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Laryngopharyngeal reflux disease: clinical presentation, diagnosis and

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Article  in  Current opinion in otolaryngology & head and neck surgery · September 2018
DOI: 10.1097/MOO.0000000000000486

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REVIEW

CURRENT
OPINION Laryngopharyngeal reflux disease: clinical
presentation, diagnosis and therapeutic challenges
in 2018
Jerome R. Lechien a,b,c,d, Sven Saussez a,b,d, and Petros D. Karkos a,e

Purpose of review
To review the recent literature on presentation, diagnosis and treatment of laryngopharyngeal reflux.
Recent findings
Patients with laryngopharyngeal reflux have a higher risk for gastroesophageal reflux and respiratory-
related diseases. Many symptoms and findings are underestimated, contributing to the inconclusive results
of many therapeutic trials. Additionally, little significance is given to nonacid and mixed refluxates,
although a significant prevalence. The association between symptoms, signs, impedance-pH studies and
pepsin detection could be the most accurate way for a clear diagnosis. ‘Reflux profiling’ is also important
for the administration of a personalized treatment based on diet, proton pump inhibitors, alginate,
magaldrate and other second-line drugs. There are only a handful of studies focusing on the addition of
alginate or magaldrate to the treatment of laryngopharyngeal reflux, although their contribution has
extensively been demonstrated.
Summary
Diagnosis remains controversial despite improvement in impedance and availability of pepsin detection in
daily practice. With recent studies exhibiting a significant prevalence of nonacid or mixed refluxes, the
addition of alginate or magaldrate to proton pump inhibitors should be considered. Future studies are
needed to assess these new therapeutic schemes in moderate and severe laryngopharyngeal reflux.
Keywords
diagnosis, laryngitis, laryngopharyngeal, reflux, treatment

INTRODUCTION and treatment. The purpose of this article is to

Laryngopharyngeal reflux (LPR) is an inflammatory review the recent literature on clinical presentation,
condition of the upper aerodigestive tract tissues diagnosis and treatment and to propose a complete
related to direct and indirect effect of gastroduode- management algorithm of LPR.
nal content reflux, which induces morphological
a
changes in the upper aerodigestive tract [1 ]. This
&&
Laryngopharyngeal Reflux Study Group of Young-Otolaryngologists of
definition differs from the past definition of the the International Federations of Oto-rhino-laryngological Societies (YO-
IFOS), Paris, France, bDepartment of Anatomy and Experimental Oncol-
2002 position statement of American Academy of
ogy, Mons School of Medicine, UMONS Research Institute for Health
Otolaryngology-Head and Neck Surgery [2] that did Sciences and Technology, cLaboratory of Phonetics, Faculty of Psychol-
not take into consideration the irritation of some ogy, Research Institute for Language Sciences and Technology, Univer-
duodenal molecules [3,4] into all upper aerodiges- sity of Mons (UMONS), Mons, dDepartment of Otorhinolaryngology and
tive tract mucosa (and not only into the laryngo- Head and Neck Surgery, CHU Saint-Pierre, Université Libre de Bruxelles,
Brussels, Belgium and eDepartment of Otorhinolaryngology and Head
pharynx), and the possible multifactorial origin of
and Neck Surgery, AHEPA University Hospital, Aristotle University of
some symptoms that can be triggered by neurore- Thessaloniki, Thessaloniki, Greece
flexive signaling and compensatory vagal responses Correspondence to Dr Jerome R. Lechien, MD, PhD, MS, Laboratory of
(indirect effect) [5]. Over the last three decades, the Anatomy and Cell Biology, Faculty of Medicine, University of Mons
number of LPR publications has progressively (UMONS), Avenue du Champ de mars, 6, B7000 Mons, Belgium.
increased (Fig. 1), however, despite this enthusiasm, Tel: +32 65 37 35 84; e-mail: [email protected]
it still remains a controversial topic particularly Curr Opin Otolaryngol Head Neck Surg 2018, 26:392–402
when dealing with clinical assessment, diagnosis DOI:10.1097/MOO.0000000000000486

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 Laryngopharyngeal reflux disease Lechien et al.

