430809
ra et alOtolaryngology—Head and Neck Surgery
2011© The Author(s) 2010
Reprints and permission:
OTOXXX10.1177/0194599811430809Miu
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Systematic Review
Association between Otitis Media and
Gastroesophageal Reflux:  A Systematic Review
Mauricio Schreiner Miura, MD, PhD1, Miguel Mascaro, MD2,
and Richard M. Rosenfeld, MD, MPH2
No sponsorships or competing interests have been disclosed for this article.
Abstract
Objective. To systematically review the association between
otitis media and gastroesophageal/laryngopharyngeal reflux
in children.
Data Sources. Cochrane library, MEDLINE (1966–September
2011), EMBASE (1974–September 2011), proceedings of Inter-
national Symposia on Recent Advances in Otitis Media, and
reference lists of relevant selected articles.
Review Methods. Studies with planned data collection, in chil-
dren with chronic otitis media with effusion/recurrent acute
otitis media, assessing gastroesophageal/laryngopharyngeal
reflux, pepsin/pepsinogen in middle ear, or antireflux therapy,
were included.
Results. Of 242 initial studies, 15 met inclusion criteria. The
authors found a mean prevalence of gastroesophageal reflux
disease in children with chronic otitis media with effusion of
48.4% (range, 17.6%-64%) and in children with recurrent acute
otitis media of 62.9% (range, 61.5%-64.3%).A mean prevalence
of laryngopharyngeal reflux of 48.6% (range, 27.3%-70.6%)
was found in children with otitis media. Mean pepsin/pepsino-
gen presence in otitis media was 85.3% (range, 60%-100%)
and of enzymatic activity was 34.2% (range, 14.5%-73%). Two
randomized trials could not find benefit after antireflux treat-
ment for 3 months, with an absolute rate difference (95%
confidence interval) of 0.23 (0.023-0.42) and 0.13 (–0.086 to
0.34), respectively. Reporting of adverse events was limited, or
absent, in most studies.
Conclusion. The prevalence of gastroesophageal reflux disease
in children with chronic otitis media with effusion/recurrent
acute otitis media may be higher than the overall prevalence
for children. Presence of pepsin/pepsinogen in the middle ear
could be related to physiologic reflux. A cause-effect relation-
ship between pepsin/pepsinogen in the middle ear and otitis
media is unclear. Antireflux therapy for otitis media cannot be
endorsed based on existing research.
Otolaryngology–
Head and Neck Surgery
146(3) 345­–352
© American Academy of
Otolaryngology—Head and Neck
Surgery Foundation 2012
Reprints and permission:
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DOI: 10.1177/0194599811430809
http://otojournal.org
Keywords
otitis media, otitis media with effusion, chronic otitis media
with effusion, recurrent acute otitis media, gastroesophageal
reflux, laryngopharyngeal reflux, reflux, pepsin, pepsinogen
Received September 13, 2011; revised October 25, 2011; accepted
November 2, 2011.
D
uring the first years of life, otitis media (OM) is fre-
quently diagnosed. It is estimated that up to 84% of
children have experienced at least 1 episode of acute
otitis media (AOM) by age 3.1 Approximately 90% of chil-
dren will have 1 episode of otitis media with effusion (OME),
experiencing hearing loss, by 4 years of age.2 Gastroesopha-
geal reflux (GER) is the passage of gastric contents into the
esophagus.3 Diagnosis of gastroesophageal reflux disease
(GERD) is established when the reflux of gastric contents
causes troublesome symptoms and/or complications.4 During
infancy and early childhood, it most often manifests as recur-
rent vomiting, occurring in 50% of infants up to 3 months of
life, in 67% of 4-month-olds, and in 5% of children between
10 and 12 months of age.3
A growing issue is the association of GER and airway dis-
eases affecting the tracheobronchial tree, larynx, pharynx,
paranasal sinus, and middle ear. The so-called laryngopharyn-
geal reflux (LPR) has been linked to OM.5 The Eustachian
tube (ET) is not fully developed in children, and compared
with adults, it is shorter and more horizontal. This anatomical
1
Universidade Federal de Ciencias da Saude de Porto Alegre, Brazil
2
State University of New York Downstate Medical Center, Brooklyn, New
York, USA
Corresponding Author:
Mauricio Schreiner Miura, MD, PhD, Coordenacao de Aperfeicoamento de
Pessoal de Nivel Superior (CAPES), Division of Pediatric Otolaryngology
at Hospital da Criança Santo Antonio, Department of Medical Surgery of
Universidade Federal de Ciencias da Saude de Porto Alegre, Rua Dona
Laura, 320-9th floor, S/N Porto Alegre, Brazil 90430-090
Email: mmiura.voy@terra.com.br
346 Otolaryngology–Head and Neck Surgery 146(3)
variation is implicated in the migration of infectious agents
through it and would be responsible for reflux mechanisms.6
Avoidance of placing children supine while bottle-feeding is
frequently recommended in pediatric practice. Doing so
would theoretically decrease the reflux content in the middle
ear; however, the benefit of this intervention to decrease the
incidence of AOM is unclear.7 Pathophysiologic models of
OME state that an inflammatory process in the middle ear
stimulates effusion production. Thus, it has been thought that
the presence of GER contents in the middle ear could trigger
