children

Review
Pediatric Laryngopharyngeal Reflux: An Evidence-Based Review
Jerome R. Lechien 1,2,3,4

1 Polyclinic of Poitiers, Elsan Hospital, 86000 Poitiers, France; [email protected];

Tel.: +32-65-37-35-84
2 Department of Anatomy and Experimental Oncology, Mons School of Medicine, UMONS Research Institute
for Health Sciences and Technology, University of Mons (UMons), B7000 Mons, Belgium
3 Department of Otolaryngology-Head and Neck Surgery, EpiCURA Hospital, B7000 Baudour, Belgium
4 Department of Otolaryngology-Head and Neck Surgery, EpiCURA Hospital, Rue L. Cathy, University of
Mons, B7000 Mons, Belgium

Abstract: AbstractPurpose: Pediatric laryngopharyngeal reflux (P-LPR) is associated with the devel-
opment of common otolaryngological symptoms and findings. In the present study, the findings
about epidemiology, clinical presentation, diagnostic and therapeutic outcomes of pediatric popu-
lation were reviewed. Methods: A PubMed, Cochrane Library, and Scopus literature search was
conducted about evidence-based findings in epidemiology, clinical presentation, diagnostic and ther-
apeutic outcomes of P-LPR. Findings: The prevalence of LPR remains unknown in infant and child
populations. The clinical presentation depends on age. Infants with LPR symptoms commonly have
both gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux and related digestive,
respiratory and ear, nose and throat symptoms. The GERD prevalence appears to decrease over the
growth, and the clinical picture is increasingly associated with LPR symptoms and findings without
GERD. The prevalence of LPR and proximal acid and nonacid esophageal reflux events may be high
in some prevalent otolaryngological conditions (chronic otitis media, laryngolomalacia and apnea).
However, the lack of use of hypopharyngeal–esophageal multichannel intraluminal impedance pH
monitoring (HEMII-pH) limits the establishment of etiological associations. Proton pump inhibitors
are less effective in P-LPR patients compared to GERD populations, which may be related to the
high prevalence of weakly or nonacid reflux events. Conclusions: Many gray areas persist in P-LPR
and should be not resolved without the establishment of diagnostic criteria (guidelines) based on
HEMII-pH. The unavailability of HEMII-pH and the poor acid-suppressive therapeutic response are
Citation: Lechien, J.R. Pediatric
all issues requiring future investigations. Future controlled studies using HEMII-pH and enzyme
Laryngopharyngeal Reflux: An
measurements in ear, nose or throat fluids may clarify the epidemiology of P-LPR according to age
Evidence-Based Review. Children
and its association with many otolaryngological conditions.
2023, 10, 583. https://doi.org/
10.3390/children10030583
Keywords: larynx; laryngitis; laryngopharyngeal; reflux; otolaryngology; head neck surgery;
Academic Editor: Luca gastroesophageal reflux; infants; children; pediatric
Oscar Redaelli de Zinis

Received: 23 February 2023

Revised: 11 March 2023
Accepted: 16 March 2023 1. Introduction
Published: 18 March 2023 The backflow of gastric content into the esophagus is a physiologic process occurring
in most infants and children without complication [1]. When the reflux leads to troublesome
symptoms and/or complications, such as esophagitis or stricturing, the gastroesophageal
reflux becomes pathologic and is defined as gastroesophageal reflux disease (GERD) [1,2].
Copyright: © 2023 by the author.
Reflux disease may be associated with upper aerodigestive tract symptoms and findings,
Licensee MDPI, Basel, Switzerland.
leading to the use of the terms “pediatric extra-esophageal reflux disease” or pediatric
This article is an open access article
distributed under the terms and
laryngopharyngeal reflux (P-LPR) [3]. Although LPR was considered as an extension
conditions of the Creative Commons
of GERD, the differences in clinical presentation and therapeutic outcomes led to the
Attribution (CC BY) license (https:// evolution of P-LPR as a distinct disease process [4]. From a clinical standpoint, symptoms
creativecommons.org/licenses/by/ and findings of P-LPR are known to vary widely by age and remain non-specific [3,4]. P-
4.0/). LPR may be associated with many laryngeal, oral, nasal or ear conditions, e.g., otitis media,

