The Laryngoscope

© 2019 The American Laryngological,

Rhinological and Otological Society, Inc.

Gastroesophageal Reflux in Laryngopharyngeal Reflux Patients:

Clinical Features and Therapeutic Response

Jerome R. Lechien, MD, PhD, MSc ; Francois Bobin, MD; Vinciane Muls, MD; Pierre Eisendrath, MD, PhD;
Mihaela Horoi, MD; Marie-Paule Thill, MD; Didier Dequanter, MD, PhD; Jean-Pierre Durdurez, MD;
Alexandra Rodriguez, MD†; Sven Saussez, MD, PhD†

Objective: To investigate the clinical features and the therapeutic response of laryngopharyngeal reflux (LPR) patients
with or without gastroesophageal reflux disease (GERD).
Methods: Patients with LPR symptoms were enrolled from three European Hospitals. The diagnosis of LPR and GERD
was made through impedance-pH monitoring (MII-pH). A gastrointestinal endoscopy was realized in patients with digestive
complaints or ≥60 years old. The 3- to 6-month treatment was based on the association of diet, pantoprazole, alginate, and
magaldrate regarding the MII-pH characteristics. Reflux Symptom Score (RSS) and Reflux Sign Assessment (RSA) were used to
evaluate the clinical evolution throughout treatment. The gastrointestinal endoscopy findings, clinical features, and therapeutic
response were compared between patients with LPR and GERD (LPR/GERD) and patients with LPR.
Results: One hundred and eleven LPR patients were included, 54 being LPR/GERD. LPR/GERD patients had a higher
number of proximal reflux episodes compared with LPR patients. The prevalence of esophagitis, hernia hiatal, and lower esoph-
ageal sphincter insufficiency did not differ between groups. The presence of GERD was strongly associated with acid LPR.
Patients without GERD had a higher proportion of nonacid and mixed LPR compared with LPR/GERD patients. The pre- to
posttreatment evolutions of RSS and RSA were quite similar in both groups, with the exception of the 3- to 6-month improve-
ment of digestive symptoms, which was better in LPR/GERD group. The therapeutic success rates were 79.6% and 77.2% in
GERD/LPR and LPR group, respectively.
Conclusion: GERD is predictive of acid LPR. The clinical evolution and the therapeutic response rates were quite similar
in both groups.
Key Words: Laryngopharyngeal, reflux, gastroesophageal, relationship.
Level of Evidence: 4
Laryngoscope, 00:1–11, 2019

INTRODUCTION which induces morphological changes in the upper

Laryngopharyngeal reflux (LPR) is an inflammatory
condition of the upper aerodigestive tract tissues related to
direct and indirect effect of gastroduodenal content reflux,
From the Laryngopharyngeal Reflux Study Group of Young-
Otolaryngologists of the International Federations of Oto-rhino-
laryngological Societies (YO-IFOS) (J.R.L., F.B., V.M., D.D., A.R., S.S.); the
Laboratory of Anatomy and Cell Biology, Faculty of Medicine, UMONS
Research Institute for Health Sciences and Technology, University of
Mons (UMons) (J.R.L., S.S.), Mons; the Department of Otorhinolaryngology
and Head and Neck Surgery, CHU de Bruxelles, CHU Saint-Pierre,
School of Medicine (J.R.L., M.H., M.-P.T., D.D., J.-P.D., A.R., S.S.); the
Department of gastroenterology, CHU Saint-Pierre (V.M., P.E.), Université
Libre de Bruxelles, Brussels, Belgium; the Department of Head and Neck
Surgery, Centre Oscar Lambret (J.R.L.), Lille; Polyclinique Elsan de
Poitiers (F.B.), Poitiers, France; and the Department of Otolaryngology-
Head and Neck Surgery, Foch Hospital, University of Paris Saclay (J.R.L.),
Poitiers, France.
Editor’s Note: This Manuscript was accepted for publication on
December 5, 2019.
†
These authors contributed equally to this work.
This study was supported by the IRIS-Recherche (Foundation Roi
Baudouin) and the Vesale Grant (CHU Saint-Pierre). The authors have
no other funding, financial relationships, or conflicts of interest to
disclose.
Send correspondence to Dr. Jerome R. Lechien, MD, PhD, MS, Lab-
oratory of Anatomy and Cell Biology, Faculty of Medicine, University of
Mons (UMONS), Avenue du Champ de mars, 6, B7000 Mons, Belgium.
E-mail: jerome.lechien@umons.ac.be
DOI: 10.1002/lary.28482
aerodigestive tract.1 LPR has often been considered as dif-
ferent condition from gastroesophageal reflux disease
(GERD), sharing some common pathophysiological mecha-
nisms.2 The reflux episodes in GERD are more frequently
liquid, recumbent, and nighttime, whereas the reflux epi-
sodes in LPR are mainly gaseous, upright, and daytime.1,3
However, irrespective of the occurrence of GERD, LPR
patients would suffer from digestive complaints, some
improving throughout treatment.3 About gastrointestinal
endoscopy, esophagitis would be more prevalent in GERD
patients compared with LPR patients.4,5 These differences
led some authors to compare the clinical therapeutic
responses of GERD and LPR patients. Overall, patients with
concomitant GERD, GERD-related symptoms, and LPR
would be better responders to anti-reflux therapy in compar-
ison with those with LPR.6–8 This thought is widespread
among otolaryngologists and gastroenterologists. However,
there are a limited number of studies using multichannel
intraluminal impedance-pH monitoring (MII-pH) for identi-
fying all types of LPR (acid, nonacid, and mixed). In fact, the
lack of consideration of nonacid and mixed LPR, which con-
cern more than 50% of LPR patients,3,9 may lead to substan-
tial biases in the comparison of therapeutic response of LPR
patients according to the occurrence of GERD. In the same

