Reviews and Meta-Analyses

The Relationship Between Otitis Media With Effusion and

Gastroesophageal Reflux Disease: A Meta-analysis
yZeng-Hong Wu, zYun Tang, zXun Niu, z§Hai-Ying Sun, and jjXiong Chen
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology,
Wuhan; yDepartment of Otorhinolaryngology; zDepartment of Critical Care Medicine, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology; §Department of Otolaryngology–Head and Neck Surgery, Stanford University
School of Medicine, Stanford, California; and jjDepartment of Otolaryngology Head and Neck Surgery,
Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China

Objective: Recent studies have investigated the mechanism
by which refluxed gastric materials reach the middle ear, to
establish otitis media with effusion (OME) causal relation
between them in both children and adults. Therefore, the
relationship between OME and gastro-esophageal reflux
disease (GERD) should be further studied extensively.
Methods: To identify eligible original articles, we searched
a range of computerized databases, including Medline via
PubMed, EMBASE, CNKI, and Web of Science with a
systematic searching strategy. Subgroup analysis was per-
formed to analyze heterogeneity and Egger and Begg funnel
plot to assess the publication bias of the included articles.
Results: The meta-analysis had an overall sample size of
1961. We identified a significant relationship between OME
and GERD, with a pooled odds ratio (OR) of 4.52 (95%
confidence interval [CI]: 2.42–8.44; p < 0.001). The pooled
data were calculated with the random-effects model as a
high significant heterogeneity was found among the studies
and there was no significant publication bias observed.
Conclusions: The meta-analysis suggested that there was a
significant association between otitis media with effusion and
gastroesophageal reflux disease. Key Words: Acute otitis
media—Children—Chronic otitis media with effusion—
Gastroesophageal reflux disease—Meta-analysis—Otitis
media with effusion.
Otol Neurotol 42:e245–e253, 2021.

Acute otitis media (AOM), chronic otitis media with
effusion (COME), and recurrent acute otitis media (ROM)
are very common diseases in children, and rank second
among causes of children hospitalization (1). It is esti-
mated that by the age of 4, up to 90% of children experi-
ence hearing loss due to at least one episode of OME (2).
Besides being associated with various manifestations in
Address correspondence and reprint requests to Hai-Ying Sun, M.D.,
Department of Otorhinolaryngology, Union Hospital, Tongji Medical
College, Huazhong University of Science and Technology, Wuhan,
Hubei, China; E-mail: sunhaiying120@163.com
Z.-H.W., Y.T., and X.N. are joint first author. These authors contrib-
uted equally to this study.
H-Y.S. and X.C. are joint corresponding authors.
Author Contributions: All authors contributed significantly to this
work. W.Z.H. and T.Y. designed the research study; W.Z.H. and N.X
performed the research study and extracted the data and analyzed the
data; W.Z.H., N.X., S.H.Y. and C.X. wrote and revised the manuscript.
In addition, all authors approved the final draft.
Competing financial interests: No financial (no Funding, Employ-
ment and Personal financial interests) and Non-financial competing
interests.
This work is supported by grants from The National Natural Science
Foundation of China (81600801).
The authors disclose no conflicts of interest.
DOI: 10.1097/MAO.0000000000002945
otorhinolaryngology, gastro-esophageal reflux disease
(GERD) is also a risk factor for AOM or COME (3,4).
Unlike in adults, the Eustachian tube is shorter and ori-
ented horizontally, in children, due to incomplete devel-
opment. This anatomical factor allows refluxed content of
the stomach to reach the middle ear cleft. Such occurrence
has been supported by the detection of gastric pepsin/
pepsinogen, acid, bile acid, and Helicobacter pylori (Hp)
in the middle ear effusions (MEE). The gastric contents
can trigger an inflammatory cascade that may cause
hearing loss and irreversible damage to the middle ear
mucosa (4). Adenoidectomy is not a treatment as it can be
for a child older than 4, but tympanostomy tube insertion
are a treatment. Therefore, identification of risk factors
may be helpful in OME treatment.
Recent studies have investigated the mechanism by
which refluxed gastric materials reach the middle ear, to
establish OME causal relation between them in both
children and adults. Presence of pepsin/pepsinogen con-
centrations in the middle ear effusions of children was
first reported by Tasker et al. (5), and it sparked a surge of
subsequent confirmatory studies. Other studies devel-
oped methods for detecting H. pylori in MEE or adenoid
tissue, and examined a possible correlation between its
presence and GERD. Besides, studies using endoscopy

ß 2020, Otology & Neurotology, Inc.

