State of the Art Review

Otolaryngology–
Head and Neck Surgery

Evaluation and Management of 2019, Vol. 160(5) 762–782

Ó American Academy of
Otolaryngology–Head and Neck
Laryngopharyngeal Reflux Disease: Surgery Foundation 2019
Reprints and permission:
State of the Art Review sagepub.com/journalsPermissions.nav
DOI: 10.1177/0194599819827488
http://otojournal.org

Jerome R. Lechien, MD, PhD, MS1,2,3,4, Lee M. Akst, MD5,

Abdul Latif Hamdan, MD, MPH1,6, Antonio Schindler, MD, PhD1,7,
Petros D. Karkos, MD, PhD, AFRCS1,8, Maria Rosaria Barillari, MD, PhD1,9,
Christian Calvo-Henriquez, MD1,10, Lise Crevier-Buchman, MD, PhD1,11,
Camille Finck, MD, PhD1,2,12, Young-Gyu Eun, MD, PhD1,13,
Sven Saussez, MD, PhD1,2,4*, and Michael F. Vaezi, MD, PhD, MS14*

Sponsorships or competing interests that may be relevant to content are dis- patient characteristics. Multicenter international studies with
closed at the end of this article. a standardized protocol could improve scientific knowledge
about LPR.
Abstract
Objective. To review the current literature about the epide-
miology, clinical presentation, diagnosis, and treatment of 1
Laryngopharyngeal Reflux Study Group of Young Otolaryngologists,
laryngopharyngeal reflux (LPR). International Federation of Oto-rhino-laryngological Societies, Paris, France
2
Department of Anatomy and Experimental Oncology, Mons School of
Data Sources. PubMed, Cochrane Library, and Scopus. Medicine, UMONS Research Institute for Health Sciences and Technology,
University of Mons, Mons, Belgium
Methods. A comprehensive review of the literature on LPR 3
Laboratory of Phonetics, Faculty of Psychology, Research Institute for
epidemiology, clinical presentation, diagnosis, and treatment Language Sciences and Technology, University of Mons, Mons, Belgium
was conducted. Using the PRISMA statement, 3 authors 4
Department of Otorhinolaryngology and Head and Neck Surgery, CHU
selected relevant publications to provide a critical analysis of Saint-Pierre, Faculty of Medicine, University Libre de Bruxelles, Brussels,
the literature. Belgium
5
Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins
Conclusions. The important heterogeneity across studies in School of Medicine, Baltimore, Maryland, USA
6
Department of Otorhinolaryngology and Head and Neck Surgery,
LPR diagnosis continues to make it difficult to summarize a
American University of Beirut Medical Center, Beirut, Lebanon
single body of thought. Controversies persist concerning epi- 7
Department of Biomedical and Clinical Sciences, Phoniatric Unit, L. Sacco
demiology, clinical presentation, diagnosis, and treatment. No Hospital, University of Milan, Milan, Italy
8
recent epidemiologic study exists regarding prevalence and Department of Otorhinolaryngology and Head and Neck Surgery,
incidence with the use of objective diagnostic tools. There is Thessaloniki Medical School, Thessaloniki, Greece
9
Division of Phoniatrics and Audiology, Department of Mental and Physical
no survey that evaluates the prevalence of symptoms and
Health and Preventive Medicine, University of Naples SUN, Naples, Italy
signs on a large number of patients with confirmed LPR. 10
Department of Otorhinolaryngology and Head and Neck Surgery,
Regarding diagnosis, an increasing number of authors used Hospital Complex of Santiago de Compostela, Santiago de Compostela,
multichannel intraluminal impedance–pH monitoring, although Spain
11
there is no consensus regarding standardization of the diag- Department of Otorhinolaryngology and Head and Neck Surgery, Foch
Hospital, Paris, France
nostic criteria. The efficiency of proton pump inhibitor (PPI) 12
Department of Otorhinolaryngology and Head and Neck Surgery, CHU
therapy remains poorly demonstrated and misevaluated by de Liège, Faculty of Medicine, University of Liège, Liège, Belgium
incomplete clinical tools that do not take into consideration 13
Department of Otorhinolaryngology and Head and Neck Surgery, School
many symptoms and extralaryngeal findings. Despite the of Medicine, Kyung Hee University, Seoul, Korea
14
recent advances in knowledge about nonacid LPR, treatment Division of Gastroenterology, Hepatology, Nutrition, Vanderbilt
University Medical Center, Nashville, Tennessee, USA
protocols based on PPIs do not seem to have evolved.
*These authors contributed equally to this article’s supervision and should
Implications for Practice. The development of multichannel be considered co–last senior authors.
intraluminal impedance–pH monitoring and pepsin and bile
salt detection should be considered for the establishment of Corresponding Author:
Jerome R. Lechien, MD, PhD, MS, Laboratory of Anatomy and Cell Biology,
a multiparameter diagnostic approach. LPR treatment Faculty of Medicine, University of Mons, Avenue du Champ de mars, 6,
should evolve to a more personalized regimen, including B7000 Mons, Belgium.
diet, PPIs, alginate, and magaldrate according to individual Email: Jerome.Lechien@umons.ac.be
Lechien et al 763

Keywords ‘‘gastroesophageal.’’ We included clinical prospective and retro-

laryngopharyngeal reflux, gastroesophageal, laryngitis spective studies, experimental research, meta-analyses, and sys-
tematic reviews. Case reports and publications focusing on LPR
Received October 3, 2018; revised November 5, 2018; accepted among children were excluded. From this initial review of the
January 10, 2019. literature, conducted by 3 authors (J.R.L., M.R.B., S.S.), articles
were selected for inclusion in the final review if they focused
on epidemiology, clinical presentation, diagnosis, and treatment
of LPR. Authors had to report inclusion and exclusion criteria;