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way, the exclusive use of proton pump inhibitors (PPIs) in
the treatment of LPR patients may lead to a therapeutic
response bias regarding the presumed poor efficacy of PPIs
in nonacid and mixed LPR.10
The aim of this study is to investigate the clinical
features and the therapeutic response of LPR patients
according to the occurrence of GERD or not.
MATERIALS AND METHODS
From January 2018 to June 2019, patients with LPR symp-
toms were enrolled from three European Hospitals (Polyclinique
Elsan de Poitiers, Poitiers, France; CHU Saint-Pierre & Cesar
De Pape Hospitals, Brussels, Belgium; local ethics committee
approbation: n BE076201837630). To be included, patients had
to have a positive LPR diagnosis through MII-pH study. Patients
were excluded if they had one of the following conditions:
smoker; alcohol dependence; pregnancy; neurological or psychiat-
ric illness; upper respiratory tract infection within the last
month; current use of anti-reflux treatment (i.e., PPIs, antihista-
mine, alginate, and magaldrate); previous history of neck surgery
or trauma; malignancy; history of ear, nose, and throat (ENT)
radiotherapy, and active seasonal allergies or asthma.
Multichannel Intraluminal Impedance-pH
Monitoring and GI Endoscopy
The details of MII-pH device, placement, and analyses have
been described in a previous publication.3 The MII-pH was com-
posed of eight impedance segments and two pH electrodes
(Versaflex Z, Digitrapper pH-Z testing System, Medtronic,
Europe). Six impedance segments were placed along the esopha-
gus zones (Z1–Z6) at 19, 17, 11, 9, 7, and 5 cm above the lower
esophageal sphincter (LES). Two additional impedance segments
were placed 1 and 2 cm above the upper esophageal sphinter
(UES) (hypopharyngeal cavity). The pH electrodes were placed
2 cm above LES and 1 to 2 cm below UES, respectively.
Distal reflux event was defined as an episode reaching the two
impedance sensors closest to the LES. Proximal reflux event was
defined as an episode that reached two impedance sensors in the hypo-
pharynx. Acid reflux episode consisted of an episode with pH ≤4.0.
Nonacid reflux episode consisted of an episode with pH > 4.0.

Fig. 1. Reflux Symptom Score. The questionnaire is subdivided into three parts according to the complaints: ear, nose, and throat (part 1, 9
items), digestive (part 2, 9 items), and respiratory (part 3, 4 items) symptoms. The frequency and severity of each symptom are rated with a
5-point scale. Regarding frequency, 0 = patient did not have the complaint over the past month; 1, 2, 3, 4 = patient had the complaint 1–2,
2–3, 3–4, 4–5 times weekly, respectively, over the past month; 5 = patient had the complaint daily over the past month. Regarding severity,
0 = the complaint is absent; 5 = the complaint is very troublesome when it occurs. For each item, the severity score is multiplied by the fre-
quency score to obtain a symptom score ranging from 0 to 25. The sum of these symptom scores is calculated to obtain the RSS final score
(range: 0–550, with possibility for the physician and patient to add 3 symptoms not identified in the RSS, leading to a maximal possible score
of 625). The RSS also assesses the symptom impact on quality of life. The total quality-of-life score is calculated by the sum of each item
score.RSS = Reflux Symptom Score.

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 The LPR diagnosis consisted of the occurrence of ≥1 proxi-
mal episode.11 LPR was defined as acid when the ratio of number
of acid reflux episodes/number of nonacid reflux episodes was >2.
LPR was defined as nonacid when the ratio of number of acid
reflux episodes/number of nonacid reflux episodes <0.5. Mixed
reflux consisted of a ratio ranged from 0.51 to 2.0. Regarding the
paper of Johnson et DeMeester, GERD was defined as a length of
time >4.0% of the 24-hour recording spent below pH 4.0 or a
DeMeester Score > 14.72.12
GI endoscopy was performed in patients with GERD-related
symptoms and in patients ≥60 years old regarding the reduced
esophageal sensitivity. The following findings were referenced
through the GI endoscopy: hiatal hernia, esophagitis (Los Angeles
Grading System13), LES insufficiency, and gastritis.
Treatment
According to the characteristics of LPR at the MII-pH (acid,
nonacid, or mixed LPR), patients were treated with a personalized
treatment scheme including diet, behavioral changes, and the use
of PPIs (pantoprazole)  alginate  magaldrate for 3 to 6 months.
The respect of diet and medication was carefully assessed post-
treatment through a structured anamnesis.
Global Refluxogenic Score (GRES) has been used to assess
the diet habits of the patients at baseline and throughout treat-
ment. GRES is a score rating the refluxogenic potential of West-
ern European foods and beverages that are usually consumed by
European people. The calculation of GRES has been described in
a previous publication.14 Overall, GRES is based on the
Refluxogenic Diet Score (REDS), classifying foods and beverages
in five categories from very low refluxogenic food/beverage
(cat.1) to very high refluxogenic food/beverage (cat.5).14 If sub-
jects ate largely highly refluxogenic foods/beverages over the
past 3 weeks, then the GRES will be high. A high GRES is asso-
ciated with a high number of proximal reflux episodes.15 Once
the reflux had been confirmed, the patient received diet recom-
mendations based on a personalized diet grid excluding
refluxogenic foods and beverages.

