol.

The definition and inclusion criteria of healthy individuals varied substantially among studies, an important source of heterogeneity. Some studies based their inclusion criteria on the presence or absence of typical esophageal symptoms of GERD,^{10-12,15,20,25} which are, in practice, often absent in patients presenting for the evaluation of LPR.^1,32 In other words, some LPR patients may present with primarily laryngeal symptoms alone, with little to no esophageal GERD symptoms, and they may, consequently, be misclassified as healthy controls in studies that used esophageal symptoms as inclusion criteria. Moreover, in most studies, the exclusion of underlying major esophageal motility disorders was based on medical records or patient recall, which remains insufficient to conclusively exclude these disorders.³³ The inclusion of smokers and alcoholics in some healthy cohorts serves as another potential source of heterogeneity, as tobacco and alcohol may both impair the tonicity of esophageal sphincters, thereby increasing the risk of LPR.³⁴ Given that the use of these substances may also be an important and independent risk factor themselves for developing laryngeal symptoms, separate analyses may be needed for normative ambulatory reflux monitoring data between those with and without a history of tobacco or alcohol consumption. In most studies included in this systematic review, the mean age of the subjects enrolled was low (overall range of mean age: 23.9-46 years). Whether the normative values observed by these studies are generalizable to patients in other age groups remains unclear. Further studies inclusive of subjects from all age groups with appropriate subgroup analyses are needed to ensure applicability of the values generated.

The heterogeneity among studies in the number, placement, and specificity of the pH sensors and impedance electrodes also hindered standardized pooling of data across study cohorts. While HEMII-pH and oropharyngeal pH monitoring both aim to objectively quantify pharyngeal reflux events, information generated by these 2 modalities could not appropriately be pooled due to their differences in technique, equipment, location of sensors, and data used to define reflux events (impedance vs pH only). This was illustrated by Ummarino et al,³⁵ who performed oropharyngeal pH monitoring and HEMII-pH testing simultaneously on the same individuals and showed that fewer reflux episodes were identified by oropharyngeal pH monitoring. This may be due to the detection solely of change in pH with oropharyngeal pH monitoring, independent of true reflux events. Events that are weakly acidic or nonacidic and could only be identified with impedance technology and thus the specificity of oropharyngeal pH monitoring may be limited by the lack of simultaneous esophageal data to verify full-column reflux events. Indeed, several prior studies have shown poor correlation between findings on oropharyngeal pH monitoring and response to acid-suppressive therapies.^36,37 The advantages/disadvantages, indications, and roles of HEMII-pH, MII-pH, or oropharyngeal pH monitoring in the evaluation for LPR need further evaluation and consensus guidance but are beyond the scope of this analysis.

The definitions of acid, weakly acid, or nonacid, as well as gas, liquid, or mixed reflux events, need further standardization for the diagnosis of LPR disease. Some consensus definitions have been developed for the evaluation of typical esophageal manifestations of GERD^38,39 and were used in some included studies for LPR,^10,11,14,16 although they are not universally employed in otolaryngology or specifically validated for the LPR population. Given the increasing evidence demonstrating the important role of weakly acidic or nonacid HRE in LPR,^40-42 it would be crucial to ensure standardization in the criteria by which these events are classified to allow accurate comparisons across studies. A better understanding and more concrete classifications of acid vs nonacid reflux episodes may also carry important therapeutic implications, allowing more personalized treatment approaches, such as the initial choice of antisecretory agents (eg, proton pump inhibitors) vs antireflux barrier agents (eg, alginate).⁴¹