Children 2023, 10, 583. https://doi.org/10.3390/children10030583 https://www.mdpi.com/journal/children

Children 2023, 10, 583 2 of 15

chronic rhinosinusitis or dysphonia, even if proving causality remains difficult in most of

them [5,6]. The diagnosis of P-LPR remains complicated regarding the non-specificity of
symptoms and signs, and the difficulty to make a pH study in pediatric population [7,8].
Thus, infants and children represent a challenging population.
The aim of this evidence-based review was to report the current knowledge about
epidemiology, clinical picture, diagnostic and therapeutic outcomes of infants and children
with laryngopharyngeal reflux disease and to provide critical evidence-based analysis of
the current literature.

2. Materials and Methods

A PubMed, Cochrane Library and Scopus database search was conducted for rele-
vant peer-reviewed publications in English and French related to incidence, prevalence,
symptoms, signs, pathophysiology, diagnosis and treatment of P-LPR. The following key
words were associated: “pediatric”, “children”, “infant”, “reflux”, “laryngopharyngeal”,
“extra-esophageal”, “gastroesophageal”, “symptoms”, “findings”, “treatment” and “phys-
iology”. Clinical prospective/retrospective controlled/uncontrolled studies, systematic
reviews or meta-analyses were considered in the review process. The papers were selected
if they provided data on epidemiology, pathophysiology, clinical presentation, diagnosis
and treatment of LPR in pediatric population. Critical analysis of the included publications
was carried out focusing on incidence and prevalence, clinical presentation, diagnosis
and treatment of infants and children with LPR. The author summarized implications
for practice. Ethics committee approval was not required for this state-of-the art review.
A systematic review or meta-analysis was not performed regarding the low number of
studies and the heterogeneity across studies in inclusion/exclusion criteria, pH-testing use,
treatment and therapeutic outcomes.

3. Epidemiology
The prevalence of GERD-related symptoms in the pediatric population varied from 2%
to 30% in Western countries [9,10] and appears to increase with the increase in the incidence
of the childhood obesity [4]. Recent studies supported that GERD occurs in 50% of infants
younger than 2 months of age, 60–70% of infants 3–4 months and 5% of infants of more
than 12 months of age [11–13].
To date, both the prevalence and incidence of P-LPR are still unknown, because there
was no investigation of prevalence or incidence in the pediatric population through ob-
jective diagnostic tools. At best, the prevalence of reflux was investigated in infants or
children with upper airway symptoms who were addressed in pediatric otolaryngology
consultations [14]. The prevalence of acid esophageal reflux events in infants and children
with apnea or stridor ranged from 27% to 73% [15–17]. Among pediatric patients with
chronic cough or hoarseness, GERD was detected in 62% to 73% of cases [17–19]. The
prevalence of P-LPR in upper respiratory diseases and symptoms remains, however, un-
certain, because the authors of these studies determined the presence of reflux through
single or dual-probe pH monitoring, which cannot detect weakly or alkaline pharyngeal
reflux events.
From an evidence-based approach, the lack of use of hypopharyngeal–esophageal
multichannel intraluminal impedance pH monitoring (HEMII-pH) makes difficult the
determination of the exact prevalence and incidence of P-LPR in infants and children.
The determination of P-LPR prevalence or incidence requires the use of HEMII-pH or
oropharyngeal pH testing, which are the only two approaches able to detect acid, weakly
acid and alkaline pharyngeal reflux events [20,21]. Moreover, to date, there have been
no international guidelines about the cutoff for the P-LPR diagnostic with HEMII-pH.
The future determination of P-LPR incidence and prevalence should consider the age of
children/infants because as with GERD, P-LPR is expected to be more prevalent during
the first 12 months of life according to the immaturity of esophageal sphincters [22].
Children 2023, 10, 583 3 of 15