Fig. 2. Clinical version of Reflux Sign Assessment. The tool is subdivided into three parts according to sign localization: oral cavity, pharynx,
and larynx. Note that some items used for this study (nasopharyngeal erythema, subglottic edema/erythema, vocal fold edema and erythema)
were removed from the clinical version of RSA because of their low prevalence. The total score is calculated by the sum of each item score.
The maximum score is 61.RSA = Reflux Sign Assessment.

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 TABLE I.
Characteristics of LPR Patients.
LPR and GERD LPR
Characteristics
Age m  SD Range m  SD Range P Value

Mean  SD 55.6  16.6 22–86 49.8  15.7 21–90 NS

Gender
Male 19 35.2% 20 35.1% NS
Female 35 64.8% 37 64.9% NS
BMI 27.4  6.1 26.0  7.3 NS

Gastrointestinal endoscopy N (43) Prevalence N (41) Prevalence

Normal 9 20.9% 8 19.5% NS

Esophagitis (LA Grading system) 11 25.5% 15 36.6% NS
Los Angeles Grade A 9 20.1% 14 34.1% NS
Los Angeles Grade B 1 2.3% 1 2.4% NS
Los Angeles Grade C 0 0% 0 0% NS
Los Angeles Grade D 1 2.3% 0 0% NS
Hiatal hernia 16 37.2% 13 31.7% NS
LES insufficiency 22 51.2% 19 46.4% NS
Gastritis 13 30.2% 14 34.1% NS
GRES 108.2  49.2 34–233 94.5  46.3 24–238 NS

MII-pH (m  SD) N N

Acid LPR 30 55.5% 11 19.3 0.001

Mixed LPR 11 20.4% 26 45.6% 0.001
Nonacid LPR 13 24.1% 20 35.1% 0.001
Proximal reflux episodes 42.3  48.0 – 24.8  25.4 – 0.001
Acid episodes 22.6  20.0 – 10.7  13.5 – 0.001
Nonacid episodes 13.6  16.9 – 14.0  17.0 – NS
Upright proximal reflux episodes 31.3  33.3 – 20.1  21.3 – 0.042
Recumbent proximal reflux episodes 7.6  21.6 – 4.0  8.4 – NS
Distal reflux episodes 91.9  87.4 – 49.6  50.5 – 0.001
Acid episodes 63.4  82.3 – 20.3  22.5 – 0.001
Nonacid episodes 24.3  26.8 – 29.8  37.3 – NS
Upright distal reflux episodes 94.2  105.2 – 49.6  43.3 – 0.003
Recumbent distal reflux episodes 15.4  13.3 – 10.9  17.1 – 0.031
DeMeester Score 43.1  76.6 – 3.1  4.3 – 0.001

Main symptom N Prevalence N Prevalence

Cough 13 24.1% 8 14.0% –

Globus 12 22.2% 9 15.8% –
Throat pain 9 16.7% 10 17.5% –
Sticky throat mucus 4 7.4% 11 19.3% –
Heartburn 3 5.6% 5 8.8% –
Throat clearing 3 5.6% 2 3.5% –
Dysphagia 3 5.6% 0 0% –
Halitosis 3 5.6% 0 0% –
Hoarseness 2 3.7% 6 10.5% –
Ear pain/pressure 2 3.7% 0 0% –
Burp or regurgitations 2 3.7% 1 1.8% –
Sleep disorder 1 1.9% 1 1.8% –
Postnasal drip 0 0% 2 3.5% –
Chest pain 0 0% 1 1.8% –
Odynophagia 0 0% 1 1.8% –

(Continues)

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 TABLE I.
Continued
Main symptom N Prevalence N Prevalence

Therapeutic response
Uncertain or no responder 11 20.4% 13 22.8% NS
Responder 43 79.6% 44 77.2% NS
Mild response 5 11.6% 3 6.8% –
Moderate response 9 20.9% 12 27.3% –
High response 10 23.3% 15 34.1% –
Complete response 19 44.2% 14 31.8% –

BMI = body mass index; GERD = gastroesophageal reflux disease; GRES = Global Refluxogenic Score; LA = Los Angeles; LES = lower esophageal sphinc-
ter; LPR = laryngopharyngeal reflux; m = mean; MII-pH = multichannel intraluminal impedance-pH monitoring; N = number; NS = nonsignificant; SD = standard
deviation.

TABLE II.
Changes of Reflux Symptom Score Throughout Treatment in Patients With GERD and LPR.
Reflux Symptom Score Pretreatment 6 Weeks Posttreatment 3 Months Posttreatment 6 Months Posttreatment