Despite the differences and limitations in pooling the data across the included studies, an important measure that seemed increasingly required to diagnose LPR was reporting the number and pH of hypo- or oropharyngeal reflux episodes as a superior method to using proximal esophageal reflux episodes alone (which may not make it into the pharynx). Indeed, some studies found that PRE may be cleared very quickly in healthy subjects.¹¹ Moreover, the pH nature of the refluxate may change while migrating from the esophagus to the hypopharynx,¹¹ with the number of nonacid hypopharyngeal reflux episodes being more prevalent than acid events in LPR patients.³⁶ The buffering capacity of saliva may be indirectly highlighted by the higher number of HRE with pH >4 in healthy individuals, although this may also pose further diagnostic challenges and further refute the ability to truly diagnose reflux events when pH-only technologies are used. Based on our systematic review and analysis, the current article provides some recommendations on the inclusion/exclusion criteria and definitions for standardization of future studies ( Table 6 ). In particular, technical/methodological recommendations were focused on HEMII-pH, given the current lack of standardization and significant heterogeneity in employment of this technology. Standardization of methodologies is key in better understanding LPR. Reflux events measured by MII-pH in the hypopharynx of more than 1 episode (acidic, weakly acidic, or nonacidic) may be employed in defining disease. Alternatively, a combination of test results (distal esophageal pH, pepsin assay, MII-pH, oropharyngeal pH) may be employed to improve sensitivity and specificity in detecting LPR, but they all must stand the rigor of outcome studies. Studies showing higher prevalence of a test finding should be replaced by those showing favorable treatment response as a function of test results.

Table 6.

Proposition of Recommendations for Future Studies.

Outcomes	Recommendations	Minimal requirement
Age	Healthy individuals of any age have to be considered in the establishment of normative data	—
Inclusion	Healthy individuals without gastroesophageal and laryngopharyngeal symptoms/signs	Nasofibroscopic examination
Exclusion	The following conditions have to be (objectively) excluded to consider the candidate as healthy:
	Gastrointestinal conditions
	Gastrointestinal motility disorders, hiatal hernia, esophagitis, or history of gastrointestinal diseases that may affect gastroesophageal functioning	Gastrointestinal endoscopy ± high-resolution manometry
	Esophageal surgery history
	Ear, nose, and throat conditions
	History of head and neck major surgery, radiation, or cancer	Medical record—miscellaneous
	Active rhinitis or chronic rhinosinusitis or laryngopharyngeal organic lesions	Nasofibroscopic examination
	Infection of upper aerodigestive tract within the last 4 weeks or unresolved infection	Medical record—nasofibroscopy
	History of laryngotracheal surgery or trauma
	Systemic or other conditions
	Systemic diseases affecting upper aerodigestive tract/stomach/esophagus	Medical record—miscellaneous
	Alcohol and tobacco consumption	Anamnesis
	History of lung or chest surgery or trauma	Medical record—miscellaneous
	Pregnancy/lactating	Anamnesis
	Neuropsychiatric disabilities	Medical record—miscellaneous
pH study features	Placement of impedance and pH sensors in esophagus and pharynx (impedance pH study)	>4 Impedance and 2 pH sensors
	Hypopharyngeal placement 0.5 to 1 cm above upper esophageal sphincter
	Control of probe placement through manometry or transnasal esophagoscopy
	Definition of the composition of PRE/HRE (HEMII-pH) respecting previous consensus report^a	—
	Gas: simultaneous increase in impedance of >3000 W in any 2 consecutive impedance sites with 1 site having an absolute value >7000 W in the absence of swallowing	—
		—
	Liquid: retrograde 50% drop in impedance starting distally (LES) and propagating at least to the next 2 or more proximal impedance measuring segments	—
		—
	Mixed: gas reflux occurring immediately before or during a liquid reflux	—
	Consideration of pH level of reflux events (acid, weakly acid, or nonacid) in the data analysis	—
	Acid reflux event may be defined as an event with pH <4.0	—
	Weakly acid reflux event may be defined as an event with pH from 4.0 to 7.0	—
	Nonacid reflux event may be defined as an event with pH >7.0	—

Abbreviations: HEMII-pH, hypopharyngeal-esophageal multichannel intraluminal impedance–pH monitoring; HRE, hypopharyngeal reflux episodes; LES, lower esophageal sphincter; PRE, proximal esophageal reflux episode; —, no information available.