EPIDEMIOLOGY
KEY POINTS
There is a consensus that recognizes LPR as one of
! LPR is a prevalent disease in otolaryngology but the the most frequently encountered chronic inflamma-
exact incidence and prevalence remain unknown. tory conditions of upper aerodigestive tract, but real
incidence and prevalence are inaccurate and diffi-
! A large number of patients may concomitantly have
LPR, GERD, and respiratory-related disorders that need cult to estimate worldwide because of lack of diag-
the use of multidimensional clinical tools for the nostic criteria. Since the initial work by Koufman [6]
diagnosis and the therapeutic outcomes. that estimated the LPR incidence at 10% of the ear,
nose, and throat (ENT) outpatients, only a few epi-
! Many symptoms and findings are not described in the
demiological studies have been published. In China
current patient-reported outcome measures and
instruments evaluating the clinical findings of and Greece, the LPR prevalence was estimated to 5
laryngopharyngeal reflux. and 18.8%, respectively, but these evaluations were
only based on patient-reported outcomes question-
! Future diagnosis may associate symptoms, upper naires that are insufficient to make the diagnosis
aerodigestive tract findings, impedance-pH metry,
[7,8]. In another report from a tertiary voice center,
pepsin and trypsin detections. This approach will help
to determine a patient profile with laryngopharyngeal an evaluation of the prevalence of patients with LPR
reflux for personalized treatment. complaints was carried out during a 5-month
period. With pH monitoring, the author showed
! Diet can be sufficient treatment for mild LPR whereas that 69% of patients had LPR symptoms and find-
alginate or magaldrate are required for mixed and
ings and 50% of total patients had positive pH
nonacid reflux, respectively. Long-term control of reflux
requires diet and lifestyle modifications. monitoring (defined as pH <4 in the esophageal
probe, "8.1% upright and 2.9% supine) [9]. Since
! Therapeutic efficiency evaluation must include changes this initial report, there is no additional study eval-
of signs and symptoms. Compliance with medication uating incidence or prevalence of LPR in voice cen-
intake is often the cause for resistant patients. When
ter with objective examination. To get precise LPR
resistance is confirmed with good compliance to diet
and medication recommendations, additional incidence and prevalence rates, future conducted
examinations are required to propose second-line studies will need to include 24-h multichannel
treatment. intraluminal impedance-pH metry (MII-pH metry)
or a future best diagnostic tool in all patients with

FIGURE 1. The evolution of publications about laryngopharyngeal reflux during the past six decades. To identify publications
about LPR, we performed a systematic electronic research on PubMED with the following keywords. ‘laryngopharyngeal,’
‘laryngitis,’ ‘reflux,’ ‘gastroeosophageal.’ This graph shows the total number of publications performed about
laryngopharyngeal reflux according to the year. LPR, laryngopharyngeal reflux.

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Laryngology and bronchoesophagology

LPR signs and symptoms presenting at the ENT complaints usually concern 32.8% of GERD patients.
consultation. The incidence and prevalence of In another study, Dore et al. [33] identified globus
LPR is particularly important when considering sensation (39%), eructation (26%), cough (24%), and
the increase in junk food [10–12], obesity, acidifica- hoarseness (23%) as the most prevalent ENT symp-
tion of foods [10], and the increase in risk factors for toms in GERD patients. Classical GERD symptoms
gastroesophageal reflux disease (GERD) and LPR in such as heartburn are usually less prevalent in LPR in
western countries [8,13–15]. comparison with GERD [34]. However, recent find-
ings support that GERD and complications seem to
Clinical presentation coexist with LPR more often that it was previously
assumed [34–37]. This controversial relationship
between GERD and LPR led to the development of
Sign and symptom pathogenesis new clinical tools integrating both GERD and LPR
LPR disease develops following macroscopic [16,17] symptoms [35,38]. Regarding findings, posterior
and microscopic [17,18 ] changes of the upper
&&