ENT symptoms
1. Voice disorder 4.36  5.89 3.00  3.38 2.20  3.91** 1.65  2.67
2. Throat pain 5.62  7.26 6.66  6.83 3.27  5.86** 1.83  3.45
3. Pain during swallowing time 3.27  5.51 2.88  3.62 1.22  2.24* 1.17  2.64
4. Dysphagia 4.67  6.57 2.59  4.42 1.71  3.59** 2.09  4.12
5. Throat clearing 12.40  9.93 7.69  8.86* 8.98  9.18** 6.52  7.70
6. Globus sensation 10.84  10.05 8.16  9.19 7.95  10.26* 5.61  8.60*
7. Excess throat mucus 13.53  10.45 6.91  8.78* 9.32  9.86* 6.78  8.14*
8. Ear pressure/pain 3.78  5.91 2.91  4.69 2.37  5.75* 0.83  1.50
9. Tongue burning 2.56  6.03 4.25  7.88 2.12  5.93 1.57  5.20
ENT total score 56.94  38.95 46.03  37.62* 36.54  33.01** 28.04  27.10*
Digestive symptoms
1. Heartburn 8.27  9.53 2.66  4.09* 3.83  6.27* 2.00  3.83
2. Regurgitations or burps 6.04  8.13 2.31  4.21** 2.22  4.00** 1.39  2.68
3. Abdominal pain 4.44  8.33 3.31  4.33 2.20  4.39 2.04  4.14
4. Diarrheas 4.67  6.57 1.09  1.90 1.20  3.99 1.26  2.72
5. Constipation 12.36  9.93 2.91  4.03 1.44  3.82** 1.57  3.42
6. Indigestion 10.84  10.05 0.94  1.72 1.12  4.57 0.61  2.02
7. Abdominal distension/flatus 13.53  10.45 5.78  7.96 5.56  7.30 3.96  7.04
8. Halitosis 3.78  5.91 3.44  5.22 4.15  6.93 3.91  7.48
9. Nausea 2.56  6.03 2.16  6.41 1.22  4.20 0.13  0.46
Digestive total score 43.28  37.60 25.78  19.43 21.38  22.85** 16.87  23.63
Respiratory symptoms
1. Cough after eating/lying down 7.07  8.95 2.06  4.28* 5.59  8.65 1.30  3.21
2. Cough 6.13  8.04 2.44  3.97* 4.27  7.91 1.39  2.62
3. Breathing difficulties 5.06  7.39 1.47  2.08 1.63  4.47 0.26  0.86
4. Chest pain 5.29  7.51 5.31  7.32 4.32  6.88 3.17  6.10
Respiratory total score 23.72  27.17 11.47  11.86* 14.52  19.64* 6.13  8.90
RSS score total 117.80  82.81 83.28  56.94* 72.44  65.15** 51.04  47.59*
Quality of life score 32.43  19.20 26.88  16.31* 20.60  16.08** 15.48  13.90**
ENT QoL 14.06  8.86 12.75  8.74* 9.66  7.47** 7.65  6.69**
Digestive QoL 12.20  9.01 9.53  6.50* 6.66  6.10** 5.74  6.83
Respiratory QoL 6.17  4.72 4.59  4.45 4.28  4.95** 2.09  2.56

*Significant improvement (P < 0.05).

**significant improvement (P ≤ 0.01; Wilcoxon Rank test).
ENT = ear, nose, and throat; GERD = gastroesophageal reflux disease; LPR = laryngopharyngeal reflux disease; QoL = quality of life; RSS = Reflux Symp-
tom Score.

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Clinical Outcomes and Therapeutic Response
The symptoms of reflux were assessed at baseline, 6-week,
3-month, and 6-month posttreatment with Reflux Symptom
Score (RSS) (Fig. 1). The Reflux Sign Assessment (RSA) (Fig. 2)
was used to rate the clinical findings at baseline, 3- and 6-month
posttreatment.16 Note that the finding assessment was per-
formed by three blinded laryngologists on the basis of oral cavity
photos and videolaryngostroboscopy. The oral photos had to visu-
alize the anterior pillar, the uvula, and the tongue for evaluating
the RSA findings (Fig. 2).
The definition of the therapeutic response was based on the
reduction of RSS. An uncertain therapeutic response was defined
as a reduction of <20% of the initial RSS. An RSS reduction of
20% to 39.9% was defined as a mild therapeutic response. An
RSS reduction of 40% to 59.9% was defined as moderate thera-
peutic response. Patients with an RSS reduction of 60% to 79.9%
were defined as high responders to treatment. An RSS reduction
of ≥80% or a posttreatment RSS ≤13 were defined as a complete
therapeutic response. The treatment was tailored with regard to
the 3-month therapeutic response and continued/changed in non-
responder patients. When possible, the patients were weaned
from medication, and they were invited to continue the respect
of diet.
Statistical Methods
Statistical analyses were performed using the Statistical
Package for the Social Sciences for Windows (SPSS version 22.0;
IBM Corp, Armonk, NY). The comparison of both groups at base-
line was made using Mann-Whitney U test. The pre- to post-
treatment changes of RSS and RSA was evaluated with Wilcoxon

TABLE III.
Changes of Reflux Symptom Score Throughout Treatment in Patients With LPR.
Reflux Symptom Score Pretreatment 6 Weeks Posttreatment 3 Months Posttreatment 6 Months Posttreatment