A
ccording to the 2002 position statement of American
Academy of Otolaryngology—Head and Neck diagnostic, incidence, and prevalence methods; therapeutic out-
Surgery, laryngopharyngeal reflux (LPR) refers to comes (eg, clinical tools, list of symptoms or signs); and the
the backflow of stomach contents into the laryngopharynx.1 treatment regimen. Article selection by PRISMA criteria is
This definition has recently been considered incomplete summarized in the flowchart in Figure 2. Critical analysis of
because irritation from LPR due to pepsin, bile salts, and this literature was then performed focusing on incidence and
other gastroduodenal proteins does not involve only laryngo- prevalence, clinical presentation, diagnosis, and treatment.
pharyngeal mucosa but extends to all upper aerodigestive Implications for practice were then summarized. Ethics commit-
tract mucosa. Additionally, the previous definition does not tee approval was not required for this review.
take into account the possible multifactorial origin of symp-
toms that can be triggered by neuroreflexive signaling and Discussion
compensatory vagal responses—the indirect effects of LPR.2 Incidence and Prevalence
In this regard, this state of the art review defines LPR as an
inflammatory condition of the upper aerodigestive tract tis- In 1991, Jamie Koufman estimated the LPR incidence at
10% of outpatients presenting to otolaryngology clinics with
sues related to the direct and indirect effects of gastroduode-
extraesophageal manifestations of GERD.4 In this cohort,
nal content reflux, which may induce morphologic changes
62% had abnormal esophageal pH studies, and 30% had
in the upper aerodigestive tract.3
documented reflux into the pharynx. This study was perhaps
Since the first publication describing LPR,4 the number
the first important research article differentiating LPR from
of publications concerning LPR has progressively increased
GERD, but there was no epidemiologic survey performed in
(Figure 1). However, many controversies persist regarding
general ear, nose, and throat consultation.4 Gaynor esti-
epidemiology, diagnosis, and treatment while the number of
ambulatory visits increases over the years.5 Currently, LPR mated that 1% of patients visiting general practitioners had
symptoms suggestive of LPR, although no testing was done
disease is still associated with recurrent symptoms and poor
to confirm the LPR diagnosis.8 In 2007, Connor et al
related quality of life3 that has a significant cost for the
assessed the LPR prevalence in the Wisconsin area with a
patient and society. Thus, the US annual costs for treating
screening LPR questionnaire, and they concluded that about
LPR and gastroesophageal reflux disease (GERD) are esti-
26.2% of subjects had both laryngeal symptoms and conco-
mated at between $9.3 billion and $50 billion.6,7 Francis
mitant GERD.9
et al found that the mean initial-year direct cost would be
Several more recent studies used the Reflux Symptom
$5438 per patient being evaluated for LPR, including con-
sultation, additional examination, and proton pump inhibitor Index (RSI) to estimate LPR prevalence in various popula-
tions with different thresholds. Chen et al estimated the
(PPI) consumption.7 In addition, although the literature con-
LPR prevalence (RSI .13)10 at 18.8% of the Chinese popu-
cerning empiric therapeutic trials of antacid medication for
lation.11 In similar studies, Spantideas et al and Kamani
LPR complaints dates back .15 years, the efficacy of PPIs
et al found that 5% (RSI 13) and 30% (RSI .10) of Greek
is still controversial, with only modest superiority over pla-
and British populations had LPR symptoms.12,13 In each of
cebo for patients with presumed LPR.3
these 4 studies, authors did not perform any additional clini-
The purpose of this article is to overview the current litera-
cal or objective examinations to confirm reflux diagnosis,
ture about epidemiology, clinical presentation, diagnosis, and
treatment and to shed light on the recent scientific advances making it possible that RSI scores were due to chronic
inflammation of other etiology.3,14,15
on LPR. With a review of this current literature, our LPR
In 2000, Koufman et al performed dual-probe pH monitor-
study group aims to propose an updated algorithm for LPR
ing in 113 patients with dysphonia. In this group, 69% of
management. This review does not apply to children.
patients had symptoms and findings of LPR, and 73% had
abnormal reflux testing.16 When those studies were inter-
Methods preted, it was obvious that the authors focused only on acid
A PubMed, Cochrane Library, and Scopus database search was reflux and did not take into consideration nonacid/mixed
conducted for relevant peer-reviewed publications in English, reflux. One of the most fundamental principles in epidemiol-
Spanish, and French related to epidemiology (incidence and ogy is that to precisely assess incidence and prevalence of a
prevalence), clinical presentation, diagnosis, and treatment of disease, researchers must have a gold standard diagnosis.
LPR. The following terms were used: ‘‘reflux,’’ ‘‘laryngitis,’’ Nowadays, there is no gold standard ensuring LPR diagnosis,
‘‘laryngopharyngeal,’’ ‘‘silent reflux,’’ ‘‘extra-esophageal,’’ and although technology is evolving—new studies are measuring
764 Otolaryngology–Head and Neck Surgery 160(5)

Figure 1. Evolution of published papers about laryngopharyngeal reflux over the past decades. This graph shows the total number of clini-
cal studies (dark blue) and the total number of publications (dark and light blue) performed about laryngopharyngeal reflux according to
the year.

diagnosis, it is still difficult to establish LPR incidence and

prevalence. To more fully comprehend LPR prevalence,
consideration of the overlap among LPR signs, symptoms,
and positive MII-pH might best identify patients with LPR.
Clinical Presentation
Pathogenesis. The reflux of pepsin, bile salts, and other gas-
trointestinal proteins into the upper aerodigestive tract
mucosa leads to mucosal modifications, including mucosal
injury, inflammation reaction, mucus dryness, epithelium
thickening, and microtrauma.20-22 Accumulation of sticky
mucus induces postnasal drip and globus sensation, throat
clearing, and cough. Certain anatomic findings, such as gran-
uloma, contact between epiglottis and hypertrophied lingual
tonsils, and oropharyngeal posterior wall, may also lead to
globus sensation. Globus sensation may also be neurogenic.
The inflammation of soft palate or rhinopharyngeal mucosa
may be associated with postnasal drip. Dysphonia could be
caused by macro- and microscopic mucosal changes that may
induce modifications of biomechanical properties of the
Figure 2. PRISMA flowchart. Since 1961, a total of 1042 publica- vocal folds, contributing to the development of chronic
tions were identified (608 clinical studies with patient data). lesions of the vocal folds.22-25
Twenty-three studies were excluded because of a lack of a full Indirect injury from vagally mediated reflexes may also
manuscript in English, Spanish, or French. Finally, 585 were included
favor the development of LPR symptoms, as the stimulation
to write this systematic review.
of gastroduodenal content into the low esophagus may sti-
mulate the mucosa chemoreceptors, leading to laryngeal
both nonacid and mixed reflux as each can cause LPR,17,18 mucus secretion, cough, globus sensation, and throat clear-
and comparative studies are showing how pH metry alone ing.2 Dysphagia, odynophagia, ear pressure, and throat
might underestimate reflux diagnoses.19 pain may also develop throughout the chronic inflammatory
In summary, regarding the nonspecificity of symptoms, reaction of the mucosa.26 Despite chronic LPR disease,
the lack of a gold standard, and the use of multichannel many patients have acute episodes of reflux through
intraluminal impedance–pH monitoring (MII-pH) for the the internalization/externalization of pepsin,27 which can
Lechien et al 765