commissure hypertrophy, thick endolaryngeal

aerodigestive tract mucosa. Mucosal irritation leads mucus, and laryngeal erythema are the most preva-
to an inflammatory reaction and dry (sticky) mucus lent LPR signs [24,30,31].
hypersecretion, as pepsin decreases the expression Recent articles support that the prevalence of
of mucin and the secretion of bicarbonate [3,17,19]. these symptoms and signs could significantly vary
The accumulation of sticky mucus triggers symp- according to sex and age; especially GERD symp-
toms such as postnasal drip sensation, globus sen- toms that are less perceived by elderly patients
sation, and throat clearing, leading to cough and [25,26 ,39,40]. Moreover, some LPR symptoms
&&

choking [20]. Mucus hypersecretion and related and signs can be found in healthy individuals. In
complaints can also be mediated by stimulation of a cohort of 91 healthy individuals, Chen et al. [41 ]
&&

mucosal chemoreceptors in the distal portion of found that laryngeal erythema, posterior commis-
esophagus, irritated by refluxed material from the sure hypertrophy, and diffuse laryngeal edema are
stomach [5,21]. At the same time, mucosal inflam- the most usual LPR findings met in healthy individ-
mation of the upper aerodigestive tract may induce uals. In addition, throat clearing and excess throat
dysphagia, globus sensation, throat pain, and ody- mucus are both prevalent symptoms of LPR in
nophagia. The pathophysiological mechanisms healthy individuals [41 ]. Similar findings were
&&

underlying the development of hoarseness are more supported by Hicks et al. [42] who objectified that
complicated and, according to a recent pathophysi- 86% of healthy people had LPR findings; certain
ological model, involves macroscopic and micro- signs (interarytenoid bar) reaching a prevalence of
scopic histological changes in the mucosa of the 70%. These results must be cautiously interpreted
vocal folds [17] and substantial modifications of because investigators assessed signs of healthy peo-
biomechanical properties of the vocal folds leading ple knowing the clinical state of individuals
to subjective and objective voice quality impair- (healthy) that strongly impacts the reliability of
ments [22–24]. Interestingly, recent data support finding assessment [43,44]. According to recent
that women could be more susceptible to hoarseness studies [45,46], the use of certain software that assess
than men because of anatomic, histological, and the erythema intensity of the laryngopharyngeal
functional sex-related differences [25]. These sex mucosa could improve the physician endoscopic
differences led some authors to consider an LPR assessment.
diagnosis in women faster than men because of
more impressive laryngeal findings [26 ]. More- Clinical tools
&&

over, pepsin irritation has been identified as risk The majority of clinical researches that have studied
factor in the development of many benign lesions LPR symptoms and signs used Reflux Symptoms
of the vocal folds [27] or leukoplakia [28]. Future Index (RSI) and Reflux Finding Score (RFS) as clinical
studies are needed to specify the exact role of LPR in tools [47,48]. Indeed, a recent systematic review
the development of benign lesions [29]. exhibited that the 11 symptoms described in RSI
and the 8 findings described in RFS are the most
Sign and symptom prevalence frequently assessed clinical outcomes in the evalua-
Globus sensation, throat clearing, hoarseness, excess tion of therapeutic efficiency [1 ]. However, the
&&

throat mucus, and postnasal drip are the most preva- same study and others [16,35,43,49] support that
lent symptoms as they are found in at least 75% of both RSI and RFS are incomplete and do not take
patients [24,30,31]. According to the initial analysis into account many LPR symptoms (throat pain,
of ProGERD Study [32] that remains the largest odynophagia, ear pressure, eructation, or halitosis)
study conducted on this topic, laryngopharyngeal and findings (vocal fold erythema, leukoplakia,

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 Table 1. Validated patient-reported outcome questionnaires and laryngopharyngeal reflux finding scores for laryngopharyngeal reflux
Scale characteristics
Objective Target and patient characteristics Assessed symptoms/signs Type Item (N) Item response Calculation Subscales