ENT symptoms
1. Voice disorder 4.14  6.58 2.48  3.65 3.43  6.67 3.12  5.67
2. Throat pain 6.11  7.82 4.46  7.78 3.14  5.38* 3.50  4.75
3. Pain during swallowing time 3.52  5.47 1.29  3.34 2.74  5.43 2.58  5.81
4. Dysphagia 3.00  4.80 1.73  3.55 1.57  3.23 1.35  2.70
5. Throat clearing 11.43  9.31 8.13  7.74* 7.60  8.74* 5.65  8.18*
6. Globus sensation 9.86  8.94 7.13  8.00 8.26  9.77 4.89  6.56
7. Excess throat mucus 13.30  10.42 8.56  9.07** 7.79  9.36** 7.04  8.55
8. Ear pressure/pain 4.86  7.45 1.71  3.38* 3.43  6.10 3.69  7.09
9. Tongue burning 2.71  5.94 2.48  6.48 2.33  6.03 1.42  2.85
ENT total score 55.56  40.83 36.77  29.51* 39.47  43.94** 33.62  33.28
Digestive symptoms
1. Heartburn 8.57  8.81 4.96  6.39 3.88  6.41** 5.62  7.80
2. Regurgitations or burps 4.61  6.65 1.63  3.01* 2.10  4.43* 4.35  6.54
3. Abdominal pain 5.07  6.95 3.42  5.88* 3.26  6.00 4.12  6.20
4. Diarrheas 2.86  5.39 0.40  0.98** 1.19  4.54** 1.73  5.40
5. Constipation 3.34  6.89 2.65  2.97 3.05  6.00 2.08  4.66
6. Indigestion 2.32  4.84 1.79  2.92 1.02  2.40 2.23  4.83
7. Abdominal distension/flatus 7.61  8.79 5.27  6.96 4.24  7.29** 4.12  6.55
8. Halitosis 6.84  9.26 3.42  6.18 4.45  8.13 3.65  6.54
9. Nausea 2.77  5.73 0.71  1.33 1.36  4.54* 1.62  5.01
Digestive total score 44.18  35.89 23.90  21.20** 28.31  45.64** 31.62  31.30
Respiratory symptoms
1. Cough after eating/lying down 5.18  7.22 3.92  5.27 3.12  6.31* 1.58  4.92*
2. Cough 5.14  7.03 3.77  5.56 3.12  6.36 3.50  7.47
3. Breathing difficulties 3.07  5.56 2.96  5.82 2.38  5.26 1.35  3.60*
4. Chest pain 4.36  7.12 1.83  3.80* 2.45  5.58* 1.27  3.65
Respiratory total score 20.61  23.71 12.48  14.82* 12.40  21.58 7.62  13.11*
RSS score total 120.20  79.93 73.15  51.74** 80.18  101.30** 72.85  60.19
Quality of life score 33.05  19.60 24.69  11.90** 20.84  14.99** 22.04  15.21
ENT QoL 14.33  9.55 11.31  6.03* 9.95  7.65** 9.92  8.15
Digestive QoL 12.54  9.19 9.04  5.91* 7.38  6.48** 9.17  8.01
Respiratory QoL 6.18  6.68 4.29  4.08** 3.54  4.53** 2.96  3.25*

*Significant improvement (P < 0.05).

**significant improvement (P ≤ 0.01; Wilcoxon Rank test).
ENT = ear, nose, and throat; GERD = gastroesophageal reflux disease; LPR = laryngopharyngeal reflux disease; QoL = quality of life; RSS = Reflux Symp-
tom Score.

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signed-rank test. The identification of predictors of therapeutic
response and the relationship between MII-pH and GI endoscopy
findings were investigated through linear regression. A level of
significance of P < 0.05 was used.
RESULTS
A total of 123 patients with laryngopharyngeal symp-
toms were recruited. One hundred and eleven patients com-
pleted the pre- to posttreatment evaluations. Twelve
patients were excluded for the following reasons: lost of
follow-up after the MII-pH (N = 4), lost of follow-up through-
out treatment (N = 6), and lack of treatment taking (N = 2).
According to Johnston et DeMeester definition, 54 patients
had LPR and GERD, whereas 57 have LPR. Both groups
were comparable regarding age, sex ratio, and body mass
index. The characteristics of patients are described in
Table I. The proportion of esophagitis, hiatal hernia, LES
insufficiency, and gastritis was similar in both groups.
Twenty percent of patients had unremarkable GI endos-
copy. The proportion of patients with acid LPR was signifi-
cantly higher in the GERD/LPR group (P = 0.001), whereas
LPR patients without GERD had a higher proportion of
mixed or nonacid LPR (P = 0.001). Patients with concomi-
tant GERD and LPR had a higher number of upright and
daytime proximal and distal reflux episodes. The linear
regression analysis supported a strong association between
acid LPR and the presence of GERD (P = 0.001). There was
a significant association between baseline GRES and the
number of both proximal (P = 0.010) and distal (P = 0.014)
reflux episodes at the MII-pH. GRES of LPR patients was
associated with the RSA oral (P = 0.010) and pharyngeal
(P = 0.034) subscores. Patients with a high GRES had a high
3-month RSA oral subscore (P = 0.013). The presence of

TABLE IV.
Changes of Reflux Symptom Score Throughout Treatment in Patients With GERD and LPR.
Reflux Sign Assessment Pretreatment 3-Month 6-Month