exacerbate these symptoms, leading to the description of the of patients with erosive esophagitis had complaints and find-
‘‘chronic course’’ of disease. The etiology of symptoms ings suggestive of LPR.56 In a cohort of 1383 patients with
may be multifactorial for patients with concomitant LPR GERD, Groome et al demonstrated a correlation between the
and obstructive sleep apnea syndrome, based on recent data severity of GERD and the development of LPR. Patients with
that supported a strong association between obstructive Barrett’s metaplasia had, however, a higher rate of LPR than
sleep apnea syndrome severity and reflux symptoms.28 those with mild erosive esophagitis.57,58
Symptoms and Signs. In practice, the prevalence of the LPR Clinical Tools. Some patient-reported outcome measures and
symptoms described so far was extensively studied in many instruments evaluating the clinical findings were developed
large cohort studies (Table 1).4,29-40 The most prevalent over the past 20 years for the diagnosis and the evaluation of
LPR symptoms are globus sensation, throat clearing, hoarse- treatment effectiveness (Tables 3 and 4).40,45,52,59-70 Among
ness, excess throat mucus, and postnasal drip. However, these, the RSI60 and RFS45 are the most popular clinical LPR
reported prevalence of these complaints varies among stud- tools, and the RSI has been adapted and validated in many
ies because of heterogeneity in inclusion/exclusion criteria, languages.10,71-76 Due to the popularity of the RSI and RFS,
diagnostic approaches, and determination/definition of clini- the 11 symptoms and the 8 findings described in them are
cal symptoms. The inclusion of patients with active the most frequently assessed clinical therapeutic outcomes.3
allergy,29 patients with chronic rhinosinusitis,30 smo- However, these tools have many weaknesses.3,59,77
kers,29,30,38 and alcoholics38 may bias the LPR symptom Regarding the RSI, LPR symptoms are usually nonspeci-
assessment because these conditions may be associated with fic, and they can be found among subjects without reflux.
similar complaints. Additionally, the prevalence of LPR Chen et al observed a significant rate of throat clearing,
symptoms could significantly vary according to sex and age, excess throat mucus or postnasal drip, and globus sensation
especially as GERD symptoms are less perceived by elderly among healthy subjects.78 This point is important because
patients.41-44 the RSI does not take into consideration many LPR
The common LPR findings are posterior commissure symptoms—namely, throat pain, odynophagia, ear pressure,
hypertrophy, laryngeal/arytenoid inflammation, and endolar- eructation, and halitosis.3,79,80 Second, the RSI provides a
yngeal mucus (Table 2).29-31,33,38 However, these studies severity evaluation of LPR complaints with a visual analog
are characterized by the same heterogeneity as those focus- scale but does not take into consideration the symptom fre-
ing on symptoms. The common characteristic of the 2 larg- quency. The only evaluation of symptom severity with a
est studies is the use of the Reflux Finding Score (RFS),45 visual analog scale is subjective and involves some socio-
excluding some other LPR signs not described in the RFS. cultural factors. Third, some symptoms described in the RSI
Even with common ‘‘language’’ for findings suggested by (heartburn, chest pain, regurgitations, and indigestion) are
the RFS, however, limitations relate to whether findings are pooled into 1 item, leading to confusion in the assessment
assessed in a blinded or nonblinded fashion, possibly affect- of these complaints. With regard to these criticisms, our
ing reliability.46,47 Interestingly, a recent study suggested group recently developed a new patient-reported outcome
that LPR findings could vary according to type of reflux questionnaire (Reflux Symptom Score) that includes evalua-
and patient characteristics.18 In the same way, women with tions of LPR and GERD symptom frequency, severity, and
LPR could have lower laryngeal signs (RFS) than men, sup- impact of quality of life, with a clear definition of each
porting the use of a sex-related cutoff in LPR diagnosis rating item.81
based on the RFS.41 Regarding findings, 80% of healthy subjects could have
Relationship between LPR and GERD. The relationship between 1 signs of laryngopharyngeal irritation, including laryngeal
LPR and GERD is controversial, although they share erythema, posterior commissure hypertrophy, and diffuse lar-
common physiologic mechanisms, but many studies sup- yngeal edema.66,78,82 The RFS does not take into consider-
ported a relationship between both conditions more often ation many LPR findings, including vocal fold erythema,
than previously assumed. It is accepted that 50% of leukoplakia, posterior pharyngeal wall inflammation, anterior
patients with LPR have GERD.29,48 For 3 decades, the over- pillars inflammation, and coated tongue.3,79,80,83 Some LPR
all trend was to consider these 2 conditions as different dis- signs are described in Figure 3. Second, the RFS allows a
eases,49 but many studies supported a relationship more subjective evaluation of some signs without clear definition
often than previously assumed. Through the ProGERD of the rating, which can be a factor explaining the low inter-
Study,48 Jaspersen et al showed that laryngopharyngeal reliability among judges.46,47,84 This observation can be
complaints were present among 32.8% of patients with attributed to the nonspecificity of LPR signs and the subjec-
GERD. Dore et al found that 39% of patients with GERD tive procedure of evaluation of some items of the RFS (mild,
had encountered globus sensation with a significant rate of moderate, or severe score of a finding). In that respect, future
eructation (26%), cough (24%), and hoarseness (23%).32 instruments could include findings of all upper aerodigestive
Erosive esophagitis was found in almost 50% of patients tract mucosa related to LPR, and the meaning of each item
with GERD,50 while for LPR, only 10% to 30% of patients should be closely defined to improve the interrater reliability
had esophagitis, with a low proportion of patients (\10%) of physicians. The evaluation of some signs with a visual
having Barrett’s metaplasia.51-55 Lai et al showed that 24% analog scale should be avoided. Moreover, because some
 Table 1. Prevalence of LPR Symptoms according to the Larger Studies (N .100 Patients with LPR).a

766
Publication Patients with LPR, n Diagnosis Criteria Clinical Instruments Assessed Symptoms Prevalent Symptoms Symptoms, %

Habermann (2012)29 1044 suspected Reflux Symptom Reflux Symptom Index VD, GS, TC, EM, DD, PC, (1) Globus sensation. (2) Throat —
Index .9, CT, HB, CP, PS, CK clearing. (3) Excess throat
Reflux Finding mucus
Score .7
Lee (2011)30 455 suspected Symptoms and signs Reflux Symptom Index VD, GS, TC, EM, DD, PC, (1) Globus sensation. (2) Throat 89, 82, 79
CT, HB, CP, PS, CK clearing. (3) Hoarseness
Chappity (2014)31 234 suspected Reflux Symptom Reflux Symptom Index VD, GS, TC, EM, DD, PC, (1) Globus sensation. (2) Pain 70, 54, 47
Index .13 CT, HB, CP, PS, CK throat. (3) Throat clearing
Dore (2007)32 226 suspected Laryngeal symptoms Unvalidated clinical tool HB, RE, DD, OD, SA, CP, (1) Globus sensation. (2) 39, 26, 24
VD, GS, TC, EM, CK, Eructation. (3) Cough
EE, HO, NA
Koufman (1991)4 225 confirmed Symptoms and signs, — GS, DD, CT, VD, HB, RE (1) Dysphonia. (2) Cough. (3) 71, 51, 47
pH monitoring Globus sensation
Youssef (2010)33 212 confirmed Symptoms and signs, — CT, TC, VD, BT, GS (1) Cough. (2) Globus sensation. 50, 46, 37
pH monitoring (3) Throat clearing
Zalvan (2017)34 188 suspected Reflux Symptom Reflux Symptom Index VD, GS, TC, EM, DD, PC, (1) Dysphonia. (2) Dysphagia. 34, 34, 32
Index .10 CT, HB, CP, PS, CK (3) Cough
Lee (2014)35 180 suspected Symptoms and signs Reflux Symptom Index VD, GS, TC, EM, DD, PC, (1) Dysphonia. (2) Cough. (3) —
CT, HB, CP, PS, CK Throat clearing
Drinnan (2015)36 177 suspected Reflux Symptom Index VD, GS, TC, EM, DD, PC, (1) Throat clearing. (2) 45, 40, 37
CT, HB, CP, PS, CK Dysphonia. (3) Globus
sensation
Vaezi (2006)37 145 suspected Symptoms, chronic Unvalidated clinical tool TC, CT, VD, PT, GS (1) Throat clearing. (2) 50, 20, 13
and confirmed posterior Dysphonia. (3) Cough
laryngitis 5, pH
monitoring
(not all)
Hanson (1995)38 141 suspected Symptoms and signs — VD, PT, PC, TC, GS, CT (1) Sore throat. (2) Dysphonia. —
(3) Postnasal drip
Nunes (2016)39 126 suspected Symptoms and signs Reflux Symptom Index VD, GS, TC, EM, DD, PC, (1) Cough. (2) Globus sensation. 40, 21, 20
CT, HB, CP, PS, CK (3) Dysphonia
Andersson (2010)40 102 confirmed Reflux Symptom Pharyngeal Reflux VD, CT, DD, HB, CP GS, (1) Cough. (2) Throat clearing. 91, 89, 88
Index .13, Symptom Questionnaire PT, RE, EM (3) Globus sensation
pH monitoring

Abbreviations: BT, bad taste; CK, choking; CP, chest pain; CT, troublesome cough; DD, dysphagia; EE, eructation; EM, excess throat mucous/postnasal drip; GS, globus sensation; HB, heartburn; HO, hiccup; LPR,
laryngopharyngeal reflux; NA, nausea; OD, odynophagia; PC, coughing after you ate/lying down; PS, pyrosis/stomach acid coming up; PT, pain throat; RE, regurgitations; SA, sialorrhea; TC, throat clearing; VD,
voice disorders.
a
The prevalence of LPR symptoms among patients with suspected or confirmed LPR. Studies focusing on patients with LPR who were resistant to medical treatment or patients with hoarseness were not
considered.
 Table 2. Prevalence of LPR Signs according to the Larger Studies (N .100 Patients with LPR).a
Publications Patients with LPR, n Diagnosis Criteria Finding Tools Findings Prevalent Findings Findings, %