4. Pathophysiology
4.1. Physiology of Laryngopharyngeal Reflux
Regardless of the patient’s age, the development of laryngopharyngeal symptoms
and findings may be attributed to the deposit of gastroduodenal content (e.g., pepsin,
bile salts) into the upper aerodigestive tract mucosa and the related development of an
inflammatory reaction [23,24]. The occurrence of pharyngeal reflux events may consist of a
liquid backflow of stomach content, especially in infants with regurgitations, or it may be
gaseous and silent in children without regurgitation [15,25]. The P-LPR appears to be more
likely weakly acid at the HEMII-pH, which is substantially different from the GERD profile
at the HEMII-pH [7,15]. Despite the lack of study investigating the P-LPR features at the
(HE)MII-pH according to the age, the presence of esophageal immaturity in young infants
should be associated with the co-existence of GERD and different HEMII-pH tracings and
features. In other words, P-LPR characteristics may vary according to the age of the patient.
The inflammatory reaction in upper aerodigestive tract mucosa may lead to mucosal
injuries, mucus dryness, epithelium thickening and micro-trauma [26]. The mucosa injuries
lead to mucus production and dehydration through a down-regulation of mucin and
carbonic anhydrase gene expression [26]. Basic science and adult clinical studies reported
that the accumulation of sticky mucus induces postnasal drip, globus sensation, throat
clearing, dysphagia and cough, which are prevalent symptoms in P-LPR patients [4,21,27].
In addition to the deposit of gastroduodenal content into the mucosa, the occurrence of
neural reflex arc between esophagus and respiratory receptors was suspected but not
yet demonstrated. This hypothesis suggests that the gastric acid stimulation of receptors
within the esophagus may cause symptoms in the pharynx via neural reflex arc as well as
cardiovascular and respiratory symptoms, including bradycardia and apnea [4].

4.2. Influence of Age on Physiology

The main mechanisms of defense against laryngopharyngeal reflux involve esophageal
motility/peristalsis, mucosa bicarbonate secretion and lower (LES) and upper esophageal
sphincter (UES) tonicity [5,26]. The backflow of gastroduodenal content into the upper
aerodigestive tract is related to esophageal dysmotility and the transient relaxation of
LES and UES, which may be frequent in infants younger than 6 months and preterm
infants. Indeed, younger infants report a high prevalence of gastroesophageal reflux
and GERD because of the impaired esophageal peristalsis, physiological immaturity of
the esophageal sphincter, and slower gastric emptying time [28,29]. The immaturity of
the upper digestive tract is more important in infants born after less than 34 weeks of
gestation with a GERD incidence reaching 22% of cases [30]. The intake of increased
volume of liquid/milk at each feeding in this period of life and the related postprandial
gastric distension and LES relaxation are additional factors supporting the high incidence
of GERD and, theoretically, P-LPR in the first 6 months of life [7]. In practice, regurgi-
tation is one of the most frequent symptoms of GERD and P-LPR in infants [12], and
each episode of regurgitation is associated with the deposit of gastroduodenal enzymes
into the upper aerodigestive tract mucosa, which is less protected against enzymes than
esophageal mucosa [23].
From an evidence-based point of view, there is a limited number of studies in which
authors used MII-pH monitoring in the pediatric population, while there is no study of
HEMII-pH. All of the above-mentioned pathophysiological mechanisms were experienced
in animal models or adults. The use of HEMII-pH may undoubtedly improve the un-
derstanding of physiological mechanisms and the differences between GERD and LPR.
Precisely, infants and children with laryngopharyngeal reflux may have pharyngeal reflux
events but no GERD findings at the gastrointestinal endoscopy or GERD symptoms [7].
HEMII-pH may specify the features of pharyngeal reflux events in terms of composi-
tion (gaseous, liquid, both), pH (acid, weakly acid, alkaline) and the time of occurrence
(upright/daytime, supine/nighttime).
Children 2023, 10, 583 4 of 15