Oral cavity findings

1. Anterior pillar erythema 3.14  1.57 2.89  1.79 2.60  1.96
2. Uvula erythema  edema 1.63  1.45 1.58  1.39 1.50  1.54
3. Coated tongue 1.28  0.86 1.29  0.84 0.95  1.02
Oral cavity subscore 6.01  2.58 4.90  2.60* 4.86  2.78
Pharyngeal findings
1. Nasopharyngeal wall erythema  inflammatory 0.78  0.88 0.14  0.53 0.01  0.01
granulations
2. Posterior oro- or hypopharyngeal wall erythema 2.38  1.82 1.04  1.60** 0.20  0.89
3. Posterior oro- or hypopharyngeal wall inflammatory 0.71  1.17 0.48  0.86 0.75  1.33
granulations
4. Tongue tonsil hypertrophy 2.31  1.31 1.89  1.27 2.55  1.57
5. Contact between epiglottis and tongue tonsils 2.88  1.79 2.23  1.89 2.32  2.03
6. Pharyngeal sticky mucus 2.25  1.82 1.71  1.75 1.40  1.96
Pharyngeal cavity subscore 9.98  4.53 5.92  3.76** 7.10  4.87
Laryngeal findings
Sub- and supraglottic areas
1. Subglottic edema  erythema 0.01  0.01 0.07  0.26 0.17  0.41
2. Ventricular band erythema  edema 1.48  0.75 1.23  0.91 0.86  1.01
3. Epiglottis redness  edema 1.18  1.33 0.76  1.16* 0.10  0.20*
Posterior commissure
1. Commissure posterior/arytenoid erythema 3.34  1.70 2.09  2.20** 0.57  1.43
2. Interarytenoid granulation tissue 0.63  0.90 0.15  0.51* 0.20  0.62
3. Posterior commissure hypertrophy 3.87  1.70 2.73  2.19* 1.00  2.05**
4. Retrocricoid erythema 1.18  1.43 0.61  1.02* 0.10  0.21*
5. Retrocricoid edema 2.32  1.80 1.70  1.79 0.60  1.47*
Vocal folds
1. Endolaryngeal sticky mucus deposit 1.40  1.32 0.81  1.14 0.45  1.10
2. Vocal fold erythema 0.11  0.26 0.01  0.06* 0.01  0.01
3. Edema of the free edge or the entire vocal folds 0.07  0.15 0.07  0.16 0.05  0.20
4. Vocal fold lesions 0.08  0.37 0.09  0.39 0.08  0.40
Laryngeal subscore 14.34  6.34 8.40  4.90** 4.05  3.07**
RSA total 27.46  10.01 19.40  7.27** 16.50  7.52

*Significant improvement (P < 0.05).

**significant improvement (P ≤ 0.01; Wilcoxon Rank test).
GERD = gastroesophageal reflux disease; LPR = laryngopharyngeal reflux disease; QoL = quality of life; RSA = Reflux Sign Assessment.

Laryngoscope 00: 2019 Lechien et al.: Reflux Disease

7
hiatal hernia was associated with a higher DeMeester Score
in the entire cohort (P = 0.033). Chronic cough, globus sensa-
tion, and throat pain were the main reasons for consultation
in patients with GERD and LPR, whereas sticky throat
mucus, throat pain, and globus sensation were the main rea-
sons in LPR patients.
There were no significant differences between groups
regarding the ENT, digestive, and respiratory symptoms at
baseline. The scores of laryngeal ventricular band inflamma-
tion (P = 0.025) and retrocricoid edema (P = 0.033) of GERD/
LPR patients were higher than those of LPR patients.
Clinical Evolution and Therapeutic Response
The pre- to posttreatment changes of RSS of GERD/
LPR and LPR groups are described in Tables II and III,
respectively.
Patients with GERD and LPR had a significant reduc-
tion of RSS (total score), ENT, and respiratory subscores
from pre- to 6-week posttreatment. The digestive subscore
of this group significantly decreased from pre- to 3-month
posttreatment. The ENT and RSS (total) scores continued
to decrease from 3- to 6-month posttreatment (Table II).
Quality-of-life scores similarly reduced throughout
treatment.
Patients with LPR had a significant decrease of RSS
(total score), ENT, digestive, and respiratory subscores
from pre- to 6-week posttreatment. Similar improvements
were found from pre- to 3-month posttreatment. Some
isolated symptoms continued to decrease from 3- to
6-month posttreatment (Table III). Similar trends have
been observed for quality-of-life scores.
There were no significant differences between groups
in the decrease of RSS, ENT, and respiratory subscores

TABLE V.
Changes of Reflux Sign Assessment Throughout Treatment in Patients With LPR.
Reflux Sign Assessment Pretreatment 3-Month 6-Month

Oral cavity findings

1. Anterior pillar erythema 3.48  1.25 3.19  1.46 2.29  2.03
2. Uvula erythema  edema 1.35  1.36 1.33  1.28 1.23  1.51
3. Coated tongue 1.16  0.81 1.42  0.82 1.00  1.02
Oral cavity subscore 5.82  2.53 4.86  2.48* 4.41  2.70
Pharyngeal findings
1. Nasopharyngeal wall erythema  inflammatory 0.77  0.97 0.29  0.60 0.01  0.01
granulations
2. Posterior oro- or hypopharyngeal wall erythema 2.42  1.65 1.78  1.71 0.64  1.50**
3. Posterior oro- or hypopharyngeal wall inflammatory 1.09  1.25 0.81  1.17 0.24  0.83*
granulations
4. Tongue tonsil hypertrophy 2.44  1.33 2.16  1.30 2.08  1.78
5. Contact between epiglottis and tongue tonsils 2.82  1.66 2.48  1.83 2.40  2.00
6. Pharyngeal sticky mucus 2.33  1.66 1.87  1.78 0.96  1.74
Pharyngeal cavity subscore 11.10  4.29 7.46  3.54** 6.32  5.15
Laryngeal findings
Sub- and supraglottic areas
1. Subglottic edema  erythema 0.06  0.21 0.01  0.01 0.01  0.01
2. Ventricular band erythema  edema 1.08  0.82 0.89  0.83 0.64  0.95
3. Epiglottis redness  edema 1.13  1.30 0.47  0.81** 0.12  0.60
Posterior commissure
1. Commissure posterior/arytenoid erythema 3.33  1.42 2.27  1.80** 0.96  1.74*
2. Interarytenoid granulatory tissue 0.24  0.57 0.12  0.39 0.01  0.01
3. Posterior commissure hypertrophy 3.31  2.00 1.89  2.00* 1.40  2.29
4. Retrocricoid erythema 0.73  1.22 0.51  0.98 0.16  0.80
5. Retrocricoid edema 1.42  1.66 1.17  1.70 0.80  0.63
Vocal folds
1. Endolaryngeal sticky mucus deposit 1.34  1.16 1.18  1.26 0.72  1.31
2. Vocal fold erythema 0.02  0.07 0.05  0.18* 0.01  0.01
3. Edema of the free edge or the entire vocal folds 0.09  0.17 0.09  0.15 0.04  0.20
4. Vocal fold lesions 0.05  0.31 0.05  0.32 0.08  0.40
Laryngeal subscore 11.31  5.66 7.56  4.58** 4.92  5.05**
RSA total 25.54  9.50 19.69  7.71** 15.12  7.98*

*Significant improvement (P < 0.05).