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e246 Z-H. WU ET AL.
and 24-hour pH monitoring to document acid reflux and
prevalence of GERD among OME patients have since been
reported. To evaluate the relationship between OME and
GERD, empiric anti-reflux treatment has also attempted.
However, this pathophysiological mechanism has yielded
mixed results with some studies reporting negative corre-
lation between them. Therefore, the relationship between
OME and GERD should be further studied extensively. We
thus performed a meta-analysis to grade the strength of
evidence and systematically explore whether OME corre-
lates with GERD in the literature. (Supporting information:
PRISMA Checklist) (6).
MATERIALS AND METHODS
Search Strategy
Studies detailing otitis media with gastroesophageal reflux
disease and otitis media with effusion were recognized as
included. To recognize qualified primitive articles, we look
for through PubMed, EMBASE, CNKI, and Web of Science for
a series of computer databases utilizing the following crucial
terms: ‘‘otitis media,’’ ‘‘gastroesophageal reflux,’’ ‘‘reflux,’’
‘‘middle ear effusions.’’ Articles were seeked in the computer-
ized databases up to January 2019 and not limited by language.
The reference list of the resulting publication was used to
recognize potential appropriate studies. We screened the titles
and abstracts of determined studies and evaluated articles that
might involve data on gastroesophageal reflux and otitis media.
The two authors searched the papers and screened the retrieved
papers and differences are determined by consensus.
Inclusion Criteria
Double-checked the original study and no national limita-
tion. The inclusion criteria were: 1) OME was restrict as the
existence of middle ear fluid for leastwise 3 months; 2) all
members of the experimental group ostracized any susceptible
factors (such as allergies, asthma, sinusitis) that may be linked
to OME development; 3) research was limited to humans,
published in English, contains original data, and appears in
full text or in abstract form; 4) Research clearly defines research
and control groups and group members to obtain observational
data; 5) research pepsin/pepsinogen concentrations, H. pylori
testing, and 24-hour pH monitoring were reported in OME
patients to record acid reflux or anti-reflux treatment.
Exclusion Criteria
Review articles, case reports, non-English publications,
abstracts, duplicate publications, and editorials were excluded.
Data Extraction
Collected for each publication are author name, publication
year, study design, age, reflux assessment method, H. pylori/
pepsin/pepsinogen analysis method, anti-reflux treatment,
study, and control standard information.
Data Availability
All data generated or analyzed among this research is
comprised in this published article.
Statistical Analysis
To assess the grade of every single consist of study through
the Newcastle-Ottawa Scale (7). Meta-analysis was conducted
by Cochrane statistical software Review Manager 5.3
Otology & Neurotology, Vol. 42, No. 3, 2021
Copyright © 2021 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited.
(Cochrane Collaboration, Copenhagen, the Nordic Cochrane
Centre). Higgins I2 test were employ to examine the heteroge-
neity. I2 values over 75% are considered high heterogeneity, I2
values between 50 and 75% are considered moderate heteroge-
neity, I2 values between 25 and 50% are considered low
heterogeneity, and I2 values of less than 25% are considered
homogeneous. When I2 values over 50% the random effects
model integrates effect size and when I2 value less 50% the
fixed effects model integrates effect size. We also attempted to
perform subgroup analysis to interpret the source of heteroge-
neity. The combined odds ratio (OR) and the corresponding
95% confidence interval (CI) of different studies were used to
predict the connection between OME and GERD. Repeat
sensitivity analyses to assess the impact of individual studies
on aggregate estimates by deleting individual studies.
RESULTS
Literature Search
We initially identified 524 potentially relevant
articles from electronic databases and three from refer-
ence lists and other sources. Finally, 46 duplicates and
423 articles were excluded for not meeting the inclusion
criteria after reviewing their titles and abstracts. Full
texts of the remaining 45 articles were further reviewed
and 24 were excluded for not reporting sufficient data
on the relationship between OME and GERD. Addi-
tional nine studies were excluded, out of which one had
inappropriate outcome measure, three were animal
studies, three were non-English, one was a duplicate,
and the full text of one could not be retrieved. Eventu-
ally, 13 eligible articles comprising 16 studies were
identified (8–20). The selection process is shown in
Figure 1 and detailed information of each study listed in
Table 1.
The meta-analysis had an overall sample size of 1,961.
In terms of sample distribution, one article only had
middle ear samples; one study included two sample
sources, middle ear effusions and adenoid tissue; one
study compared the effectiveness of two clinical methods
(PCR and culture) for detection of HP in clinical; and one
article used 24-hour pH monitoring and anti-reflux treat-
ment to evaluate the relationship between OME and
GERD in cases and controls.
Meta-analysis Results
The forest plot result for association of OME with
GERD is shown in Figure 2. We identified a significant
relationship between OME and GERD, with a pooled
OR of 4.52 (95% CI: 2.42–8.44; p < 0.001). The
pooled data were calculated with the random-effects
model as a high significant heterogeneity was found
among the studies. Meanwhile, in the fixed-effects
model, the pooled OR of 4.98 (95% CI: 3.83–6.42,
p < 0.001, I2 ¼ 75%).
Subgroup Analysis
Pepsin
Under the fixed-effects model, analysis of the pepsin
subgroup revealed a significant corresponding value of
 RELATIONSHIP BETWEEN OTITIS MEDIA WITH EFFUSION e247