an inflammatory reaction.8
In the past decade, a number of studies were conducted to
evaluate the mechanism of reflux to middle ear and establish a
causal relation between them. Studies evaluating GERD and
LPR through esophageal and dual-probe pH monitoring were
conducted in children with OM.9-13 Experimental studies were
published to prove the mechanism of reflux to middle ear and
consequences of repeated exposure of its mucosa to pepsin
and hydrochloric acid.8 Other studies developed methods for
pepsin detection in middle ear effusion of children undergoing
tympanostomy tube placement due to OME or recurrent AOM
and searched for a correlation with GERD.12,14-20 Even thera-
peutic tests with antireflux medications were attempted to
evaluate a decrease in OM episodes in children.13,21,22
The objective of this review is to assess quality, quantity, and
consistency of published research evaluating the prevalence of
GERD/LPR, pepsin, and pepsinogen in children with chronic
OME, recurrent AOM, or both. We also sought to summarize evi-
dence regarding the efficacy of antireflux treatment for OM.
Methods
Protocol and registration. To report this study, we followed
the statements of Preferred Reporting Items for Systematic
reviews and Meta-Analyses (PRISMA). A detailed research
protocol was designed a priori with the purpose of defining
the study scope, objectives, hypothesis, and methodology,
comprising also a data collection form and quality assessment
score. The protocol was neither registered nor published.
Eligibility criteria. To ensure that source articles were similar
and relevant, we established unambiguous inclusion and
exclusion criteria. The patient population was defined with
children of either sex followed in pediatric or otolaryngology
practice due to chronic OME or recurrent AOM. We searched
for studies in which GER or LPR were evaluated through
esophageal or dual-probe pH monitoring, measurement of
pepsin/pepsinogen in the middle ear, or a therapeutic test.
Inclusion criteria:
•• Planned data collection
•• Patients with chronic OME or recurrent AOM
•• Evaluation/treatment of GERD or LPR
Exclusion criteria:
•• Adults
•• Duplicate patients
•• Nonhuman studies
Information sources and search. The information sources
sought were the database of Cochrane library, MEDLINE
(from 1966–September 2011), EMBASE (from 1974–Sep-
tember 2011), and proceedings of the International Symposia
on Recent Advances in Otitis Media. The last search was per-
formed in September 2011. The electronic search strategy was
conducted in the database above and did not include limits. It
is fully described in the appendix (available at otojournal.org).
Study selection. Identification of studies was conducted by
one reviewer (M.S.M.). After removal of duplicates, 2 inde-
pendent reviewers (M.S.M. and M.M.) screened records by
title and abstract, applying the established inclusion/exclusion
criteria. Eligible articles were assessed in full text by the 2
independent reviewers. Studies matching eligibility criteria
were included in the systematic review.
Data collection process. Data were extracted from studies
independently by 2 reviewers through a quality assessment
score and a data collection form. Quality assessment score,
ranging from 0 to 4, evaluated the following items: consecu-
tive samples (1 = yes; 0 = no or nonstated), inclusion/exclu-
sion criteria (1 = stated; 0 = unclear or nonstated), method of
reflux evaluation (1 = validated; 0 = nonvalidated), and diag-
nosis of OM (1 = tympanogram, microscopy, or pneumatic
otoscopy; 0 = physical examination or nonstated). The data
collection form consisted of predetermined variables with
checks for interobserver agreement regarding study character-
istics, population, interventions, comparisons, and outcomes.
Data items. The following data items were sought:
•• Study characteristics: location, study design, level of
evidence, inclusion criteria, exclusion criteria
•• Population: age range, mean age, gender, number
at start, number of withdraws, number at end, num-
ber of chronic OME, number of recurrent AOM,
definition of chronic OME, definition of recurrent
AOM, indication of tympanostomy tubes, patients
with effusion, patients with “dry ears,” evaluation of
environmental risk factors (attendance at day care,
tobacco exposure, lack of breast-feeding, others)
•• Intervention: method of reflux evaluation, reflux
index, questionnaire name, pepsin/pepsinogen
(marker) analysis method, antireflux treatment, anti-
reflux treatment adverse events
•• Comparison: presence of control group
•• Outcomes: children with chromic OME and recur-
rent OM diagnosed for GERD and LPR, children
with chromic OME and recurrent OM positive for
pepsin/pepsinogen in middle ear effusion, marker
range and mean concentration, posttreatment tympa-
nogram results
Risk of bias in individual studies. Risk of selection and infor-
mation bias was evaluated at the study level considering the
sample selection (consecutive or not), eligibility criteria (clear
or unclear), and methods of diagnosis (accurate or not), ana-
lyzing data registered in collection form. Chart review data
collection studies were excluded. Potential confounding risk
Miura et al 347