Patient-reported outcome measures

TQ [38] Diagnosis Patients with globus GS, PT, DT, DD, EM, VD, IS, CD, TO, HK VAS 12 Severity: 0–4 Complex calculation 0
(pharyngeal symptoms)
Therapeutic outcome Total score: 32
GETS [39] Diagnosis Patients with globus GS, PT, DT, TO, DD, SW, CD, HK, FS VAS 12 Severity: 0–7 N.P. 3
(pharyngeal symptoms)
Therapeutic outcome Total score: each item
RSI [33] Diagnosis Suspected or confirmed LPR VD, GS, TC, EM, CP, DD, PC, CT, VAS 9 Severity: 0–5 Sum of items 0
HB, RE, CK
Therapeutic outcome Total score: 45
LPR-HRQL [40] Therapeutic outcome Suspected or confirmed LPR HRQL related to VD, CT, TC, DD VAS 43 Severity: 0–7 or 0–10 By subscales 5
of HRQL
Total score: 30-90
&&
SERQ [41 ] Diagnosis Pharyngolaryngeal complaints TC, CT, GS, ST, DD VAS 9 Severity: 0–4 N.P. 0
Therapeutic outcome VD, HB, RE, DC, NC
LPR-34 [42] Diagnosis Suspected or confirmed LPR TC, GS, EM, PT, VD, DA, FF, PN, VAS 34 Severity: 0–5 N.P. 0
TB, BO, HA, RS, HB, DD, PC, IS,
WH, VI, BL, RE, BR, CK, NA, HO
Therapeutic outcome
PRSQ [43] Diagnosis Suspected LPR CT, VD, DD, RE, HB VAS 24 Severity: 0–5 Multiplication of 4
Therapeutic outcome Frequency: 0–5 Severity and frequency
for each item
Finding instruments

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RFS [34] Diagnosis Suspected LPR SE, VV, EH, VE, LE, PH, GR, TM PRI 8 Severity: 0–4 Sum of items 0
Therapeutic outcome Confirmed LPR or 0–2 Total score: 26
Vaezi Diagnosis Uncured LPR PY, PW, GG, EH Yes/no 12 Presence: yes/no Signs prevalence 0
Instrument [44] Therapeutic outcome PH, KT, LE, VE, VR, PP, SP, SR Total score: N.A.
LRDI [45] Therapeutic outcome Suspected LPR PH, SP, SE, VR, SR, SU, ND, PP, LL, GG, WW VAS 12 Severity: 0–3 Sum of items 0
Total score: 36
LGS [46] Therapeutic outcome Suspected LPR LE, EH, VE, VR PRI 4 Laryngitis grade: 0–4 – 0
SE, SU, UC Each grade is defined
LRG [47] Therapeutic outcome Confirmed LPR EH, VE, LE, PH, VR, GG, ND, UC, SE Likert Scale Signs: 6 Severity: 0–4 Sum of items Signs scale
VC wave: 4 Total score: 24þ16 VC wave
CPLI [48] Therapeutic outcome Suspected LPR EH, GG, LE, PW VAS 10 Severity: 0–3 Sum of items 0
PH, VR, VE Total score: 30

AN, anterior pillars erythema/edema; BB, bad breath; BL, belching; BO, bloating; BR, breathing difficulties; CC, chocking; CD, Catarrh down throat; CP, chest pain; CPLI, chronic posterior laryngitis index; CT,
troublesome cough; DA, decreased appetite; DC, dry cough; DD, dysphagia; DT, discomfort in throat; EH, laryngeal/arytenoids erythema; EM, excess throat mucous/postnasal drip; F/M, female/male; FF, flatulence;

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

FS, food sticking when swallowing; GETS, Glasgow Edinburgh Throat Scale; GG, interarytenoid granulation and/or granuloma; GS, globus sensation; HA, headache; HB, heartburn; HK, have to keep swallowing; HO,
hiccup; IS, indigestion; KT, laryngeal keratosis; LE, laryngeal edema; LGS, laryngoscopic grading scale; LL, leukoplakia; LO, loss light reflect; LPR, laryngopharyngeal reflux; LPR-34, 34-Item Symptom Questionnaire; LPR-
HRQ, Laryngopharyngeal Reflux Health-Related Quality of Life; LRDI, laryngopharyngeal reflux disease index; LRG, laryngeal reflux grade; N.A., not available; NA, nausea; NC, nasal congestion; ND, nodules; NN,