To allow comparison with studies conducted in gastroenterology, our propositions of definitions were based on the consensus report of Sifrim et al.³⁸

Our study has several strengths, including the comprehensive review of the literature to date on healthy subjects using currently available ambulatory reflux monitoring technology to help establish normative guidelines. Reviews and recommendations were provided by a diverse, international group of clinicians and investigators with expertise in LPR. Included studies also represent a wide range of geographical locations and patient populations. However, this systematic review also has several limitations. First, the relatively low number of healthy individuals in all included studies may limit the findings and analyses. Second, many local and geographical factors may affect and confound the risk of gastroesophageal dysfunction and reflux, such as diet, genetic differences, and lifestyle variations. These factors, many of which remain insufficiently understood in LPR, may serve as another important source of heterogeneity across studies.

Conclusion

Ambulatory reflux monitoring remains a crucial and the most objective way to guide the diagnosis and management of LPR. The significant heterogeneity among studies to date with regards to inclusion criteria, definitions, system setup, and interpretation precludes the establishment of universal normative thresholds. Further large multicenter studies based on standardized testing protocols are needed to help determine appropriate reference ranges for clinical use.

Supplemental Material

sj-docx-1-oto-10.1177_01945998211029831 – Supplemental material for Normative Ambulatory Reflux Monitoring Metrics for Laryngopharyngeal Reflux: A Systematic Review of 720 Healthy Individuals

Supplemental material, sj-docx-1-oto-10.1177_01945998211029831 for Normative Ambulatory Reflux Monitoring Metrics for Laryngopharyngeal Reflux: A Systematic Review of 720 Healthy Individuals by Jerome R. Lechien, Walter W. Chan, Lee M. Akst, Toshitaka Hoppo, Blair A. Jobe, Carlos M. Chiesa-Estomba, Vinciane Muls, Francois Bobin, Sven Saussez, Thomas L. Carroll, Michael F. Vaezi and Jonathan M. Bock in Otolaryngology–Head and Neck Surgery

Footnotes

Author Contributions

Jerome R. Lechien, design, acquisition of data, data analysis and interpretation, drafting, accountability for the work, final approval of the version to be published, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Walter W. Chan, design, acquisition of data, data analysis and interpretation, drafting, accountability for the work, final approval of the version to be published, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Lee M. Akst, data interpretation, revising the manuscript for important intellectual content, final approval of the version to be published, accountability for the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Toshitaka Hoppo, data interpretation, revising the manuscript for important intellectual content, final approval of the version to be published, accountability for the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Blair A. Jobe, data interpretation, revising the manuscript for important intellectual content, final approval of the version to be published, accountability for the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Carlos M. Chiesa-Estomba, design, acquisition of data, data analysis and interpretation, drafting some parts of the manuscript, final approval of the version to be published, accountability for the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Vinciane Muls, design, acquisition of data, data analysis and interpretation, drafting some parts of the manuscript, final approval of the version to be published, accountability for the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Francois Bobin, design, acquisition of data, data analysis and interpretation, drafting some parts of the manuscript, final approval of the version to be published, accountability for the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Sven Saussez, data interpretation, revising the manuscript for important intellectual content, final approval of the version to be published, accountability for the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Thomas L. Carroll, data interpretation, revising the manuscript for important intellectual content, final approval of the version to be published, accountability for the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Michael F. Vaezi, data interpretation, revising the manuscript for important intellectual content, final approval of the version to be published, accountability for the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; Jonathan M. Bock, data interpretation, revising the manuscript for important intellectual content, final approval of the version to be published, accountability for the work, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Disclosures

Competing interests: None.

Sponsorships: None.

Funding source: None.

Supplemental Material

Additional supporting information is available in the online version of the article.

*

References 13, 14, 16 -19, 21, 23, 24, 26, .

References

Lechien

Akst

Hamdan

, et al. Evaluation and management of laryngopharyngeal reflux disease: state of the art review. Otolaryngol Head Neck Surg. 2019;160(5):762-782.

Kamani

Penney

Mitra

Pothula

The prevalence of laryngopharyngeal reflux in the English population. Eur Arch Otorhinolaryngol. 2012;269(10):2219-2225.

Spantideas

Drosou

Bougea

Assimakopoulos

Laryngopharyngeal reflux disease in the Greek general population, prevalence and risk factors. BMC Ear Nose Throat Disord. 2015;15:7.