**significant improvement (P ≤ 0.01; Wilcoxon Rank test).

Laryngoscope 00: 2019 Lechien et al.: Reflux Disease

8
throughout treatment. The 3- to 6-month decrease of
digestive subscore was significantly higher in GERD/LPR
group compared with the LPR group (P = 0.019). Consid-
ering symptoms individually, the reduction of heartburn
was higher in GERD/LPR compared with LPR group
(P = 0.016), whereas the reduction of chest pain was
higher in LPR group compared with GERD/LPR group
(P = 0.040). No further differences were found between
groups.
The RSA total score significantly decreased from pre-
to 3-month posttreatment in both groups. The laryngeal
subscore continued to decrease from 3- to 6-month post-
treatment in patients with GERD and LPR (Table IV).
Both the RSA total score and laryngeal subscore continued
to decrease from 3- to 6-month posttreatment in LPR
group (Table V). The evolution of RSA total score, sub-
scores, and finding item scores was comparable between
groups.
Respectively, 79.6% and 77.2% of patients with GERD/
LPR and LPR responded to treatment (Table I). There were
no significant differences between groups. Note that four
and six patients required 9 months of treatment to respond
to treatment in GERD/LPR and LPR groups, respectively.
Among the remaining patients, 13.0% of GERD/LPR and
12.3% of LPR patients had a chronic course of the disease
(defined as an RSS reduction <20%) without impact on qual-
ity of life. The remaining patients were resistant to conven-
tional therapy (persistent symptoms associated with
substantial impairment of quality of life) and required
unconventional treatment associating very strict diet, baclo-
fen, amitriptyline, or surgery. The medication weaning rates
were 88.9% and 89.5% in GERD/LPR and LPR groups,
respectively.
DISCUSSION
It has long been suggested that patients with concomi-
tant GERD and LPR have different profile of patients with-
out GERD, especially in the response to anti-reflux therapy.
However, only a few studies investigated the potential dif-
ferences between these two types of LPR patients. This lack
of interest is probably related to the low use of pH monitor-
ing or MII-pH in otolaryngology,17 which are indispensable
to make the GERD diagnosis. Moreover, the recent develop-
ment of MII-pH in gastroenterology led to the identification
of three LPR subtypes, acid, nonacid, and mixed LPR,
regarding the proportion of proximal acid or nonacid reflux
episodes. To our knowledge, the relationship between GERD
and LPR subtypes has never been studied in otolaryngology.
The results of this study suggest that LPR and GERD
are not two separate diseases but are interlinked conditions.
Reflux episodes differently occur in LPR and GERD (liquid
vs. gas, distal vs. proximal). There seems to be two main pro-
files of LPR patients according to MII-pH: patients with con-
comitant GERD and acid LPR and those without GERD who
have in a similar proportion nonacid or mixed LPR. At base-
line, we believed that the strong association between GERD
and acid LPR was related to the Johnston et DeMeester defi-
nition of GERD (DeMeester Score or distal pH < 4, >4% of
time), which only considers acid distal reflux episodes; how-
ever, our analysis demonstrated that patients with nonacid
Laryngoscope 00: 2019
or mixed LPR did not have a higher number of nonacid or
mixed distal reflux episodes than those with GERD and con-
sequently had no nonacid or mixed GERD. Moreover, the
GERD/LPR patients had a higher number of proximal reflux
episodes compared with LPR patients, irrespective to the
type of LPR. This observation strengthens the existing rela-
tionship between GERD and LPR. Thus, because GERD is
associated with a higher number (or longer) of LES transient
relaxations, the occurrence of GERD leads to a higher expo-
sure of gastric content in the esophagus. In that respect and
as found in the present study, patients with GERD have a
higher probability to have distal reflux episodes that extend
to proximal esophagus and hypopharynx compared with
LPR patients who have less LES dysfunction. Similar expla-
nations have been suggested by Groome et al., who identified
that patients with a severe reflux esophagitis had a higher
prevalence of LPR.18 In the same vein, Benjamin et al. found
that GERD patients had a high proportion of abnormal UES
function.19 According to our data and those of the literature,
GERD would be considered a risk factor of LPR development
and a predictor of acid LPR type.
The prevalence of esophagitis, hiatal hernia, LES
insufficiency, and gastritis were quite similar in both
groups; and the presence of hiatal hernia was positively
associated with the DeMeester Score. The relationship
between hiatal hernia and DeMeester Score is not new,
well-understood, and reported in many studies.20,21 How-
ever, only a few studies investigated the occurrence of esoph-
agitis, LES insufficiency, and hiatal hernia in LPR patients
according to the occurrence of GERD. Our results suggest
that a significant number of LPR patients may have hiatal
hernia (34.5%), LES insufficiency (48.8%), or esophagitis
(31.0%). Regarding previous studies, the rates of esophagitis
and hiatal hernia in LPR patients range from 19% to
65%4,5,7 and from 13% to 62%,4,22 respectively. However,
43 GERD/LPR (79.6%) and 41 LPR (71.9%) patients had no
GI endoscopy, respectively. The reasons were the patient
opposition or the lack of GERD-related symptoms, which
may be considered as a weakness of the study, limiting the
generalization of the prevalence of the GI findings. Because