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nocturnal cough; NP, not provided; PC, coughing after you ate/lying down; PH, posterior commissure hypertrophy; PI, mucous pooling in the pyriform sinus; PN, postnasal drip; PO, posterior oropharyngeal wall
erythema; PP, polyp/Reinke edema; PRI, predefined item; PRSQ, Pharyngeal Reflux Symptom Questionnaire; PT, pain throat; PW, posterior pharyngeal wall erythema; PY, postpharyngeal cobblestoning; RCT,
randomized controlled trial; RE, regurgitations; RFS, reflux finding Score; RS, rush of saliva; RSI, Reflux Symptom Index; SE, subglottic edema/pseudosulcus/stenosis; SERQ, Supraesophageal Reflux Questionnaire; SP,
supraglottis edema; SR, supraglottis erythema; SU, subglottic erythema; SW, swelling in the throat; TB, tongue burning; TC, throat clearing; TM, thick endolaryngeal mucus; TO, Throat closing off; TQ, throat
questionnaire; TT, tongue tonsil hypertrophy; UC, laryngeal ulcerations; UV, uvula erythema/edema; VAS, visual analog scale; VC, vocal cords; VD, voice disorders; VE, vocal fold edema; VO, vomiting; VR, vocal fold
Laryngopharyngeal reflux disease Lechien et al.

395
erythema; VV, ventricular obliteration; WH, wheezing; WW, vocal web.
Laryngology and bronchoesophagology

keratosis, posterior pharyngeal wall inflammation, Because of the relationship between GERD, LPR,
anterior pillars inflammation, coated tongue), and some respiratory disease (bronchial responsive-
which are prevalent in LPR [1 ,50,51]. The overuse ness), the LPR study group of the Young Otolaryng-
&&

of RSI and RFS in the assessment of the prevalence of ologists of the International Federation of Oto-
signs and symptoms may correspond to an evalua- Rhino-Laryngological Societies (YO-IFOS) has devel-
tion bias. Other patient-reported outcomes ques- oped a new clinical tool to index symptoms of LPR,
tionnaires or instruments evaluating clinical LPR GERD, and pulmonary-related disease [38]. Termed
findings have been developed and they are the Reflux Symptom Score (RSS), this is in process of
described in Table 1 [47,48,52–62]. Nowadays, they validation in English, French and Italian, and is
are underused in comparison with RSI and RFS. described in Fig. 2.

FIGURE 2. Reflux symptom score. Reflux symptom score (RSS) is in the process of validation in French, English, and Italian
language. Symptoms are assessed within the last month. For each symptom, patient evaluates the occurrence of symptoms (1:
once a week; 2: two or three times a week; 3: four or five times a week; 4: six times a week or almost every day; 5: every
day), the severity of symptoms (1: symptom is not severe, 5: very severe when it occurs). RSS also assesses the impact of
symptoms on quality of life (0: no impact on my quality of life; 5: significant impact on my quality of life). The clinical total
score is calculated by the sum of all scores of both severity and frequency of items. The quality of life score is calculated
separately. Three subcategories of RSS may be identified according to the affected system: ear, nose, and throat area
versus intestinal area versus chest area. From these three sub-scores, future studies could develop thresholds indicating
gastroenterological or chest examinations (i.e. gastroscopy, lung function tests, etc.). At the end of the questionnaire, all
patients must assess if the questionnaire includes all of the complaints. Additional complaints may be added.

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 Laryngopharyngeal reflux disease Lechien et al.

DIAGNOSIS led to an increasing number of otolaryngologists to

As there is no gold standard, LPR diagnosis is proba- base LPR diagnosis on empirical therapeutic trials
bly the most controversial aspect of the disease. In only [63,64]. This approach is based on the utiliza-
2018, the two most commonly used techniques to tion of some clinical scores such as RSI (RSI >13) and
make the diagnosis consist of the use of MII imped- RFS (RFS >7) at baseline and the prescription of
ance-pH metry and, when it is unavailable, the proton pump inhibitors (PPIs) for a 3-month setup
positive response to a well conducted empirical period. Note that initial thresholds can be adapted
with regard to sex [26 ] and the allergic status [73].
&&