4.3. Associated Conditions

The inflammatory reaction related to the deposit of gastroduodenal enzymes into
the laryngopharyngeal, nasopharyngeal or nasal mucosa may favor the development of
some ear, nose and throat diseases. Thus, P-LPR was objectively identified in the following
conditions: apnea and cardiorespiratory events [15,31–36], laryngomalacia [21,37–39],
subglottic stenosis [21,40], and chronic otitis media with effusion [41–55] (Table 1). Precisely,
infants with apnea reported a high prevalence of acid and nonacid proximal esophageal
reflux events at the MII-pH with or without temporal association between reflux and
cardiorespiratory events (Table 1). Regarding laryngomalacia, reflux was identified in
infants and children through oropharyngeal pH study, dual-probe pH monitoring or pepsin
analyses [21,37–39]. Note that there were no controlled studies comparing the prevalence
of P-LPR in apnea, laryngolomalacia and subglottic stenosis patients vs. healthy controls
(Table 1). The most exhaustive and evidence-based literature concerned the association
between reflux and chronic otitis media with suppuration (Table 1). Pepsin or bile salts were
found in 14% to 100% of ear secretions (Table 1). According to controlled studies, infants or
children with chronic otitis media with suppurations reported higher pepsin concentrations
in middle ear secretions and acid pharyngeal reflux events at the dual-probe pH study
than controls [50,54]. Other studies supported a potential association between reflux and
chronic rhinosinusitis [56–58], choanal atresia [59], asthma and chronic aspirations [60–63],
but the lack of controlled study with (HE)MII-pH limits the draw of reliable conclusions.
Children 2023, 10, 583 5 of 15

Table 1. Laryngopharyngeal reflux detection in ear, nose and throat conditions.

Condition Population Reflux identification References

Apnea was associated with high rate of acid and nonacid
Apnea Infants MII-pH monitoring Pavic, 2021 [15]
reflux events.
Infants Reflux is associated with cardiorespiratory events in 11% of cases. MII-pH monitoring Nobile, 2019 [31]
There is a temporal association between nonacid reflux events and
Infants MII-pH monitoring Cresi, 2017 [33]
apnea events.
Preterm infants The frequency of apnea is increased after nonacid reflux events. MII-pH monitoring Corvaglia, 2011 [28]
Preterm infants Reflux is associated with a high risk of apnea MII-pH monitoring Nunez, 2011 [32]
GERD is not associated with cardiorespiratory event prolongation
Preterm infants MII-pH monitoring Di Fiore, 2010 [35]
or severity.
Reflux events are prevalent in infants with apnea without reporting
Infants MII-pH monitoring Peter, 2002 [36]
a temporal relationship.
Laryngomalacia Children Pharyngeal reflux events were prevalent in children with laryngomalacia. Oropharyngeal pH testing Messalam, 2016 [21]
Pepsin saliva was more frequently detected in laryngomalacia infants
Infants Pepsin saliva measurement Klimara, 2020 [38]
than controls.
Pepsin was detected in lavage laryngomalacia of 80% of infants and
Infants Pepsin lavage laryngo-malacie measurement Luebke, 2017 [39]
was absent in controls.
Reflux was the primary cause of airway compromise or a cofactor
Infants Dual-probe pH testing Mattheuws, 1999 [37]
exacerbating preexisting neurologic/anatomic abnormality.
Pharyngeal reflux events were prevalent in children with
Subglottic stenosis Children Oropharyngeal pH testing Messalam, 2016 [21]
subglottic stenosis.
Infants and children Reflux events were prevalent in patients with subglottic stenosis. MII-pH monitoring Hart, 2014 [40]
Otitis media Infants and children Pepsin was detected in otitis secretions of 77% of infants or children. Pepsin otitis media secretion measurements Samuels, 2022 [41]
67.9% of children with middle ear effusion had weakly acid proximal
Infants and children MII-pH monitoring Gorecka, 2016 [42]
esophageal reflux events.
Patients with chronic otitis media reported higher prevalence of acid
Infants and children Dual-probe pH testing Martines, 2015 [43]
pharyngeal events in the pH study.
Children Pepsin was found in 32% of middle ear otitis secretions. Pepsin in ear secretions Formanek, 2015 [44]
Children Pepsin was found in 70% of children with chronic otitis media effusion. Pepsin in ear secretions Luo, 2014 [45]
Infants and children Pepsin was found in 50% of children with chronic otitis media effusion. Pepsin in ear secretions O’Reilly, 2014 [46]
All children with chronic otitis media with effusion had positive acid
Children Dual-probe pH-testing Abdel-Aziz, 2013 [47]
LPR at the pH study.
Children 2023, 10, 583 6 of 15

Table 1. Cont.