Koufman

Amin

Panetti

Prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. Otolaryngol Head Neck Surg. 2000;123(4):385-388.

Brauer

Tse

Lin

Schatz

Simon

RA.

The utility of the reflux symptom index for diagnosis of laryngopharyngeal reflux in an allergy patient population. J Allergy Clin Immunol Pract. 2018;6(1):132-138.e1.

Lechien

Saussez

Schindler

, et al. Symptoms and signs outcomes of laryngopharyngeal reflux treatment: a critical systematic review and meta-analysis. Laryngoscope. 2019;129(5):1174-1187.

Thompson

Tiwari

Moe

Buckley

DI.

A Framework to Facilitate the Use of Systematic Reviews and Meta-Analyses in the Design of Primary Research Studies. Agency for Healthcare Research and Quality; 2012.

McInnes

MDF

Moher

Thombs

, et al. Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: the PRISMA-DTA statement. JAMA. 2018;319(4):388-396.

Viswanathan

Berkman

Dryden

Hartling

Assessing Risk of Bias and Confounding in Observational Studies of Interventions or Exposures: Further Development of the RTI Item Bank. Agency for Healthcare Research and Quality; 2013.

10.

Shay

Tutuian

Sifrim

, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol. 2004;99(6):1037-1043.

11.

Zentilin

Iiritano

Dulbecco

, et al. Normal values of 24-h ambulatory intraluminal impedance combined with pH-metry in subjects eating a Mediterranean diet. Dig Liver Dis. 2006;38(4):226-232.

12.

Xiao

Lin

Cheung

, et al. Normal values of 24-hour combined esophageal multichannel intraluminal impedance and pH monitoring in the Chinese population. Digestion. 2009;79(2):109-114.

13.

Sun

Muddana

Slaughter

, et al. A new pH catheter for laryngopharyngeal reflux: normal values. Laryngoscope. 2009;119(8):1639-1643.

14.

Wang

Liang

Jiang

, et al. Gastroesophageal and laryngopharyngeal reflux detected by 24-hour combined impedance and pH monitoring in healthy Chinese volunteers. J Dig Dis. 2011;12(3):173-180.

15.

Xiao

Liu

, et al. Gastroesophageal and laryngopharyngeal reflux profiles in patients with obstructive sleep apnea/hypopnea syndrome as determined by combined multichannel intraluminal impedance-pH monitoring. Neurogastroenterol Motil. 2012;24(6):e258-e265.

16.

Hoppo

Sanz

Nason

, 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(1):16-25.

17.

Desjardin

Roman

des Varannes

, et al. Pharyngeal pH alone is not reliable for the detection of pharyngeal reflux events: a study with oesophageal and pharyngeal pH-impedance monitoring. United Eur Gastroenterol J. 2013;1(6):438-444.

18.

Feng

Wang

Zhang

Liu

A study to draw a normative database of laryngopharynx pH profile in Chinese. J Neurogastroenterol Motil. 2014;20(3):347-351.

19.

Jetté

Gaumnitz

Birchall

Welham

Thibeault

SL.

Correlation between reflux and multichannel intraluminal impedance pH monitoring in untreated volunteers. Laryngoscope. 2014;124(10):2345-2351.

20.

Kawamura

Kohata

Kawami

, et al. Liquid-containing refluxes and acid refluxes may be less frequent in the Japanese population than in other populations: normal values of 24-hour esophageal impedance and pH monitoring. J Neurogastroenterol Motil. 2016;22(4):620-629.

21.

Hou

Chen

, et al. Study on laryngopharyngeal and esophageal reflux characteristics using 24-h multichannel intraluminal impedance-pH monitoring in healthy volunteers. Eur Arch Otorhinolaryngol. 2020;277(10):2801-2811.

22.

Chen

Liang

Zhang

, et al. A study of proximal esophageal baseline impedance in identifying and predicting laryngopharyngeal reflux. Gastroenterol Hepatol. 2020;35(9):1509-1514.

23.

Doo

Kim

Park

Kwon

Lee

Eun

YG.