therapeutic trial [63,64]. Over the past few years,

pepsin detection is increasingly used as a LPR diag- Depending on improvement or not titration of the
nostic biomarker [27]. PPI dose upwards may be proposed for three addi-
tional months. LPR diagnosis is only considered
Multichannel intraluminal impedance-pH metry if the patient responds after 3 or 6 months of treat-
ment. The diagnosis of nonresponder patients
MII impedance-pH metry is, to date, the most reli-
remains uncertain and requires additional examina-
able examination to perform the diagnosis. Accord-
tions (MII impedance-pH metry). Currently, there are
ing to the significant rate of nonacid reflux
many definitions concerning the response to treat-
[4,65,66], it is important to perform this examina-
ment, that is, improvement of 50% of symptom score
tion in place of classical pH-metry that does not after treatment [74]; reduction of 5–10 points at RSI
detect nonacid reflux. However, the use of MII [30,75]; and the reduction of both RSI less than 13 and
impedance-pH metry is associated with a myriad
RFS less than 7 after 3 or 6 months of treatment
of LPR diagnostic criteria and probe placements
[24,76]. In an overall way, the clinical diagnosis
[67], which contribute to the selection of different
remains difficult as most of the LPR symptoms may
patient profiles. Overall, the proximal probe is usu-
be encountered in all conditions affecting laryngo-
ally placed 1 cm below or 1–3 cm above upper
pharyngeal mucosa such as allergies, addiction
esophageal sphincter and the distal sensor at 5 cm
(alcohol, tobacco and drugs), asthma inhalers, envi-
above lower esophageal sphincter. The placement of ronmental irritants, poor vocal hygiene, muscle ten-
the proximal probe remains controversial (intra- sion dysphonia; alone or in addition to LPR. Thus, the
esophageal versus hypopharyngeal) as the move-
establishment of LPR diagnosis of empirical therapeu-
ments of pharyngeal probe during the test period
tic trial might carefully involve the exclusion of all
may precipitate pseudoreflux episodes secondary to
cofactors or differential diagnoses of LPR [1 ]. More-
&&

mucosal irritation [68]. With reference to diagnostic

over, the knowledge of these clinical entities finds all
criteria, recent data suggest that one or more LPR
of its importance in case of resistance to PPI treat-
events in proximal probe should be considered
ment. This approach also assumes that acid is the
abnormal in patients with LPR symptoms [67] injurious factor when it is known that pepsin alone
but, to date, there is no international consensus. and bile acids are also inflammatory stimuli. Further-
The difficulty in standardizing diagnostic criteria is
more, volume escape from the stomach may trigger
related to the fact that normal values for the test
pharyngeal reflex responses that can be interpreted by
could not be definitely established, given the diffi-
some patients as symptomatology and this will not be
culty of carrying out MII impedance-pH metry in a
addressed by PPI therapy and is best managed by
large number of normal volunteers. The main cur-
blocking or binding agents.
rent criticism about MII impedance-pH metry con-
cerns the significant rates of false-positive (7–17%),
because of probe placement [69,70], and false-nega- Pepsin and trypsin detection
tive because of the lack of reflux episodes during the
The analyses of pepsin or trypsin [4] detection are
24-h period of testing [71]. The false negative prob-
conducted on saliva, or in pharyngeal or laryngeal
lem could be mitigated by the use of 48-h studies.
biopsies (which is more sensitive but invasive)
Indeed, a recent study reported better correlation
[77,78 ]. According to a recent meta-analysis [79],
&&

analysis between reflux episodes and symptoms in

the sensitivity and specificity of salivary pepsin
patients with 48-h MII impedance-pH metry in
detection are 64 and 68%, respectively. To date,
place of 24-h studies [72]. Moreover, 48-h studies no research studied the trypsin sensitivity and spec-
could capture significantly more reflux episodes as ificity in combination or not with pepsin. In fact,
compared with 24 h of monitoring alone [72].
the reliability of pepsin or trypsin detection (sensi-
tivity, specificity, positive and negative predictive
Empirical therapeutic trial values) would be unknown as long as there will be
Cost and other weaknesses and the unavailability of no gold standard. In the 11 studies that assessed the
MII impedance-pH metry in many countries have interest of pepsin detection in the LPR diagnosis,