Condition Population Reflux identification References

Nasopharyngeal acid reflux was detected in 20% of patients
Children Dual-probe pH-testing Aydin, 2011 [48]
with chronic otitis media.
Bile salts were found in 42% of middle ear secretions of patients
Infants and children Bile salts Klokkenburg, 2009 [49]
with chronic otitis media.
Patients with chronic otitis media and controls had 14% and 7%
Infants and children Pepsin in ear secretions He, 2007 [50] *
positive pepsin in ear secretions.
Pepsin was found in 58% of children with chronic otitis media
Infants Pepsin in ear secretions Crapko, 2007 [51]
with effusion.
Infants and children Pepsin was found in 100% of ear secretion samples. Dual-probe pH-testing Pepsin in ear secretions Abd El-Fattah, 2007 [52]
Pepsin was detected in 73% to 77% of ear secretions of patients
Infants Pepsin in ear secretions Lieu, 2005 [53]
with chronic otitis media.
Acid pharyngeal reflux events were found in 48% vs. 8% of
Children Dual-probe pH testing Keles, 2004 [54] *
patients with chronic otitis media and controls, respectively.
27% of patients with chronic otitis media with effusion had
Children Dual-probe pH testing Rozmanic, 2002 [55]
proximal esophageal reflux events.
* controlled studies. Abbreviations: GERD = gastroesophageal reflux disease; MII-pH = multichannel intraluminal impedance pH monitoring; LPR = laryngopharyngeal reflux.
Children 2023, 10, 583 7 of 15

5. Clinical Presentation
Infants and children with P-LPR may present a myriad of non-specific symptoms and
findings. The potential associations between P-LPR and the above-mentioned ear, nose and
throat conditions make the clinical presentation even more non-specific. Surprisingly, few
studies investigated the prevalence of symptoms and signs associated with P-LPR with
validated clinical instruments. Clinical studies with the largest number of P-LPR cases are
summarized in Table 2 [61,64–68]. The most prevalent symptoms associated with P-LPR
include breathing disorders, chronic cough, hoarseness, and postnasal drip. GERD-related
symptoms include less prevalent overgrowth, especially in children [61,64–68]. The GERD
symptoms are more prevalent in infants. Infants present more frequently a clinical picture
characterized by GERD and LPR symptoms, while children report a clinical presentation
closest from adults, with LPR symptoms and few GERD symptoms.

Table 2. Symptoms of Pediatric Laryngopharyngeal Reflux.

References Patients (N) Diagnosis Symptoms (%)

Kosec, 2020 [61] 89 infants/children MII-pH Epigastric pain 17%
F/M: 56/33 Nausea 16%
Age (md): 12 yo Regurgitations 11%
Tasting acid in mouth 3%
Dy, 2016 [64] 50 infants/children MII-pH Chronic cough 84%
F/M: 16/34 Asthma symptoms 71%
Age (me): 9 yo Croup 48%
Ear infections/symptoms 24%
Sinus infections/symptoms 16%
Baudoin, 2014 [65] 50 infants/children Dual-probe Asthma symptoms 33%
F/M: N.P. pH testing Chronic cough 28%
Age (md): 11 yo Dysphonia 7%
Chest pain 6%
Li, 2014 [66] 62 infants/children Dual-probe Hoarseness 90%
F/M: N.P. pH testing Postnasal drip 77%
Age: N.P. Dysphagia 74%
Abdominal/chest pain 73%
Throat clearing 64%
Chronic cough 56%
Globus 48%
Andrews, 2013 [67] 63 infants/children Oropharyngeal Nasal obstruction 76%
F/M: N.P. pH study Chronic cough 54%
Age: 6 mo-17 yo Postnasal drip 40%
Otalgia 30%
Halitosis 18%
Sore throat 16%
Loss of appetite 14%
Rhinosinusitis symptoms 10%
Stomachache 10%
Greifer, 2012 [68] 63 infants/children MII-pH Asthma/cough 59%
F/M: 24/39 Hoarseness 22%
Age (me): 7 yo Vocal cord nodules 14%
Pharyngitis 5%
Abbreviation: F/M = female/male; md = median; me = mean; MII-pH = multichannel intraluminal impedance
pH monitoring; mo = month; NP = not provided; yo = years old.