Records idenfied through Addional records

MEDLINE, EMBASE and idenfied through manual
Identification Cochrane Database reference search
searching (n = 1)
(n = 242)

Records a­er duplicates

Screening removed
(n = 197)

Records screened Records excluded

(n = 197) (n = 173)

Full-text arcles assessed Full-text arcles excluded

Eligibility for eligibility (n = 9)
(n = 24) Reasons:
- Type of OM non-stated (3)
-Duplicate (1)
-Different outcome (3)
- Arcle in Polish (2)
Studies included in
Included qualitave synthesis
(n = 15)

Figure 1. Flowchart of article selection.

factors, such as attendance at day care, tobacco exposure,
breast-feeding, and allergy, were searched in all studies. Treat-
ment studies were also assessed at the outcome level for ran-
domization, blinding, and withdrawals.
Summary measures. Measures were summarized in preva-
lence of GERD in OM, prevalence of LPR in OM, prevalence
of pepsin/pepsinogen in OM, and rate of posttreatment type A
tympanogram.
Synthesis of results. Data recorded from outcomes were syn-
thesized into 3 tables, according to the studies’ scopes. One
table was designed to describe the prevalence of GERD and
LPR in OM, chronic OME, and recurrent OM. Another table
was related to the prevalence of pepsin/pepsinogen in chronic
OME and recurrent OM, marker range, and mean concentra-
tion. Studies in which antireflux treatment was tested were
organized in a table with posttreatment tympanogram results.
Due to heterogeneity in methodology across studies, no
attempt was made to perform a meta-analysis.
Results
Study selection (Figure 1). Through MEDLINE, EMBASE,
and the Cochrane database, we identified 242 records. One addi-
tional record was identified by manual reference search. After
removal of duplicates, we screened 197 records, and 173 were
excluded since the subject was obviously different. For eligibil-
ity, we assessed 24 full-text articles for inclusion/exclusion crite-
ria. Nine articles were excluded for the following reasons: type of
OM nonstated (3), duplicate (1), different outcome (3), and arti-
cles in Polish (2). Fifteen studies were included in the qualitative
synthesis, in which children with chronic OME or recurrent
AOM were evaluated for GER or LPR through esophageal or
dual-probe pH monitoring, measurement of pepsin/pepsinogen
in the middle ear, or a therapeutic test.
Study characteristics. The design of selected studies was as
follows: 9 cross-sectional, 2 case-control, 2 prospective cohort,
and 2 randomized, nonblind trials (Table 1). In all studies,
data collection was planned, and children were followed in
pediatric or otolaryngology practice for at least 3 months. A
total of 1513 patients (53% male) were evaluated in the studies.
The mean of ages across the studies ranged from 1.1 to 7.05
years. Quality assessment score varied; 1 study scored 1, 5 stud-
ies scored 2, 8 studies scored 3, and 2 studies scored 4 (Table 1).
Six studies described consecutive samples.13,16,19,20,21,23 Eligibil-
ity criteria were clear in 9 studies.10,11,12,15,16,19,21-23 In 7 studies, a
control group was assigned for comparison.11-13,18,19,21,23
Chronic OME was evaluated in all studies, except the Kotsis
et al study,23 which evaluated recurrent AOM alone. In 5 stud-
ies, the reflux evaluation was performed in both chronic OME
and recurrent AOM patients.9,10,15,18,22 Reflux was assessed by
pepsin/pepsinogen measurement in middle ear effusion in 8
studies, by 24-hour pH monitoring in 6 studies, by validated
questionnaire in 3 studies, by therapeutic trial in 3 studies, and
by fiber-optic laryngoscopy in 2 studies (Table 1). We could
estimate the prevalence of GERD in OM in 5 studies, the
prevalence of LPR in OM in 3 studies (Table 2), and the prev-
alence of pepsin/pepsinogen in OM in 8 studies (Table 3);
posttreatment tympanogram results were evaluated in 3 stud-
ies (Table 4).
348