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Laryngology and bronchoesophagology

there was an important heterogeneity with regard to use of PPIs in the LPR therapeutic course can be
the diagnosis method, the exclusion criteria, and challenged. It is becoming clear that we must person-
the material used for the pepsin detection [79]. The alize treatment to the patient’s reflux profile (diet,
various techniques include Peptest commercial kit lifestyle changes, acid, nonacid, mixed reflux). For
(immunoassay), ELISA or western blot; the latter example, patients with biliary reflux cannot be
being expensive but providing quantitative analy- treated by PPIs alone as the increase of stomach pH
ses. Concerning the sample time, the best time of can favor the trypsin activity in the upper aerodiges-
day for the pepsin collection would be upon waking tive tract mucosa, leading to a disease worsening [3].
[80] irrespective of the severity of symptoms because Thus, as proposed in our therapeutic algorithm
as yet, there is no association between saliva pepsin (Fig. 3), the first-line LPR treatment combines diet,
level and the symptom severity [81]. PPIs, sodium alginate (acid or mixed reflux), magal-
The place of pepsin and trypsin detection in LPR drate anhydrous (biliary reflux), in association or not
diagnosis remains unknown. Future investigations with gastroprokinetic. Alginate drugs make particular
have to respond to many unanswered questions sense in case of nonacid, mixed reflux, or in patients
about optimal timing for the sampling, location, with postprandial symptoms. The combination of
nature, and threshold values for pepsin testing; magaldrate (after the meals) and alginate in bedtime
whilst taking into consideration that pepsin can may be useful for many patients. H2-receptor antag-
easily be endocytosed in mucosal cells, which may onists (at bedtime) are only recommended as second-
lead to erroneous detection of pepsin in the upper line treatment in patients with LPR and GERD, or
aerodigestive tract tissue [17]. Currently, pepsin and partial response to PPIs but physicians must keep in
trypsin can be used as additional diagnostic meth- mind that these molecules have a relatively short
ods alongside MII impedance-pH metry in patients duration of action (4–8 h) [86].
with LPR symptoms and signs. The occurrence of Resistant patients must be primarily assessed for
symptoms, signs, and positive MII impedance-pH treatment compliance. Indeed, Pisegna et al. [87]
metry, and pepsin or trypsin detection can be con- demonstrated that 62.7% of patients recommended
sidered as the best gold standard that we have. PPIs did not adequately take their treatment, corre-
sponding to the first cause of therapeutic failure. In
case of long-term resistance, differential diagnoses
TREATMENT of laryngopharyngeal diseases must be carefully
PPI efficacy in LPR has long been called into ques- reviewed. On the basis of our review of the literature,
tion but a recent meta-analysis/systematic review we established a nonexhaustive list of differential
suggests that PPIs are effective for both LPR signs diagnoses of LPR (Table 2) [88–92]. The true resis-
and symptoms [1 ]. In this article, our group found tant patients to the previously cited drugs can ben-
&&

an important heterogeneity between studies accord- efit from inhibition of transient lower esophageal
ing to diagnostic criteria, lack of exclusion criteria, sphincter relaxations (baclofen) or, in preselected
treatment and outcomes that explains the contro- resistant cases (i.e. severe hiatal hernia), fundopli-
versy [1 ]. The lack of consideration of many signs cation. Although the results for GERD are excellent,
&&

and symptoms related to reflux is one important results with LPR patients are less impressive with
factor that may help explain the negative results of uncertain laryngeal symptoms improvement [93].
some studies that did not observe significant clinical After 3 or 6 months of treatment, it has been
improvement after treatment. suggested that the weaning of patients is successful in
The importance of diet and lifestyle changes has approximately 66% [94], although 25–50% patients
long been underestimated by gastroenterologists would have chronic course of the disease [6]. For
and otolaryngologists, although diet is undeniably these patients, the continuation of diet control is
the first therapeutic step. Indeed, some studies sug- important and severe episodes of LPR recurrence
gest that diet could be sufficient for the treatment of can be treated with short-term PPI and alginate (or
mild LPR [82 ]. For moderate-to-severe LPR, the full magaldrate) treatment according to the patient pro-
&&

respect of diet can substantially improve the positive file. The long-term prescription of PPIs is currently no
evolution of signs and symptoms in combination longer recommended because of long-term side
with PPIs [10,82 ,83,84]. Strict and alkaline diet effects of these drugs (i.e. calcium, iron, vitamin
&&

could also be the therapeutic key for resistant malabsorption, renal failure, drug interactions, atro-
patients to medical treatment [10]. phic gastritis, paediatric growth risks) [95 ].
&&