Habermann (2012)29 1044 suspected Reflux Symptom Index Reflux Finding SE, VV, EH, VE, LE, PH, (1) Posterior commissure —
.9, Reflux Finding Score GG, TM hypertrophy. (2) Laryngeal
Score .7 erythema. (3) Thick
endolaryngeal mucus
Lee (2011)30 455 suspected Symptoms and signs Reflux Finding SE, VV, EH, VE, LE, PH, (1) Posterior commissure 89, 80, 79
Score GG, TM hypertrophy. (2) Vocal fold
edema. (3) Laryngeal erythema
Chappity (2014)31 234 suspected Reflux Symptom Index — DT, EH, LE, NC, PY, PW, (1) Dull tympanic membrane. 45, 44, 43
.13 VR, PH (2) Arytenoid inflammation.
(3) Posterior pharyngeal wall
inflammation
Youssef (2010)33 212 confirmed Symptoms and signs, pH — LE, EM, UC, GG (1) Arytenoid erythema. (2) 55, 28, 11
monitoring Endolaryngeal mucus. (3)
Laryngeal ulcer
Hanson (1995)38 141 suspected Symptoms and signs — EH, LE, PH, PW, GG, TM, (1) Laryngeal erythema. (2) —
KT Hypopharyngeal wall
erythema. (3) Laryngeal and
hypopharyngeal edema
Abbreviations: DT, dull tympanic membrane; EH, laryngeal/arytenoids erythema; EM, excess throat mucous/postnasal drip; GG, granuloma/granulations (posterior commissure); KT, laryngeal keratosis; LE, laryn-
geal edema; LPR, laryngopharyngeal reflux; NC, nasal congestion; PH, posterior commissure hypertrophy; PW, posterior pharyngeal wall erythema; PY, postpharyngeal cobblestoning; SE, subglottic edema; TM,
thick endolaryngeal mucous; UC, laryngeal ulcerations; VE, vocal folds edema; VR, vocal folds erythema; VV, ventricular obliteration.
a
The prevalence of LPR findings among patients with suspected or confirmed LPR. Studies focusing on patients with LPR who were resistant to medical treatment or patients with hoarseness were not
considered.

767
768
Table 3. Validated Patient-Reported Outcome Measures.
Scale Characteristics

Patient-Reported Outcome Target and Patient Patients for Users or

Measures Objective Characteristics Validation Studies, n Assessed Symptoms Type Item, n Item Response Calculation Subscales

Throat Questionnaire Diagnosis, therapeutic Patients with globus 89 suspected LPR 0-5 GS, PT, DT, DD, EM, VD, IS, VAS 12 Severity: 0-4 Complex calculation. 0
(Wilson61) outcome (pharyngeal CD, TO, HK Total score: 32
symptoms)
Glasgow Edinburgh Throat Diagnosis, therapeutic Patients with globus 105 globus 5-25 GS, PT, DT, TO, DD, SW, VAS 12 Severity: 0-7 Not provided. Total 3
Scale (Deary62) outcome (pharyngeal CD, HK, FS score: each item
symptoms)
Reflux Symptom Index Diagnosis, therapeutic Suspected or 25 confirmed LPR 50-100 VD, GS, TC, EM, CP, DD, VAS 9 Severity: 0-5 Sum of items. Total 0
(Belafsky60) outcome confirmed LPR PC, CT, HB, RE, CK score: 45
Laryngopharyngeal HRQL Therapeutic outcome Suspected or 117 suspected LPR 0-5 HRQL related to VD, CT, VAS 43 Severity: 0-7 By subscales. Total 5
(Carrau63) of HRQL confirmed LPR TC, DD or 0-10 score: 30-90
Supraesophageal Reflux Diagnosis, therapeutic Pharyngolaryngeal 985 suspected LPR 0-5 TC, CT, GS, ST, DD, VD, VAS 9 Severity: 0-4 Not provided 0
Questionnaire (Dauer64) outcome complaints HB, RE, DC, NC
Laryngopharyngeal Reflux-34 Diagnosis, therapeutic Suspected or 62 suspected LPR 0-5 TC, GS, EM, PT, VD, DA, FF, VAS 34 Severity: 0-5 Not provided 0
(Papakonstantinou65) outcome confirmed LPR PN, TB, BO, HA, RS, HB,
DD, PC, IS, WH, VI, BL,
RE, BR, CK, NA, HO
Pharyngeal Reflux Symptom Diagnosis, therapeutic Suspected LPR 228 suspected LPR 0-5 CT, VD, DD, RE, HB VAS 24 Severity: 0-5. Multiplication of 4
Questionnaire outcome Frequency: 0-5 severity and
(Andersson40) frequency for each
item

Abbreviations: BL, belching; BO, bloating; BR, breathing difficulties; CD, Catarrh down throat; CK, choking; CP, chest pain; CT, troublesome cough; DA, decreased appetite; DC, dry cough; DD, dysphagia; DT,
discomfort in throat; EM, endolaryngeal mucus; FF, flatulence; FS, food sticking when swallowing; GS, globus sensation; HA, headache; HB, heartburn; HK, have to keep swallowing; HO, hiccup; HRQL, health-
related quality of life; IS, indigestion; LPR, laryngopharyngeal reflux; NA, nausea; NC, nasal congestion; PC, coughing after you ate/lying down; PN, postnasal drip; PT, pain throat; RE, regurgitations; RS, rush of
saliva; ST, sore throat; SW, swelling in the throat; TB, tongue burning; TC, throat clearing; TO, throat closing off; VAS, visual analog scale; VD, voice disorders; VI, vomiting; WH, wheezing.
 Table 4. Validated Instruments Evaluating the Clinical Findings.
Scale Characteristics

Target and
Patient Patients for Users or
Finding Instruments Objective Characteristics Validation Studies, n Assessed Signs Type Items, n Item Response Calculation Subscales

Reflux Finding Diagnosis, Suspected LPR, 40 confirmed LPR 25-50 SE, VV, EH, VE, LE, Predefined item 8 Severity: 0-4 or 0-2 Sum of items. Total 0
Score45 therapeutic confirmed LPR PH, GR, TM score: 26
outcome
Vaezi Instrument66 Diagnosis, Uncured LPR 72 suspected LPR 0-5 PY, PW, GG, EH, PH, Yes/no 12 Presence: yes/no Signs prevalence. 0
therapeutic KT, LE, VE, VR, PP, Total score: NA
outcome SP, SR
Laryngopharyngeal Therapeutic Suspected LPR Suspected 0-5 PH, SP, SE, VR, SR, VAS 12 Severity: 0-3 Sum of items. Total 0
Reflux Disease outcome LPR, N = NA SU, ND, PP, LL, GG, score: 36
Index67 WW
Laryngoscopic Suspected LPR 20 suspected LPR 0-5 LE, EH, VE, VR, SE, Predefined 4 Laryngitis grade: — 0
Grading Scale68 SU, UC item 0-4. Each grade
is defined
Laryngeal Reflux Therapeutic Confirmed LPR 42 LPR 0-5 EH, VE, LE, PH, VR, VAS Signs: 6. VC Severity: 0-4 Sum of items. Total Signs scale.
Grade69 outcome GG, ND, UC, SE wave: 4 score: 24116 VC wave
Chronic Posterior Therapeutic Suspected LPR 145 suspected 0-5 EH, GG, LE, PW, PH, VAS 10 Severity: 0-3 Sum of items. Total 0
Laryngitis Index70 outcome VR, VE score: 30

Abbreviations: 1, criterion met; EH, laryngeal/arytenoids erythema; GG, interarytenoid granulation and/or granuloma; GR, laryngeal granulation/granuloma; KT, laryngeal keratosis; LE, laryngeal edema; LL, leu-
koplakia; LPR, laryngopharyngeal reflux; NA, not available; ND, nodules; PH, posterior commissure hypertrophy; PP, polyp/Reinke edema; PW, posterior pharyngeal wall erythema; PY, postpharyngeal cobbleston-
ing; SE, subglottic edema/pseudosulcus/stenosis; SP, supraglottis edema; SR, supraglottis erythema; SU, subglottic erythema; TM, thick endolaryngeal mucus; UC, laryngeal ulcerations; VAS, visual analog scale;
VC, vocal cords; VE, vocal fold edema; VR, vocal fold erythema; VV, ventricular obliteration; WW, vocal web.