Changes in pharyngeal baseline impedance in patients with laryngopharyngeal reflux. Otolaryngol Head Neck Surg. 2020;163(3):563-568.

24.

Yadlapati

Adkins

Jaiyeola

, et al. Abilities of oropharyngeal pH tests and salivary pepsin analysis to discriminate between asymptomatic volunteers and subjects with symptoms of laryngeal irritation. Clin Gastroenterol Hepatol. 2016;14(4):535-542.e2.

25.

Ayazi

Lipham

Hagen

, et al. A new technique for measurement of pharyngeal pH: normal values and discriminating pH threshold. J Gastrointest Surg. 2009;13(8):1422-1429.

26.

Chheda

Seybt

Schade

Postma

GN.

Normal values for pharyngeal pH monitoring. Ann Otol Rhinol Laryngol. 2009;118(3):166-171.

27.

Klimara

Johnston

Samuels

, et al. Correlation of salivary and nasal lavage pepsin with MII-pH testing. Laryngoscope. 2020;130(4):961-966.

28.

Zerbib

Roman

Bruley Des Varannes

, et al. Normal values of pharyngeal and esophageal 24-hour pH impedance in individuals on and off therapy and interobserver reproducibility. Clin Gastroenterol Hepatol. 2013;11(4):366-372.

29.

Sakin

Vardar

Sezgin

, et al. The diagnostic value of 24-hour ambulatory intraesophageal pH-impedance in patients with laryngopharyngeal reflux symptoms comparable with typical symptoms. United Eur Gastroenterol J. 2017;5(5):632-640.

30.

Merati

Lim

Ulualp

Toohill

RJ.

Meta-analysis of upper probe measurements in normal subjects and patients with laryngopharyngeal reflux. Ann Otol Rhinol Laryngol. 2005;114(3):177-182.

31.

Chae

Richter

JE.

Wireless 24, 48, and 96 hour or impedance or oropharyngeal prolonged pH monitoring: which test, when, and why for GERD?

Curr Gastroenterol Rep. 2018;20(11):52.

32.

Lechien

Saussez

Schindler

, et al. Clinical outcomes of laryngopharyngeal reflux treatment: a systematic review and meta-analysis. Laryngoscope. 2019;129(5):1174-1187.

33.

Song

Lee

Jeen

, et al. Inconsistent association of esophageal symptoms, psychometric abnormalities and dysmotility. Am J Gastroenterol. 2001;96(8):2312-2316.

34.

Lechien

Bobin

Mouawad

, et al. Development of scores assessing the refluxogenic potential of diet of patients with laryngopharyngeal reflux. Eur Arch Otorhinolaryngol. 2019;276(12):3389-3404.

35.

Ummarino

Vandermeulen

Roosens

Urbain

Hauser

Vandenplas

Gastroesophageal reflux evaluation in patients affected by chronic cough: restech versus multichannel intraluminal impedance/pH metry. Laryngoscope. 2013;123(4):980-984.

36.

Yadlapati

Adkins

Jaiyeola

37.

Yadlapati

Pandolfino

Lidder

, et al. Oropharyngeal pH testing does not predict response to proton pump inhibitor therapy in patients with laryngeal symptoms. Am J Gastroenterol. 2016;111(11):1517-1524.

38.

Sifrim

Castell

Dent

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.

39.

Modlin

Kidd

GERD 2004: issues from the past and a consensus for the future. Best Pract Res Clin Gastroenterol. 2004;18(suppl):55-66.

40.

Lee

Jung

Park

Lee

Eun

YG.

Comparison of characteristics according to reflux type in patients with laryngopharyngeal reflux. Clin Exp Otorhinolaryngol. 2018;11(2):141-145.

41.

Lechien

Bobin

Muls

, et al. Gastroesophageal reflux in laryngopharyngeal reflux patients: clinical features and therapeutic response. Laryngoscope. 2020;130(8):E479-E489.

42.

Wang

Zhao

Guo

The role of nonacid reflux in laryngopharyngeal reflux diseases. Eur Arch Otorhinolaryngol. 2020;277(10):2813-2819.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.01 MB