Table 1. Characteristic of Studies Included in the Systematic Review

Quality
Sample Mean Age Assessment Otitis Media
Author,Year Country Size (Range), y Study Design Scorea Selection Criteria Subtype Reflux Assessment
19
Al-Saab et al, 2008 Canada 54 4.7 (1-12) Cross-sectional 4 Effusion at tube insertion with COME Pepsinogen (ELISA)
adenoidectomy
Ardehali et al, 200821 Iran 90 5.3 (2-12) Randomized trial 3 OM diagnosed in ENT office COME Therapeutic test
Crapko et al, 200716 United States 20 2.48 (0.5-6) Cross-sectional 4 Effusion at tube insertion COME Pepsin (Western blot)
Abd El-Fattah Egypt 31 6.37 (1.25-10) Cross-sectional 3 Effusion at tube insertion COME Pepsin (ELISA), validated questionnaire,
et al, 200712 and 24-h dual-probe pH monitoringc
He et al, 200717 United States 152 2.8 (0.5-10) Cross-sectional 2 Effusion or dry earb COME Pepsin (enzyme assay)
at tube insertion
Keleş et al, 200411 Turkey 37 6.8 (3-12) Case-control 3 OM diagnosed in ENT office COME 24-h dual-probe pH monitoring
Kotsis et al, 200923 Greece 187 1.5 (0.1-2.75) Prospective cohort 3 OM diagnosed in patients with ROM 24-h dual-probe pH monitoring
GERD
Lieu et al, 200515 United States 31 1.7 (1-6.5) Cross-sectional 3 Effusion or dry earc at tube COME and Pepsin (enzyme assay and ELISA) and
insertion ROM validated questionnaire
McCoul et al, 201122 United States 47 1.6 (0.5-7) Prospective cohort 3 OM and GERD diagnosed in ENT COME and Fiber-optic laryngoscopy and validated
office ROM questionnaire
O’Reilly et al, 200818 United States 573 2.7 (0.25-17) Case-control 2 Effusion or “dry ear”c at tube COME and Pepsin (enzyme assay and Western blot)
and Canada insertion ROM
Rozmanic et al, Croatia 27 6.8 (2-13) Cross-sectional 2 OM diagnosed in ENT office COME and 24-h esophageal pH monitoring
200210 ROM (subgroup with dual probe)
Serra et al, 200713 Italy 127 1.1 (0-2) Randomized trial 3 Effusion diagnosed after failed hearing COME Fiber-optic laryngoscopy and 24-h
screening esophageal pH monitoring
Tasker et al, 200214 United Kingdom 65 NA (2-8) Cross-sectional 2 Effusion at tube insertion COME Pepsin (enzyme assay and ELISA)
and United
States
Toros et al, 201020 Turkey 42 7.05 (3-12) Cross-sectional 3 Effusion at tube insertion COME Pepsinogen (ELISA)
Velepic et al, 20009 Croatia 30 7 (2-13) Cross-sectional 1 OM diagnosed in ENT office COME and 24-hour esophageal pH monitoring
ROM
Abbreviations: COME, chronic otitis media with effusion; ELISA, enzyme-linked immunosorbent assay; ENT, ear, nose, and throat; GERD, gastroesophageal reflux disease; OM, otitis media; ROM, recurrent acute otitis
media.
a
Quality assessment score: 0 to 4, with a higher score indicating higher quality; see the Methods section for details.
b
Children evaluated for reflux with pH monitoring after tube insertion with adenoidectomy or adenotonsillectomy.
c
In ears with no appreciable effusion, sterile saline was injected to bathe middle ear mucosa and collected as a sample.
Miura et al 349