769
770 Otolaryngology–Head and Neck Surgery 160(5)

Figure 3. Arrows show prevalent findings associated with laryngopharyngeal reflux: sticky secretions (1), erythema of the anterior pillars
and coated tongue (2), nodularity of the posterior pharyngeal wall (3), laryngeal keratosis (4), posterior commissure hypertrophy and inter-
arytenoid granulation (5), diffuse laryngeal erythema (6), endolaryngeal mucus (7), laryngeal ulcerations (8), and granuloma (9). These find-
ings are nonspecific and should be considered in a complete finding score.

findings could probably require more time to change, it could and it is associated with pH monitoring. The single-use 2-
be interesting to follow patients with LPR over longer mm-width MII-pH catheter contains ring electrodes that are
follow-up periods. usually positioned 3, 5, 7, 9, 15, and 17 cm from the tip
In summary, the most prevalent complaints and findings and combined with at least 1 pH electrode at the tip.
found in the larger cohorts of patients with suspected LPR Intraesophageal/pharyngeal content transit (liquid and air) is
are also the most prevalent complaints and findings found detected as sequential changes in impedance along the
among healthy subjects, confirming the nonspecificity of catheter. MII-pH is the most reliable means to precisely
LPR symptoms and signs and the need to combine symp- diagnose of acid, nonacid, or mixed reflux. Addition of
toms and findings with objective examinations for the diag- impedance testing improves the sensitivity (70%-80%) and
nosis. From an epidemiologic standpoint, the lack of the false-negative rate (20%-50%) of classical pH monitor-
consideration of some clinical outcomes of a disease may ing, which is unable to detect nonacid reflux or some aero-
undeniably affect the establishment of a clinical diagnosis solized molecules.19,50,89 The replacement of pH metry by
and the evaluation of therapeutic efficiency.85 This fact has MII-pH makes sense regarding the significant rate of nona-
to lead to the use of complete clinical instruments at base- cid LPR that can be resistant to PPIs.17,18,90,91
line and throughout treatment to precisely assess the evolu- However, MII-pH has several limitations. First, the
tion of laryngeal and extralaryngeal symptoms and signs. number and characteristics of reflux episodes may vary
Furthermore, in an attempt to minimize subjectivity in the from day to day, and the results can be associated with
reflux finding assessment,46 software was recently devel- false-positive and false-negative rates.92 A lack of reflux
oped to improve the assessment of the erythema intensity of episodes during the 24-hour testing period does not necessa-
the laryngopharyngeal mucosa.86-88 rily signify that the patient does not have LPR; it only indi-
Objective Testing cates that there were no reflux episodes during the test
period.93 Thus, some authors recently recommended the use
MII-pH Monitoring. MII is able to detect esophageal bolus of 48-hour studies to mitigate the false-negative problem.94
movement by measuring changes in electrical resistance, The patient’s diet the day of the examination also has a
Lechien et al 771

significant impact on the results.95,96 Second, the results of metry, there is no consensus about the diagnostic criteria,
pH study probes may be inaccurate if drying of the proximal although the majority of studies used similar criteria: Ryan
sensor leads to inaccurate measurement, resulting in pseudo- score .9.4 (upright) or .6.8 (supine).125-131
reflux.96,97 Third, MII-pH does not systematically predict Empirical Therapeutic Trial. Another tool used for ‘‘diagnosis’’
LPR symptom response throughout the PPI therapeutic is an empiric trial of antacid medication.132,133 Formal
trial.50,98-100 Finally, there is no standardization of interpreta- application of this approach involves the utilization of some
tion for results at the proximal sensor—in the existing litera- clinical scores for the diagnosis (typically RSI .13 and/or
ture concerning MII-pH and reflux, there is a myriad of RFS .7), followed by treatment with dietary recommenda-
diagnostic criteria (Table 5).* tions and PPIs for 3 months and then reassessment of clini-
According to our review, some physicians still consider cal status. At the time of reassessment, many definitions of
criteria based on pH results without regard for impedance response are considered positive for assignment of a reflux
events,90,104,117,120 and others use the criteria for GERD diagnosis. These include a 50% improvement of symptoms
developed for measurement at the distal pH sensor.92,107 In score after treatment,134 both a 3-point RFS reduction and a
fact, only a few authors used 1 or several pH drops or 5-point or 6-point RSI reduction,34 or a reduction of
impedance events at the proximal probe irrespective to the scores to RSI \13 and RFS \7 after 3 or 6 months of treat-
absolute pH at that time.18,121 Further difficulty in standar- ment.135-137 In many cases, authors did not define the criteria
dization of diagnostic criteria is partly related to the fact of improvement.108,132,133 Overall, many authors defined
that normative values for the test are incompletely estab- response on the basis of only symptoms and not signs.
lished, given the difficulty of carrying out MII-pH monitor- There are several limitations in the use of response to
ing in a large number of normal volunteers. Other barriers empiric treatment to retroactively assign reflux diagnoses.
to the use of MII-pH are the cost, the inconvenience to the One is that confounding etiologies, such as allergy, might
patient, and the unavailability in all centers. However, in drive patient complaints138 and influence degree of improve-
the absence of a gold standard for diagnosis, current ment. A second issue is that response to PPIs does not tell
research on diagnosis, treatment, and other issues concern- the treating physician what to do with nonresponders—while
ing LPR remains limited by an inability for different articles it is possible that those with persistent cough, globus sensa-
to be discussing the same population—each different set of tion, throat clearing, and/or other presumed LPR complaints
diagnostic criteria likely leads the population from one may not actually have reflux if they do not respond to
study to be different in potentially meaningful ways from empiric treatment, it is also possible that refractory reflux or
the populations of other studies. nonacid reflux may be present; this would be identified on
MII-pH but cannot be excluded on the basis of empiric treat-
Oropharyngeal pH Monitoring. Among various approaches ment. Finally, a critical drawback of empiric treatment is the
that are designed to address some of the limitations of pH nonspecific nature of the vague laryngopharyngeal com-
metry for LPR, one is a novel pH device (Restech; plaints, which often lead physicians to presume LPR. These
Respiratory Technology Corp, San Diego, California), complaints may instead be related to self-limited laryngo-
which was developed for purposeful hypopharyngeal rather pharyngeal inflammation from overuse, dryness, upper
than proximal esophageal measurement. It consists of a respiratory tract infection, habituated behavioral trauma,
single hypopharyngeal probe designed to measure pH of allergy, and the like, and trials often show no benefit from
aerosolized droplets, and it is not subject to drying artifacts, PPIs over placebo in the treatment of patients with presumed
which can occur if traditional esophageal probes are posi- LPR.3,139 In this way, Ross et al found that patients with sus-
tioned above the upper esophageal sphincter. A few studies pected LPR had increased abnormal perceptual voice charac-
have since used oropharyngeal pH metry for LPR diagnosis teristics (eg, musculoskeletal tension, hard glottal attack,
in the place of MII-pH. Studies that used pharyngeal and glottal fry, restricted tone placement, and hoarseness) as com-
dual pH esophageal probes simultaneously showed that pared with the controls, which can raise the LPR-attributed
the oropharyngeal probe does reliably capture reflux epi- symptoms.140 If these patients without LPR would have expe-
sodes, which moved proximally from esophagus to phar- rienced symptomatic improvement over time in the absence
ynx.92,122-124 Thus, Becker et al showed that oropharyngeal of PPIs, then results of an empiric PPI trial might subject
pH metry detected only 11% of reflux episodes detected by these patients to unnecessary medication and assign reflux
MII-pH.92 Studies that compared the ability of pharyngeal diagnosis falsely. Nowadays, it is recommended to carefully
versus esophageal pH monitoring to predict symptom exclude many confounding factors associated with laryngo-
response to PPI treatment among patients with presumed pharyngeal complaints (chronic laryngopharyngitis due to
LPR suggested that the oropharyngeal probe may have tobacco, alcohol, allergy, infections, asthma inhalers, environ-
higher positive predictive capability than that of esophageal mental irritants, poor vocal hygiene, muscle tension dyspho-
measurement, but these findings are based on low numbers nia, etc).3
of patients and remain preliminary.92 As with MII-pH
Pepsin and Bile Salt Detection. The detection of pepsin, bile
salts, and probably trypsin on saliva and pharyngeal or lar-
*
References 18, 53, 84, 90, 92, 98, 101-121 yngeal mucosa is a promising diagnostic approach.141 A
772 Otolaryngology–Head and Neck Surgery 160(5)