Recent studies underlined the importance of

nonacid reflux and the role of trypsin in the patho- CONCLUSION AND RECOMMENDATIONS
genesis of biliary and mixed refluxes [4,66,85]. With LPR is a complex disease spectrum because of epi-
regard to these studies, the systematic and exclusive demiological, pathophysiological, diagnostic and

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 Laryngopharyngeal reflux disease Lechien et al.

FIGURE 3. Algorithm for assessment and management of suspected or confirmed laryngopharyngeal reflux. The confirmation
of LPR is based on positive results at both pepsin detection and pH impedance metry. The lack of reflux in one of these two
examinations leads to the suspicion of the diagnosis and the prescription of an empirical treatment. The presence of symptoms
related to GERD or pulmonary dysfunction in the fulfilled clinical tools (RSI or RSS or other) may indicate the realization of
additional examinations (esogastroduodenoscopy, lung function test, etc.). According to the characteristics of pH impedance

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Laryngology and bronchoesophagology

Table 2. Differential diagnoses of laryngopharyngeal reflux

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
Esophageal candidosis Tuberculosis (alcohol, tobacco pharyngolaryntidis)
Heterotopic esophageal gastric mucosa Rheumatologic/auto-immune disorders Stress
Neoplasia Rheumatic arthritis Anxiety
Esophageal/sphincter motor disorders Sjogren’s syndrome Depression
Hypertonicity of upper esophageal sphincter Laryngeal sarcoidosis Drugs
Hypertonicity of lower esophageal sphincter Amyloı̈dosis Anticholinergic (salivary hypofunction)
Achalasia Granulomatosis with polyangiitis
Esophageal spasm Fibromyalgia
Absent peristaltism Allergy
Hypercontractile esophagus Laryngeal musculoskeletal disorders
Gastroparesis Muscle tension dysphonia
Cervical osteophytes
Benign or malign tumors
Anatomical disorders
Size and shape of the epiglottis
Tongue tonsil hypertrophy
Uvula hypertrophy
Retroverted epiglottis
(touching the posterior pharyngeal wall)
Traumatic
Laryngeal fracture
Upper aerodigestive tract injury
Other
Aging voice
Allergy
Upper aerodigestive tract neoplasia
Thyroid disease (nodules, goiter, etc.)

A nonexhaustive list of differential diagnoses of laryngopharyngeal reflux. COPD, chronic obstructive pulmonary disease.

findings, the treatment is based on diet with or without PPIs with alginate or magaldrate in order to treat acid, nonacid or
mixed reflux. The lack of reflux in pH impedance metry or in the case when the patient had no pH impedance metry,
empirical treatment is based on diet with or without PPIs with alginate in order to treat acid and a significant part of nonacid
refluxes (conjugated biliary salt). Note that patients with low symptoms and signs of LPR can be treated with diet and lifestyle
changes. The improvement of at least 50% of LPR signs and symptoms according to the clinical tools used lead to a titration of
the treatment with regard to the symptom pattern (patients with postprandial complaints may preferably keep alginate after the
meals and reduce PPIs). An improvement of 1–50% of clinical tool scores may lead to the increase or, at least, the
continuation of treatment for three additional months. The worsening or the lack of changes of symptoms and signs need
additional examinations to better understand the underlying disorder. Patients with LPR and esophageal dysmotility may be
treated by baclofen whereas those with a lack of efficiency of PPIs may be treated with strict diet and the use of H2-receptor
antagonists. Surgery is indicated if there is a resistance to all above-mentioned drugs or strict diet. GERD, gastroesophageal
reflux disease; LPR, laryngopharyngeal reflux; PPI, proton pump inhibitors.

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 Laryngopharyngeal reflux disease Lechien et al.

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