Table 2. Relationship between OM and GERD/LPR Evaluated through 24-Hour pH Monitoring, Reflux Index

Prevalence of GERD Prevalence of LPR

in Patients with in Patients with

Author, year OM (%) COME (%) ROM (%) OM (%)

Abd El-Fattah et al, 200712 3/17 (17.6) 3/17 (17.6) — 12/17 (70.6)
Keleş et al, 200411 16/25 (64) 16/25 (64) — 12/25 (48)
Rozmanic et al, 200210 15/27 (55.5) 7/14 (50) 8/13 (61.5) 3/11 (27.3)
Serra et al, 200713 69/127 (54.3) 69/127 (54.3) — —
Velepic et al, 20009 18/30 (60) 9/16 (56.2) 9/14 (64.3) —

Abbreviations: COME, chronic otits media with effusion; GERD, gastroesophageal reflux disease; LPR, laryngopharyngeal reflux; OM, otitis media; ROM, recur-
rent acute otitis media.

Table 3. Prevalence of Reflux Markers in Middle Ear Effusion

Author, year Reflux Marker Marker Presence (%) Marker Activity (%) Range Mean
Al-Saab et al, 200819 Pepsinogen 21/25 (84) — 0.16-1.07 µg/mL 0.364 µg/mL
Crapko et al, 200716 Pepsin 12/20 (60) — 0.08-1 µg/mL NA
Abd El-Fattah et al, 200712 Pepsin 17/17 (100) — 0.085-5.02 µg/mL 1.91 µg/mL
He et al, 200717 Pepsin — 22/152 (14.5) 0.0125-0.687 µg/mK 0.0966 µg/mL
Lieu et al, 200515 Pepsin 17/22 (77.2) 16/22 (73) 2.68-196 µg/mL NA
O’Reilly et al, 200818 Pepsin — 103/509 (20.2) 0.0125-2.3 µg/mL 0.2 µg/mL
Tasker et al, 200214 Pepsin 59/65 (90.7) 19/65 (29) 0.8-213.9 µg/mL 43.9 µg/mL
Toros et al, 201020 Pepsinogen 42/42 (100) — NA 0.267 µg/mL
Abbreviation: NA, not available.