LPR is obviously associated with LES and UES transient
relaxations, hiatal hernia and LES insufficiency may consist
of favoring factors of esophagus exposure of gastric content,
and in case of UES relaxation may lead to deposit of gastric
content in the mucosa of upper aerodigestive tract.
LES and esophageal acid exposure have long been
suspected to be associated with the consumption of some
refluxogenic foods and beverages. In this study, we
observed that a high refluxogenic diet was associated with
a high number of distal and proximal reflux episodes, con-
firming the key role of diet in the development of LPR and
GERD. To date, the profile of LPR patients requiring GI
endoscopy is not formally identified. The observations of
the present study may support that the GI endoscopy also
has to be proposed to patients without GERD for identify-
ing esophagitis, LES insufficiency, and hiatal hernia—the
latter being a risk factor of recurrence or chronic course of
the reflux disease.23
From a therapeutic standpoint, there were no differ-
ences in the therapeutic response between patients with
concomitant GERD and LPR and those with LPR. The
Lechien et al.: Reflux Disease
9
overall symptom and finding improvements were quite
similar in both groups as well as the therapeutic success
rates. These results do not corroborate the findings of previ-
ous studies.6–8 Two points may explain the discrepancy with
the literature.
First, in the previous studies, the diagnosis of LPR was
based on pH monitoring without impedance7 or with MII-
pH without consideration of nonacid LPR,8 the patients
being treated by PPIs as single therapy.7,8,24 Consequently,
the selected LPR patients only had acid or mixed LPR, the
latter being prevalent3,9 and less responder to PPIs.10 In
that way, it is not surprisingly that LPR patients did not bet-
ter respond to PPI therapy compared with patients with
GERD. Indeed, GERD patients mainly had a high propor-
tion of acid reflux episodes following the current criteria of
Johnston et DeMeester12 or Montreal consensus (defining
GERD on the basis on acid episodes).25 Thus, it is probable
that some previous cohort studies were composed of an
implicit selection of LPR patients: those with GERD and
acid LPR (characterized by a good PPI response), as well as
those with LPR (acid and mixed) with an uncertain PPI
response.
Second, in the present study, the treatment was based
on the type of reflux at the MII-pH. The combination of
PPIs and alginate or magaldrate provided a better protec-
tion of the upper aerodigestive tract mucosa. The pepsin
activity requires an acidic environment. PPIs make sense
in patients with acid reflux episodes. They increase the pH
of the gastric content and the related aerolized refluxate
droplets in the upper aerodigestive tract mucosa, which is
associated with a decrease of the extracellular pepsin activ-
ity.26 Because PPIs do not reduce the reflux episodes, the
gastric content (e.g., pepsin, lipase, trypsin, bile salts) con-
tinues to refluxate through aerolized alkaline droplets.
Furthermore, pepsin may be internalized and reactivated
into the Golgi, which is associated with an intracellular tox-
icity on which the PPIs cannot impact.27 The intracellular
pathway of pepsin and the potential involvement of tryp-
sin, bile salts, and other gastroduodenal enzymes (active at
alkaline pH)28 may explain the resistance to high-dose PPI
therapy in some patients with mixed or nonacid LPR. Thus,
the use of alginate or magaldrate in nonacid and mixed
LPR patients makes sense. Alginate and magaldrate form
a raft floating over gastric content and a protective biofilm
on the mucosa of esophagus and upper aerodigestive tract,
which limits extra- and intracellular activities of pepsin
and other gastroduodenal enzymes.29 Moreover, contrarily
to PPIs, alginate and magaldrate may reduce the number
of reflux events, limiting the deposit of gastroduodenal
enzymes in the upper aerodigestive tract mucosa.30,31 It
seems highly probable that the addition of alginate or
magaldrate to PPIs for acid and mixed LPR and the exclu-
sive use of alginate/magaldrate for nonacid LPR lead to an
optimal protection for LPR patients and, irrespective to the
type of reflux, similar therapeutic response rates. In addi-
tion to medication, the respect of anti-reflux diet is impor-
tant because associated with a substantial improvement of
both symptoms and findings. No additional analyses have
been performed in the present study for investigating the
differentiated effect of medication and diet in the improve-
ment of the clinical state.
Laryngoscope 00: 2019
10
CONCLUSION
The prevalence of GERD among LPR patients is high,
and GERD is associated with a high number of proximal
reflux episodes, both conditions being interlinked. Irres-
pective to the occurrence of GERD, LPR patients have GI
endoscopy abnormalities and suffer from otolaryngological,
respiratory, and digestive complaints, which significantly
improved throughout treatment. The therapeutic success
rate of LPR patients treated with the association of diet,
alginate, magaldrate, or PPIs is high, ranging from 77.2% to
79.6%. Apart from the 3- to 6-month digestive symptom
improvement, patients with LPR and GERD are not better
responders to anti-reflux therapy compared with those
with LPR.
ACKNOWLEDGMENT
IRIS-Recherche Grant (Foundation Roi Baudouin), Vesale
Grant. We acknowledge the IRIS-Recherche Grant and
Vesale Grant (CHU Saint-Pierre).
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