Oral, pharyngeal and laryngeal finding prevalence were reported in two studies, in
which P-LPR was confirmed with objective tools [65,69]. From a fiberoptic examination
standpoint, larynx appears to be the most affected organ (Table 3), which may be related to
the pseudostratified epithelium that is less resistant to pepsin aggression than the multilayer
Children 2023, 10, 583 8 of 15

epithelium or pharynx or oral cavity. However, there would be an overestimation of

laryngeal findings and an underestimation of pharyngeal LPR-signs in studies, because
most investigators assessed the P-LPR signs with Reflux Finding Score (RFS), which only
considers laryngeal signs [70,71]. To date, there is no large-cohort study evaluating the
prevalence of oral, laryngeal and pharyngeal signs in P-LPR patients.

Table 3. Signs of Pediatric Laryngopharyngeal Reflux.

References Patients (N) Reflux Diagnostic Signs (%)

Baudoin, 2014 [65] 50 infants/children Dual-probe Vocal fold edema 63%
F/M: N.P. pH testing Oropharyngeal wall or 54%
Age (md): 11 yo posterior larynx granulation
Vocal fold nodules 26%
Oropharyngeal wall
14%
granulations
Posterior laryngitis 10%
Vocal nodules 1%
Galli, 2020 [69] 35 infants/children MII-pH Arytenoid erythema 100%
F/M: 11/24 Vocal mucosa edema 76%
Age: 2 mo-16 yo Pharyngeal wall granulations 51%
Laryngeal edema 50%
Posterior commissure edema 34%
Tracheal hyperemia 30%
Subglottic edema 5%
Abbreviation: F/M = female/male; MII-pH = multichannel intraluminal impedance-pH monitoring; mo = month;
NP = not provided; yo = years old.

In sum, a few studies investigated the clinical picture of P-LPR in infants and children
with patient-reported outcome questionnaires considering otolaryngological, digestive
and respiratory symptoms. The consideration of respiratory and digestive symptoms is
particularly relevant in infants who have both GERD and LPR. Similar observations may be
found for clinical instruments that do not include oral, pharyngeal and laryngeal signs. The
development of such tools in the pediatric population is a future important step to establish
the prevalence of symptoms and signs in infants and children with a documented LPR at
the HEMII-pH [72,73]. The clinical tools should be adapted to patient age, considering the
parent observations for infants and the higher prevalence of GERD-related symptoms in
infants than children.

6. Diagnostic
The past consideration of P-LPR as an extra-esophageal manifestation of GERD led
some authors to use gastrointestinal (GI) endoscopy, barium contrast radiography, scintig-
raphy or single-probe pH monitoring for the P-LPR diagnostic. However, none of these
methods may detect weakly acid or alkaline pharyngeal reflux episodes or the deposit of
gastroduodenal content into the upper aerodigestive tract mucosa.

6.1. Multichannel Intraluminal Impedance pH Monitoring

Multichannel intraluminal impedance pH monitoring was introduced to capture
weakly acidic or alkaline reflux episodes in the proximal esophagus. To date, the MII-pH
profile of P-LPR infants and children was poorly investigated. Dy et al. reported that
infants and children with suspected P-LPR had a similar number of proximal esophageal
acid (pH < 4.0) and weakly/non-acid reflux events [64]. Mantegazza et al. observed that
infants reported more weakly acid proximal esophageal reflux events than children [74].
The time (post-meals), the nature (gaseous, liquid, or mixed) and the position (upright,
supine) features of occurrence of reflux events at the MII-pH have not been investigated in
P-LPR. This information is, however, important for improving the therapeutic management
of infants and children with P-LPR. In adults, LPR is mainly weakly acid (pH = 4.0 to 7.0)
Children 2023, 10, 583 9 of 15