In 5 studies, children with chronic OME or recurrent AOM
were diagnosed in the otolaryngology office, and reflux was
assessed through 24-hour pH monitoring (Table 2). Otitis
media evaluation consisted of tympanogram and otoscopic12,13
or otomicroscopic examination11; the method was not
described in 2 studies.9,10 Reflux was measured with 24-hour
dual-probe pH monitoring in 3 studies10-12 and 24-hour esoph-
ageal pH monitoring in 2 studies.9,13 The prevalence of GERD
in children with chronic OME ranged from 17.6% to 64%
(mean, 48.4%).11,12 The prevalence of GERD in recurrent
AOM ranged from 61.5% to 64.3% (mean, 62.9%).9,10 The
prevalence of LPR ranged from 27.3% to 70.6% (mean,
48.6%).10,12 A consecutive sample is described in only 1
study.13 Eligibility criteria were clear in only 2 studies.10,11
In one study, GERD was diagnosed with 24-hour dual-
probe pH monitoring, and children were followed during 6 to
8 years, registering AOM episodes. A total of 187 patients
were assigned in 3 different groups according GERD severity
(without, mild-moderate, severe). Logistic regression showed
that the strongest risk factor for recurrent AOM was severe
GERD (odds ratio [OR], 4) and day care centers (OR, 3).23
Potential reflux markers pepsin and pepsinogen were mea-
sured in the effusion of children with OM in 8 studies. Chronic
OME or recurrent AOM were diagnosed in the otolaryngol-
ogy office, and middle ear effusion was collected during tym-
panostomy tube insertion in the operating room. The method
for pepsin/pepsinogen detection was enzyme-linked immuno-
sorbent assay (ELISA) in 3 studies,12,19,23 enzymatic assay and
ELISA in 2 studies,14,15 enzymatic assay in 2 studies,17,18 and
Western blot in 1 study.16 The marker’s prevalence in OM
ranged from 60% to 100% (mean, 85.3%), considering
ELISA/Western blot,12,17,20 and it decreased between 14.5%
and 73% (mean, 34.2%), considering enzymatic assay.
Detection of pepsin was possible in concentrations as low as
0.0125 µg/mL.17,18 The marker’s mean concentration was
widely variable across studies, ranging from 0.09 to 43.9 µg/
mL.14,17 All studies collected samples from children with
chronic OME; in 2 studies, samples were also collected from
recurrent AOM.15,18 However, data regarding the prevalence
of the marker by OM subtype was not available. In 3 studies,
when no appreciable effusion was present during myringot-
omy, sterile saline was injected to bathe the middle ear mucosa
and recollected a sample, called “dry ear.”15,17,18 Distinct data
comparing dry ears versus ears with effusion was not avail-
able from Lieu et al.15 He et al17 found a prevalence of 7%
(8/114) in dry ears and 13.5% (15/111) in ears with effusion.
O’Reilly et al18 found a prevalence of 13% (25/193) in dry
ears and 24% (76/316) in ears with effusion.
In 3 studies, a therapeutic test with antireflux medications in
children with OM was conducted (Table 4).13,21,22 Serra et al13
diagnosed GERD in 69 of 127 children with chronic OME.
GERD patients were randomized to the treatment and notreat-
ment group and followed for 3 months. Treatment consisted of
postural and alimentary changes plus anti-acids and proton-pump
inhibitors. Improvement in tympanogram was shown in 75%
(30/40) in the treatment versus 62% (18/29) in the no-treatment
350 Otolaryngology–Head and Neck Surgery 146(3)
Table 4. Tympanometric Outcomes after Treatment of Gastroesophageal Reflux
Double-
Author, year Follow-up Randomized Blind Withdrawals
Ardehali et al, 200821 3 mo Yes No
McCoul et al, 201122 3 mo No No
Serra et al, 200713 3 mo Yes No
group, a difference that was not statistically significant. The abso-
lute rate difference with 95% confidence interval (CI) is 0.13
(–0.086 to 0.34). No mention of adverse events was found. The
study was not double-blind, and randomization as well as eligi-
bility criteria was unclear. Ardehali et al21 included 90 children
with chronic OME, and GERD was not assessed. Children
were randomized to 3 groups of 30 patients each: cisapride,
amoxicillin-clavulanate, and no medication. Cisapride treat-
ment consisted of postural and alimentary changes plus medica-
tion. Improvement in tympanogram was shown in 33% (10/30)
in the reflux group, 40% (12/30) in the antibiotic group, and 10%
(3/30) in the no-treatment group. The difference between the
reflux treatment group and no-treatment group was significant.
The absolute rate difference (95% CI) was 0.23 (0.023-0.42). No
mention of adverse events was found. The study was not double-
blind, and the randomization method was not described. The
study by McCoul et al22 included 47 children diagnosed with
chronic OME/recurrent AOM and GERD. Thirty-seven patients
were treated for 3 months with lansoprazole with ranitidine or
nizatidine. Tympanometry was repeated in 21 children after 8 to
12 weeks of treatment, who presented type B/C tympanograms in
baseline; 7 returned to type A (33.3%). No mention of adverse
events was found. No control group was assigned. The study was
not blind and not randomized.
Discussion
The increasing interest in the association between OM and
GER led to several publications in this field during the past
decade. The idea of gastric contents insulting the ET or mid-