Table 5. Diagnostic Criteria of Multichannel Intraluminal Impedance–pH Monitoring and Probe Placements.a
References Diagnostic criteria Probe Placement

Jiang (2011)102 NP Proximal: 0.5 cm above UES. Distal: 5 cm above LES

Wang (2011)103 Total acid exposure time pH \4 .4% of time Proximal: 0-1 cm above UES. Distal: 3-5 cm above
LES
Wang (2012)104 Total acid exposure time pH \4 .4% of time Proximal: 0-1 cm above UES. Distal: 3-5 cm above
LES
de Bortolini (2012)105 Distal acid exposure .4.2% of time Proximal: 17 cm above LES. Distal: 5 cm above LES
Beckers (2012)92 Total acid exposure time pH \4 .4% of time or Proximal: NP. Distal: 5 cm above LES
number of reflux episode .73
Xiao (2012)106 1 proximal events Proximal: 0.5 cm above UES. Distal: 5 cm above LES
Wang (2011)107 Total acid exposure time pH \4 .4% of time Proximal: 0-1 cm above UES. Distal: 3-5 cm above
LES
Wan (2014)108 3 LPR pharyngeal episodes or proximal acid Proximal probe: esophagus 2 cm below UES. Distal
exposure time .1% or impedance proximal acid probe: 20 cm below the proximal probe
exposure 4
Jetté (2014)84 Proximal probe: decrease in pH by .2 units within Proximal probe: 0.5-1 cm above UES. Distal probe:
30 s to a value \4 units 5 cm above LES
Mazzoleni (2014)109 Number of reflux episode .73 or distal acid Proximal: NP. Distal: 5 cm above LES
exposure .4.2% of time
Sereg-Bahar (2015)17 Positive DeMeester score NP
Falk (2015)110 Proximal acid episode .1% of 24 h Proximal: below UES. Distal: 5 cm above LES
Na (2016)111 Proximal episode 1 time/24 h Proximal: above UES. Distal: esophagus. Proximal:
hypopharynx
Cumpston (2016)112 1 proximal events or .40 proximal extent Distal: 5-10 cm above LES
impedance events
Hoppo (2012)53 1 events daily and/or full column reflux; reflux 2 Proximal probe: 0.5 cm above UES. Distal probe:
cm distal to the UES .4/d (24 h) esophagus 5 cm above LES
Nennstiel (2016)98 Distal probe: pH4 (4.0% time). Impedance: .73 Proximal probe: NP. Distal probe: esophagus 5 cm
fluids/22 h or esophageal mixed reflux episodes above LES.
Jung (2017)113 Proximal episode .1 time/24 h. Acid/nonacid: every Proximal probe: hypopharynx. Distal probe: low
event: pH \4 / pH .4. Mixed: pH .4 and pH \4 esophagus
Formánek (2017)114 Proximal probe 6 events daily Proximal probe: 2 cm above UES. Distal probe: low
esophagus
Weitzendorfer (2017)115 Number of reflux episode .73 or DeMeester Proximal probe: 5 cm above LES. Distal probe: 15
exceeded 14.7 cm below the LES.
Kim (2017)116 Proximal episode 1 time/24 h Proximal probe: 25 cm above LES. Distal probe: 6
cm above LES
Du (2017)117 Total acid exposure time pH \4 .1% of time NP
Dulery (2017)118 1 proximal events preceded by retrograde Proximal probe: 0.5 cm above UES. Distal probe:
impedance drop esophageal distally and proximally low esophagus
and without swallow event.
Wang (2017)119 Proximal probe: decrease in pH by .2 units within Proximal probe: 0.5-1 cm above UES. Distal probe:
30 s to a value \4 units 5 cm above LES
Tseng (2018)120 Distal probe: pH 4 (4% time) Proximal probe: NP. Distal probe: esophagus 3 cm
above LES
Lee (2018)90 Proximal episode .1 time/24 h. Acid/nonacid: every Proximal probe: hypopharynx. Distal probe: low
event: pH \4 / pH .4. Mixed: pH .4 and pH \4 esophagus
Suzuki (2018)121 1 events daily and/or full column reflux, reflux 2 Proximal probe: 0.5 cm above UES. Distal probe:
cm distal to the UES .4/d (24 h). esophagus 5 cm above LES
Lee (2018)18 Acid reflux episodes: decrease in pH \4 for at least Proximal probe: 25 cm above LES. Distal probe: 6
5s cm above LES
Abbreviations: LES, lower esophageal sphincter; LPR, laryngopharyngeal reflux; NP, not provided; UES, upper esophageal sphincter.
a
In this table, we considered studies of patients primarily diagnosed with LPR; research focusing on patients with resistant LPR was not considered.
Lechien et al 773