or alkaline (pH > 7.0), with an increase in the pH of the event from the low to the upper
esophagus [25]. Most events are gaseous and occur daytime and upright, which may
explain the lack of heartburn or regurgitations in most patients [25,75,76]. Consequently,
the deposit of pepsin and other gastroduodenal enzymes into the upper aerodigestive tract
mucosa occurs after the meals through the transient relaxations of LES and UES [25,77].
The knowledge of the LPR profile at the HEMII-pH may contribute to the development of
more personalized therapeutic approaches [78,79], which may include diet and lifestyle
modifications, PPIs (acid LPR or GERD), alginate or magaldrate (weakly acid/alkaline
reflux events).
In sum, the profile and the features of P-LPR at the HEMII-pH are still unknown in
both infants and children because the authors used MII-pH, and not HEMII-pH. MII-pH is
currently the most used approach for the objective diagnostic of P-LPR, but physicians have
to take into consideration that only some proximal reflux events reach the pharynx. Indeed,
Ulualp et al. reported in a cohort of children with acid P-LPR that 6/9 proximal esophageal
reflux episodes reached pharynx [80]. From an evidence-based approach, the consideration
of proximal esophageal reflux events for the P-LPR diagnostic may be insufficient due to
the lack of objectification of pharyngeal event and the potential lack of related deposit of
gastroduodenal enzymes.

6.2. Pepsin Saliva Measurement

The development of less invasive objective methods for the LPR diagnosis makes
particularly sense in infants and children who do not frequently tolerate the 24 h pH-
testing probe [21,81]. Nowadays, the usefulness and the accuracy of pepsin saliva detection
(PepTest® , RDBiomed, Hull, UK) have been poorly investigated in infants and children
with P-LPR. Haddad et al. observed that pepsin was detected in 48% of infants and children
with a positive GERD diagnosis at the MII-pH. The pepsin A was 43% sensitive and 50%
specific in predicting an abnormal impedance result. Among pepsin A positive samples,
72% of samples corresponded to a gastroesophageal reflux episode. The authors reported
that pepsin peak levels were significantly correlated with acid GERD [82]. The usefulness
of pepsin measurement in pediatric patients was supported by Klimara et al. in a controlled
study where authors compared pepsin saliva measurements between pediatric patients
with laryngomalacia and healthy controls [38]. These authors detected pepsin in the saliva
of 81% of infants with laryngomalacia and suspected P-LPR, while controls reported a
positive pepsin rate in 12% [38]. The accuracy of pepsin saliva detection was investigated
in infants and children with GERD undergoing 24 h MII-pH [83]. The authors collected
several saliva samples (before catheter placement, before and 30 min after each of three
meals, and upon awakening), and they reported that 85.6% of GERD patients have at
least one positive saliva pepsin test compared with 9.3% of controls [83]. Interestingly,
they observed a significant positive correlation between the frequency of pepsin-positive
samples and the reflux symptom index [83].
To date, the pepsin saliva measurement is not ready for clinical application for many
reasons [84]. First, the pepsin saliva concentration may significantly vary throughout the
testing day [85–87]. This variation may be attributed to both physiologic and pathologic
modifications of esophageal motility and sphincter tonicity, which may be related to
lifestyle, meal composition and autonomic nerve dysfunction (anxiety/stress) [85–88].
Second, the best time of saliva collection, which may be defined as the saliva collection
associated with the highest accuracy, sensitivity and positive predictive value pepsin test,
remains unknown. The fasting collection of saliva appears to be adequate, but studies were
only conducted on LPR adults [85–89]. Third, as recently suggested, the mucosa injury may
be related to other gastroduodenal enzymes, such as bile acids, trypsin or elastase [90,91].
Thus, the only consideration of saliva pepsin detection as a diagnostic approach may bias
the detection of P-LPR.
In sum, the detection of gastroduodenal enzymes into the infant or child saliva is
an interesting noninvasive approach that should provide the profile of P-LPR in terms of
Children 2023, 10, 583 10 of 15

involved enzymes in the inflammatory process underlying LPR symptoms and findings.
The determination of the enzyme profile and the knowledge of their pH activity may
theoretically indicate the use of PPIs or alginate in some pediatric patients. In practice,
infants and children with a prominence of saliva enzymes that are active in weakly acid
or alkaline pH (e.g., bile salts, elastase) should benefit from alginate and not PPIs, which
increase the pH of reflux events. Thus, some enzymes, e.g., elastase, trypsin or bile salts,
are activated in alkaline environments and may therefore lead to mucosa injuries and
inflammation from the use of PPIs [91]. Alginate and magaldrate form a raft floating
over gastric contents that can be maintained within the stomach for up to 4 h. Alginate is
endowed with bio-adhesive potential, which is a property due primarily to its polymer
chain length and ionizable groups that provide a protective biofilm on the mucosa of
esophagus and, potentially, upper aerodigestive tract [92].