dle ear mucosa seems attractive to help explain the pathogen-
esis of OM. The studies investigated have 3 categories:
•• Prevalence of GERD or LPR in children with
chronic OME or recurrent AOM evaluated through
pH monitoring
•• Prevalence of pepsin/pepsinogen in the middle ear of
children with chronic OME or recurrent AOM under-
going tympanostomy tube insertion
•• Therapeutic test with antireflux medication in chil-
dren with chronic OME or recurrent AOM
Symptom descriptions of GERD are nonspecific and unre-
liable in infants and young children.4 Thus, esophageal pH
monitoring, a valid and reliable measure of acid exposure,3
was chosen in studies evaluating GERD/LPR in children with
OM. The percentage of the total time that the esophageal pH
Posttreatment Type A Tympanogram in (n)
Treatment Group, Control Group, Absolute Rate
n (%) n (%) Difference (95% CI) 
 0 10/30 (33.3) 3/30 (10) 0.23 (0.023-0.42)
12 7/21 (33.3) — —
 4 30/40 (75) 18/29 (62) 0.13 (–0.086 to 0.34)
is <4 is called the reflux index (RI) and is considered the most
valid measure of reflux. In children, an RI >7% is considered
abnormal, an RI <3% is considered normal, and an RI
between 3% and 7% is indeterminate.4
Prevalence of GERD in OM. Evaluating the prevalence data
in patients with OM in Table 2, it is observed that most results
are similar, except for the study by Abd El-Fattah et al,12 in
which prevalence of GERD is 17.6%, compared with 54.3%
to 64% of other studies. These studies selected children with
chronic OME or recurrent AOM and performed pH monitor-
ing. El Fattah et al12 selected patients with the same character-
istics; however, they were submitted to ventilation tubes as
well as adenoidectomy/tonsillectomy, and after recovery from
surgery, pH monitoring was performed. As the effect of these
procedures on GERD are not well established, it seems that
the most appropriate time for pH monitoring would be before
surgical interventions, in the presence of chronic OME, and
this difference in methodology could explain outlier results.
Two studies stratified data of GERD prevalence by OM
subtype.9,10 It ranged between 50% and 56.2% for chronic
OME and between 61.5% and 64.3% for recurrent AOM.
Based on these results, prevalence of GERD is approximately
10% higher in children with recurrent AOM when compared
with chronic OME. Also, it infers that more than half of chil-
dren with chronic OME or recurrent AOM have GERD, a rate
higher than studies of GERD symptoms, which have found a
prevalence of 5% in children from 10 to 12 months of age3 and
less than 10% in children between 3 and 17 years old.24
However, these results should be interpreted with caution
since GERD prevalence in children with OM could be overes-
timated when searched for research purposes.
Prevalence of LPR in OM. Prevalence data of LPR in OM are
variable and could suggest a lack of criteria for diagnosis
through pH monitoring. Abd El-Fattah et al12 considered every
single reflux episode as LPR, describing a prevalence of
70.6%. Keleş et al11 considered LPR when the RI was greater
than 0.8% of time with a pH <4 and found a prevalence of
48%. Rozmanic et al10 considered LPR when the RI was
greater than 5% of time with a pH <4 and found a prevalence
of 27.3%. It is likely that Abd El-Fattah et al12 detected most
physiologic reflux episodes, while Rozmanic et al10 diagnosed
only patients with more severe LPR.
Prevalence of pepsin/pepsinogen in OM. Since Tasker et al5
described the presence of pepsin/pepsinogen in middle ear
effusions, several authors has been investigating this topic,
and along the years, more sensitive methods for detection
Miura et al 351
were developed, reflected in the marker’s range and mean
(Table 3). Measurement of pepsin/pepsinogen can be per-
formed to analyze the marker’s proteolytic activity, applying
an enzymatic method,14,15,17,18 or to evaluate its presence using
ELISA or Western blot (Table 1). Considering both methods,
the marker’s prevalence ranges from 14.5% to 100% (Table
3). Analyzing only the presence of the marker, the prevalence
rises, ranging between 60% to 100%.
One concern regarding the presence of pepsin/pepsinogen in
the pathogenesis of OM is the pH level necessary to activate pep-
sin and for damage to occur in the mucosa. The pH of middle ear
effusion is alkaline. Pepsinogen is completed converted to pepsin
at pH 4.5 or less, and pepsin has substantial proteolytic activity
only at pH 2. At pH 8, pepsin is irreversibly inhibited.11 It means
the high prevalence shown in Table 3 could confirm a reflux
mechanism through ET to the middle ear. However, pepsin/pep-
sinogen detection does not mean proteolytic activity in middle
ear mucosa. Proteolytic activity was measured through different
methods in 4 studies. Tasker et al found acidic protease activity in
only 29% of samples, compared with 90.7% of marker’s pres-
ence with ELISA.14 He et al17 and O’Reilly et al18 measured only
the proteolytic activity, and the marker’s prevalence they found
was 14.5% and 20.2%, respectively. The lower activity found in
these 2 studies could be explained because they collected sam-
ples also from dry ears.17,18 Compared with the marker’s pres-
ence, it seems that a lower prevalence is expected when analyzing