recent meta-analysis of 11 studies suggested that sensitivity supported in a recent meta-analysis.3 The positive effect of
and specificity of salivary pepsin detection would be 64% an alkaline and low-fat diet was even demonstrated to be
and 68%, respectively,142 but in practice, the lack of a gold helpful for patients whose symptoms were refractory to
standard limits us in the determination of the epidemiologic PPIs.146
characteristics of this approach. In fact, there was notable Regarding pharmacologic treatment, PPIs have been the
heterogeneity in the diagnosis method, the exclusion cri- most prescribed drugs for reflux.5,144 However, the superior-
teria, and the material used for the pepsin detection in these ity of PPIs over placebo remains poorly demonstrated.3
11 studies.142,143 This point is crucial because the reliability Unfortunately, this uncertain benefit exists in a climate in
of the pepsin detection seems to depend on the technique which the costs of reflux treatment7 and the side effects
(immunoassay, ELISA, or Western blot), the threshold for from PPIs are becoming increasingly recognized.147
determining a test result to be positive or negative, the Naturally, these studies showing rough equivalency between
number of positive samples needed to assign a LPR diagno- PPIs and placebo are not meant to suggest that patients with
sis, and the timing of samples themselves.143 In the current true LPR will not benefit from PPI therapy; the inability
literature, these characteristics substantially vary among of studies to demonstrate the role of PPIs in treatment
studies, and there is no consensus about the best time for likely reflects an inability to include only patients with
the sample collection. Recently, Na et al suggested that the reflux. Indeed, there is notable heterogeneity among studies
best time for the pepsin collection would be in the morning according to diagnosis, inclusion and exclusion criteria,
upon waking,111 but future studies are needed to confirm variability of treatment algorithms, and differences in mea-
these data with a large number of patients because LPR usu- sured outcomes. Our recent meta-analysis, which included
ally occurs while upright and during the daytime.4 Another 10 placebo randomized controlled trials comparing PPIs
important point that is underestimated in the current litera- with placebo, identified 7 different methods for diagnosis,
ture is the potential impact of trypsin and biliary salts on 10 different lists of exclusion criteria, 9 different therapeutic
the mucosal damage, although recent data supported the key regimens, 10 different combinations of clinical outcomes
role of these molecules.17,90 Future research has to respond used to assess response to treatment, and 3 different treat-
to many unanswered questions about the number and opti- ment durations.3
mal timing for the sampling, the location and nature, the In light of increasing studies that identify acid and nona-
threshold values for pepsin testing, the impact of diet, and cid reflux as important LPR etiologies,17,90,91 our therapeu-
the reliability of detection of pepsin and biliary salts in the tic approach could evolve. The exclusive use of PPIs in the
same sample. LPR therapeutic course can be challenged, since they are
In summary, there is no gold standard for the LPR diag- less effective on nonacid or mixed reflux.27 Given the
nosis. However, it is accepted that patients with LPR symp- required alkaline pH for trypsin activity,17 the administra-
toms, signs, and 1 proximal esophageal reflux episodes at tion of high doses of PPIs may be associated with a worsen-
the MII-pH can be considered patients with LPR. The use ing of complaints.17 It is possible that many patients who
of MII-pH makes sense in comparison with oropharyngeal were considered resistant to PPI treatment in the previous
pH monitoring in regard to the detection of LPR and GERD studies (which used classical pH metry) just had mixed or
that may coexist. In case of doubt or in case of symptoms, biliary LPR. Alginate drugs make particular sense in the
signs, but negative MII-pH, pepsin detection could be useful case of nonacid or mixed reflux or for patients with post-
for the diagnosis. Future technologies are needed to improve prandial symptoms and, according to a recent article, could
the LPR diagnosis. We could imagine a 96-hour MII-pH have similar efficiency to that of PPIs and alginate.148,149
with additional probes able to collect pepsin and other gas- Moreover, in practice, the combination of magaldrate and
troduodenal enzymes in the pharyngeal tissue and measure alginate at bedtime may be useful for many patients with
their concentrations. nonacid or mixed reflux according to MII-pH. H2-receptor
antagonists are second-line treatment regarding the short
Treatment duration of action (4-8 hours) of these drugs.150 In case of
Management for presumed LPR can include behavioral acid reflux, the prescription of twice-daily PPIs could be
modifications and pharmacologic treatment. The use of phy- associated with better symptom improvement than a once-
sician counseling for diet and lifestyle modification of fac- daily PPI prescription.151
tors known to affect LPR remains very low.144 However, Regarding patients who are resistant, the first step is to
recent studies suggested that diet and lifestyle modifications assess the treatment compliance, since 62.7% of such
are an important part of treatment. Zalvan et al showed that patients do not adequately take the treatment.152 The second
patients with LPR who were treated with alkaline water and step consists of the exclusion of differential diagnoses that
a Mediterranean-style diet had improvement similar to those can be associated with similar symptoms and findings
placed on PPIs.34 Similarly, our team found that patients (Table 7). Patients who are truly LPR resistant, who have
with LPR who focused on dietary modifications in addition no cofactors, and who respect the treatment may benefit
to PPIs did better with respect to LPR symptoms and vocal from additional gastrointestinal examinations (eg, manome-
improvement than those who used PPIs alone (Table 6).145 try, gastrointestinal endoscopy) to identify some conditions
The potentiating effect of diet on the efficacy of PPIs was explaining the therapeutic resistance (eg, hiatal hernia,
774 Otolaryngology–Head and Neck Surgery 160(5)

Table 6. Alkaline, Protein, and Low-Fat Diet.a

Lifestyle Habits Foods to Favor Foods to Avoid

1. Stress control 1. Meat, fish, chicken, eggs 1. Meat, fish, chicken, eggs
2. Tobacco and other addiction(s) reduction Shrimps, lobster, shellfish, fresh and thin fish Fat fish, fish oil (sardines, cods, herrings)
3. Reduction of size of meals Chicken fillet (without skin) Fat chicken
4. Hot lunch in place of hot diner Turkey or duck (without skin and fat) High-fat meat
5. Eat slowly Low-fat meat (remove fat from meat) Kidneys, bacon, ground meat
6. Do not talk while eating Veal cutlet, horse, pork tenderloin Lamb chops, shoulder or legs of lamb
7. Avoid tight clothing Rindless, fatless, cooked ham Ribs, rib steak, foie gras, delis, sausage
8. If possible avoid the following drugs: Steak, fillet, striploin roast veal, veal, chop Pork chops, roast, and shoulder, salami
Nonsteroidal anti-inflammatory drugs Egg white Paté, tripes
Corticosteroids, aspirin, theophylline Other:.............. Other:..............
Progesterone, iron supplementation 2. Dairy products 2. Dairy products
Calcium channel blockers Low-fat cheese Chocolate, ice cream, whole milk
Nitroderivatives, anticholinergic Skim milk Hard cheese, full-fat cheese
If heartburn Other:.............. Goat cheese, cheddar, Roquefort, Fontina,
gruyere, parmesan, munster, etc
1. Reduction of overweight
2. Elevating the head of the bed Other:..............
3. Cereals and starches 3. Cereals and starches
Laryngopharyngeal reflux treatment Oat, wheat, cracker, pasta, boiled potatoes Nut, cashew, hazelnut, peanut
Drug: ............. Wholemeal or brown bread, rice, brown rice French fries and frying, chocolate cookies
To take: before - during - after Other:.............. White bread
Other:..............
Meals (circle the adequate response): 4. Fruit and vegetables 4. Fruit and vegetables
Breakfast Agave, asparagus, cooked mushrooms Shallot, spicy, chili
Lunch Banana, melon, peach, ginger, spirulina Onion, garlic, tomato (sauce/raw tomato)
Diner Broccoli, celery, cauliflower, fennel, tofu Aspartame
Laryngopharyngeal reflux treatment Green beans, lentil, chickpeas, turnip, parsley Rhubarb, blueberry, beet/cane sugar
Drug: ............. Other:.............. Other:..............
To take: before - during - after Preparation:
Cooked by steaming or boiling in water
Meals (circle the adequate response): 5. Beverage 5. Beverage
Breakfast Chamomile Strong alcohol, red and rosé wines
Lunch Water, alkaline water Sparkling beverage (water, soda, beer, etc)
Diner Appel/pear juices (no sugar added) Coffee, tea
Laryngopharyngeal reflux treatment Melon/banana juices (no sugar added) Citrus juices (orange, lemon, grapefruit)
Drug: ............. Other:.............. Other:..............
To take: before - during - after 6. Greasy substances 6. Greasy substances
Olive oil Butter, spicy oils
Meals (circle the adequate response): Other:.............. Sauces (mayonnaise, mustard, ketchup, etc)
Breakfast Other:..............
Lunch 7. Sugar 7. Sugar
Diner Honey Sweets
a
Protein foods improve the esophageal sphincters tonicity. Carbonated beverages, caffeine, alcohol, fat, and tobacco decrease the sphincter tonicity promot-
ing laryngopharyngeal reflux.145 Acidic foods (spicy, caffeine, beer, chocolate, etc) promote the pepsin activity in refluxate gaz.