7. Therapeutic Strategies
Therapeutic strategies for P-LPR include diet and lifestyle changes, medical treatment
or surgery. From a cost-effective standpoint, the first therapeutic step has to be based
on lifestyle and diet changes. Lifestyle and diet modifications may include the reduction
in foods and beverages associated with sphincter tonicity and esophageal motility im-
pairments, the suppression of reflux triggers, and the management of autonomic nerve
dysfunction, which is commonly associated with anxiety or stress management [93,94].
Among diet modifications, the utility of GERD recommendations, such as thickening feeds
or avoiding cow’s milk protein, remains undemonstrated in P-LPR regarding the lack of
studies including infants or children with a positive diagnostic at the HEMII-pH. Similar
observations may be made regarding the influence of type of milk on the occurrence of pha-
ryngeal reflux events, because previous studies included GERD patients [95–97]. Smaller
and frequent meals as well as sleep positioning (elevating the head of the bed) may provide
benefit to infants with GERD and ‘reflux extension’ into the upper aerodigestive tract [6,98],
but the utility of these approaches is still not demonstrated in children with only P-LPR [4].
If lifestyle and diet modifications are insufficient in resolving P-LPR symptoms, a
medical approach might be considered. The medical treatment of P-LPR was long-standing
based on the use of histamine (H2) blockers or PPIs. PPIs and histamine (H2) blockers bind
irreversibly to active proton pumps and increase the pH of gastroesophageal and esophago-
pharyngeal reflux events without influencing the number and duration of events [4,99]. In
adults, the superiority of PPIs over placebo is not demonstrated [100]. The success rate
of PPI therapy is significantly lower that of PPI therapy in GERD patients [101]. To date,
there is no randomized controlled trial comparing the effectiveness of PPIs over placebo in
pediatric population. In recent prospective studies, Li et al. reported a success rate of PPIs
in 53% of P-LPR patients [66], while Jadcherla et al. reported 33% of symptom improvement
in young infants [102]. The poor efficacy of PPIs in the P-LPR treatment and the lack of
confidence by practitioners were supported in the recent survey of the American Society of
Pediatric Otolaryngology. Thus, the authors reported that 37% of otolaryngologists would
not prescribe oral PPIs in neonates, with 50% not prescribing IV PPIs. PPIs were prescribed
by only 10% and 60% of otolaryngologists as first or second/third-line treatment for infants
aged from 10 weeks to 1 year, respectively [103].
Despite the lack of study using HEMII-pH, weakly acid or alkaline reflux events in
the proximal esophagus will be weakly acid or alkaline in the pharynx. Thus, from an
evidence-based standpoint, the high prevalence of weakly acid or alkaline reflux events
at the MII-pH may make the consideration of PPIs or histamine (H2) blockers as first-
line single medication in infants or children with P-LPR outdated. In infants with both
GERD and P-LPR, acid-suppressive therapy should be used most likely in the context
of symptoms that suggest erosive esophagitis [96]. Future controlled studies comparing
diet/lifestyle modifications vs. PPIs vs. alginate vs. PPIs and alginate as empirical
therapeutic approaches are needed to determine the place of medication in the management
of infants and children. From a personalized medicine point of view, future treatments of
Children 2023, 10, 583 11 of 15

infants or children should consider the type of P-LPR and their characteristics at the HEMII-
pH (types and composition of LPR, time of occurrence, etc.). Regarding fundoplicature,
there is no evidence about a potential benefit on P-LPR.

8. Conclusions
Many gray areas persist in P-LPR. The lack of international guidelines for the diagnos-
tic of P-LPR, the unavailability of HEMII-pH and the poor acid-suppressive therapeutic
response are all issues requiring future investigations. Future controlled studies using
HEMII-pH and enzyme measurements in ear, nose or throat fluids may clarify the epidemi-
ology of P-LPR according to age and its association with many otolaryngological conditions.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not available.
Conflicts of Interest: The authors declare no conflict of interest.

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