proteolytic activity. The study of Lieu et al15 was the only with
correlation between activity and presence of the marker (73% vs
77%). This higher prevalence in activity could be explained by
the different technique in enzyme assay or different group of
patients. The study describes positive results for pepsin in all
serous, purulent, and mucopurulent effusions, and negative
results were found in mucoid effusions and dry ears. Except for
Tasker et al, who selected children with mucoid chronic OME,
these studies included children with chronic OME and recurrent
AOM. However, we could not retrieve data specifically for each
OM subtype that would be helpful for the understanding of these
discrepancies.
Antireflux medication in OM. The therapeutic test studies
have methodological limitations. We chose tympanometric
evaluation for outcome analysis because it is the most objec-
tive data in these studies. From initially 47 children with type
B tympanogram treated for GERD, 21 patients were reevalu-
ated by McCoul et al22 3 months later, and 7 returned to type
A tympanogram (33.3%). As no control group was assigned, it
is difficult to tell if this reduction is related to treatment or
could be explained by the spontaneous resolution rate of OM.
Serra et al13 and Ardehali et al21 performed clinical trials; how-
ever, these were not double-blinded or placebo controlled.
The absolute rate difference was 13% (95% CI, –0.086 to
0.34) and 23% (95% CI, 0.023-0.42) respectively, meaning
there was no statistical difference in the Serra et al study and a
wide range in CI in the Ardehali et al study.
Despite study limitations, Kotsis et al23 performed a logis-
tic regression showing an OR of 4 for recurrent OM in chil-
dren with severe GERD when compared with children without
GERD. Reflux severity may be the key to explain why chil-
dren with chromic OME/recurrent OM and GERD do not ben-
efit from antireflux treatment.
The treatment results are not encouraging for nonjudicious
GERD medication use in children with OM. Antireflux ther-
apy is not free of adverse events, and the physician must be
aware of potential effects of the major classes of drugs.4 We
looked for adverse events information in therapeutic test stud-
ies; however, no protocol or measures were available in the
methods nor results section. Idiosyncratic side effects occur in
up to 14% of children when proton-pump inhibitors are pre-
scribed and include headache, diarrhea, constipation, and nau-
sea, each occurring in 2% to 7% of patients. Histamine-2
receptor antagonists are related to irritability, head banging,
headache, and somnolence.4 Both drug categories can lead to
hypochlorhydria and may increase rates of community-
acquired pneumonia and gastroenteritis in children.4 We can-
not draw any conclusions about potential adverse effects of
antireflux treatment for OM because the 3 treatment studies
identified (Table 4) had only short-term follow-up and did
not explicitly report adverse events in the published articles.
To cover all relevant studies, we undertook this systematic
review with broad inclusion criteria. Most studies failed to
score 4 in our quality assessment since the selection of a con-
secutive sample was not described and/or eligibility criteria
for children inclusion/exclusion was unclear in most of them.
The considerable variability among studies has limited data
analysis and prevented a meta-analysis.
Conclusions
Prevalence of GERD in children with chronic OME/recurrent
OM may be higher than the overall prevalence for children.
The lack of definition of values to diagnose LPR through pH
monitoring prevents the knowledge of its actual prevalence
in OM. A cause-effect relationship between pepsin/pepsino-
gen in middle ear and OM is unclear, and its high prevalence
seems to be related to physiologic reflux. Proteolytic activity
may indicate a subgroup of patients with GERD prone to
OM. On the basis of the current literature, there is uncer-
tainty about the benefits of antireflux treatment in patients
with chronic OME or recurrent OM. Liberal usage of antire-
flux medications should be discouraged without proper
investigation, and potential adverse effects should not be
ignored. Most studies are observational, and their quality is
low because of a lack of consecutive samples, lack of clear
eligibility criteria, and lack of control group. Heterogeneity
in the available literature prevented us from performing a
meta-analysis. More research is needed to provide high-
quality evidence studies.
Author Contributions
Mauricio Schreiner Miura, conception and design, acquisition of
data, data analysis, interpretation, drafting, revision, final approval.
Miguel Mascaro, acquisition of data, data analysis, interpretation,
drafting, revision, final approval. Richard M. Rosenfeld, conception
and design, data analysis, interpretation, revision, final approval.
352 Otolaryngology–Head and Neck Surgery 146(3)
Disclosures
Competing interests: None
Sponsorships: None
12. Abd El-Fattah AM, Abdul Maksoud GA, Ramadan AS,
Funding source: None
Supplemental Material
Additional supporting information may be found at http://oto.sagepub
.com/content/by/supplemental-data
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