gastroparesis). For these patients, the inhibition of transient regeneration. Ideally, an initial period of 3 months may be
lower esophageal sphincter relaxations or, in preselected proposed, after which a therapeutic revision can be made
resistant cases (eg, severe hiatal hernia), fundoplication can for 3 additional months. Approximately 25% to 50% of
be proposed. patients would have a chronic course of the disease.4 For
Irrespective to the treatment scheme, it is recommended this reason, patients could keep their diet and lifestyle
to treat patients for a minimum of 8 weeks, corresponding changes. Physicians have to fully avoid the chronic prescrip-
to the time necessary for the mucosal healing and tion of PPIs in regard to their long-term side effects.147
Lechien et al 775

Table 7. Differential Diagnoses of Laryngopharyngeal Reflux.a

Reported Differential Diagnoses of Symptoms of Laryngopharyngeal Reflux

Esophageal disorders Ear, nose, and throat disorders Other

Mucosa disorders Infections Lung disorders
Eosinophilic esophagitis Chronic rhinosinusitis COPD
Zenker diverticulum Mycosis Psychological
Esophageal sclerodermia Recurrent angina Addiction (alcohol, tobacco
pharyngolaryngitis)
Esophageal candidosis Tuberculosis Stress
Heterotopic esophageal gastric mucosa Rheumatologic/autoimmune disorders Anxiety
Neoplasia Rheumatic arthritis Depression
Esophageal/sphincter motor disorders Sjögren’s syndrome Drugs
Hypertonicity of upper esophageal sphincter Laryngeal sarcoidosis Anticholinergic (salivary hypofunction)
Hypertonicity of lower esophageal sphincter Amyloidosis
Achalasia Granulomatosis with polyangiitis
Esophageal spasm Fibromyalgia
Absent peristaltism Allergy
Hypercontractile esophagus Laryngeal musculoskeletal disorders
Gastroparesis Function laryngeal disorders
Other Muscle tension dysphonia
Rumination Benign or malign tumors
Aerophagia Anatomic disorders
Size and shape of the epiglottis
Tongue tonsil hypertrophy
Uvula hypertrophy
Retroverted epiglottis (touching the
posterior pharyngeal wall)
Traumatic and other
Laryngeal fracture
Upper aerodigestive tract injury
Cervical osteophytes
Aging voice
Upper aerodigestive tract neoplasia
Thyroid disease (nodules, goiter, etc)
a
This table was constructed according to publications focusing on differential diagnoses of the main prevalent laryngopharyngeal reflux symptoms (globus, dys-
phonia, throat clearing, and cough).154-158

In summary, the high heterogeneity among randomized con- prevalence of cofactors associated with similar complaints
trolled trials comparing PPIs and placebo leads to inconclusive should be taken into consideration.
results about the superiority of PPIs over placebo. In fact, mild The prevalence of LPR symptoms and signs strongly
LPR could be treated with diet and behavioral changes, and in depends of the characteristics of studies—that is, the diag-
case of nonresponse, patients could benefit from a personalized nostic method, inclusion/exclusion criteria, and clinical
therapeutic scheme according to the reflux profile at the MII- tools used. The assessment of signs and symptoms with
pH results. The association of diet with many drugs, including complete tools is needed with consideration of the type of
PPIs, alginate, and magaldrate, could significantly improve the reflux (nonacid, acid, mixed). The methods used to assess
therapeutic efficacy. In case of nonresponse to treatment, thera- signs are important and should be as objective as possible.
peutic compliance should be assessed. The use of software to assess mucosal inflammation is
another future way.
Implications for Practice The recent findings about the role of pepsin and biliary
Laryngopharyngeal symptoms are prevalent, but the exact salts and the development of MII-pH open new prospects
prevalence of LPR is unknown. Future epidemiologic stud- within the scope of diagnosing and treating LPR. Future
ies should focus on objective examination of patients with diagnostic direction could associate symptoms, signs, MII-
LPR symptoms and signs to better delineate LPR incidence pH, and pepsin and trypsin detection to obtain a multipara-
and prevalence. Local lifestyle habits, diet, and the meter diagnostic approach as a gold standard. Clinical tools
776 Otolaryngology–Head and Neck Surgery 160(5)

Figure 4. Algorithm for management of suspected or confirmed laryngopharyngeal reflux (LPR). In practice, the use of pepsin detection
can be useful for patients with suspected LPR with negative impedance-pH monitoring. Treatment is based on diet 6 proton pump inhibitor
(PPIs) 1 alginate or magaldrate according to the LPR characteristic (acid, nonacid, or mixed reflux). The improvement of 50% of LPR
signs and symptoms leads to a treatment titration.148 Pending the development of new complete clinical tools (Reflux Symptom Score and
Reflux Sign Assessment), the use of clinical tools involves the adoption of validated thresholds for the diagnosis (Reflux Symptom Index
.13 and Reflux Finding Score .7).

should include a screening of GERD and pulmonary symp- With regard to the high level of controversy about preva-
toms that are associated with LPR. The assessment of these lence, clinical manifestation, diagnosis and treatment, oto-
patients in multidisciplinary settings (ie, involving clinicians laryngologists, gastroenterologists, and surgeons have to
from different specialties) is also crucial. The development define a multiparameter diagnostic approach with consen-
of a future clinical model to estimate the pretest probability sual MII-pH criteria and an overall therapeutic management
of abnormal pH among patients who failed PPI therapy plan for reflux. For this last point, we have proposed a new
could improve the diagnosis approach.153 management algorithm that is currently a course of reflec-
According to the LPR profile and the clinical manifesta- tion for the future debates (Figure 4).
tion, a personalized treatment can be proposed. Diet and
lifestyle changes should be considered as the first step of Author Contributions
treatment and could be sufficient to treat mild LPR. The Jerome R. Lechien, substantial contributions to the conception or
addition of alginate and magaldrate to PPIs should improve design of the work; & the acquisition, analysis, or interpretation of
the therapeutic management of nonacid and mixed LPR. data for the work; drafting the work; final approval of the version
Lechien et al 777

to be published; agreement to be accountable for all aspects of the questions related to the accuracy or integrity of any part of the work
work in ensuring that questions related to the accuracy or integrity are appropriately investigated and resolved; Michael F. Vaezi, sub-
of any part of the work are appropriately investigated and resolved; stantial contributions to the conception or design of the work; and the
Lee M. Akst, substantial contributions to the conception or design interpretation of data for the work; revising the paper critically for
of the work; and the interpretation of data for the work; revising important intellectual content; final approval of the version to be pub-
the paper critically for important intellectual content; final lished; agreement to be accountable for all aspects of the work in
approval of the version to be published; agreement to be accounta- ensuring that questions related to the accuracy or integrity of any part
ble for all aspects of the work in ensuring that questions related to of the work are appropriately investigated and resolved.
the accuracy or integrity of any part of the work are appropriately
investigated and resolved; Abdul Latif Hamdan, substantial con- Disclosures
tributions to the design of the work; the acquisition and the analy- Competing interests: Lee M. Akst, KeyPentax—consultant;
sis of data; drafting some parts of the work; final approval of the Olympus—advisory board.
version to be published; agreement to be accountable for all
Sponsorships: None.
aspects of the work in ensuring that questions related to the accu-
racy or integrity of any part of the work are appropriately investi- Funding source: None.
gated and resolved; Antonio Schindler, substantial contributions
to the design of the work; the acquisition and the analysis of data;
drafting some parts of the work; final approval of the version to be References
published; agreement to be accountable for all aspects of the work
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