524 Reference idenfied through 3 from reference lists and

database searching other sources

Records aer duplicates removed 38 Records excluded(review;

(n = 478 ) report; case)

Titles and abstracts reviewed 423 Reference excluded

(n =45) (not relevant)

33 Arcles Excluded
45 Full-text arcles assessed
24 No data or insufficient
3 Non-English
3 Animals

Studies included in 1 Duplicate data

quantave synthesis 1 Inappropriate
(meta-analysis)
(n=13)

FIG. 1. Search strategy to identify articles on the relationship between otitis media with effusion and gastroesophageal reflux disease.

16.30 (95% CI, 8.01–33.17, p > 0.001). Forest plot of the
subgroup analysis is shown in Figure 3. These results
implied that the amount of pepsin in the middle ear
effusion is a key factor in OME pathogenesis.
Anti-reflux Therapy
Anti-reflux therapy subgroup analysis revealed a sig-
nificant corresponding value of 2.57 (95% CI, 1.13–5.84,
p > 0.001), under the fixed-effects model. Its forest plot
is shown in Figure 4. We observed that anti-reflux
therapy in GERD patients significantly alleviated the
signs and symptoms of OME.
Sensitivity Analysis
Besides the coupled forest plots showing moderate
heterogeneity (Tau2 ¼ 1.01; x2 ¼ 59.83, df ¼ 15,
p < 0.00001; I2 ¼ 75%), removal of any study from the
meta-analysis did not affect the pooled results under the
random-effects model. In the sensitivity analysis results,
pooled ORs ranged from 3 to 5. Moreover, high hetero-
geneity was observed from the subgroup analyses, with I2
index recorded at 0, 1, 86, and 27% for pepsin, anti-reflux
therapy, H. pylori, and 24-hour pH monitoring, respec-
tively. However, the I2 index rapidly decreased from 27
to 0% upon removal of Keles’ study.

Helicobacter pylori Publication Bias

H. pylori subgroup analysis revealed a significant
corresponding value of 4.16 (95% CI: 0.82–21.22,
p < 0.001) under the random-effects model. Its forest
plot is shown in Figure 5. We found a significantly strong
relationship between OME and H. pylori.
24-hour pH Monitoring
Under the fixed-effects model, the 24-hour pH moni-
toring subgroup analysis revealed a significant corre-
sponding value of 1.52 (95% CI: 0.79–2.92, p > 0.001).
Figure 6 shows its forest plot. These results implied that
the gastroesophageal reflux materials may play an impor-
tant role in OME pathogenesis.
We performed Egger’s and Begg’s funnel plot to
assess the publication bias of the included articles. The
Begg’s tests ( p ¼ 0.444) and Egger’s tests ( p ¼ 0.165)
funnel plots showed that there is no publication bias
(Fig. 7). Besides, the trim and fill method showed that no
study needed to be statistically corrected for funnel plot
asymmetry. The methodological quality of each included
study is shown in Table 2.
DISCUSSION
Through this meta-analysis, we revealed that GERD is
a significant predisposing factor for OME development

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 e248

TABLE 1. Description of included studies

Source, year Country Mean Age (Range), y Sample Size Study Design Reflux Criteria/Marker OM Subtype Selection Criteria Study and Control Group
a
He et al., 2007 United States 2.8 (0.5–10) 152 Cross-sectional Enzyme assay /Pepsin COME Myringotomy with Pepsin positivity in dry
(8) tube placement versus effusion ears
O’Reilly et al., United States 2.7 (0.25–17) 573 Case–control Enzyme assay and COME and Myringotomy with COME/ROM versus
2008 (9) Western blot/pepsin ROM tube placement negative OM undergoing
cochlear implantation
Ardehali et al., Iran 5.3 (2–12) 90 Randomized trial Antireflux therapy COME Management and no Antireflux therapy versus
2008 (10) treatment children antibacterial treatment

Otology & Neurotology, Vol. 42, No. 3, 2021

treated versus untreated
Serra et al., 2007 Italy 1.1 (0–2) 127 Randomized trial Laryngoscopy and COME Risk for auditory Adenoidectomy with
(11) 24-hour pH monitoring illnesses myringotomy versus dry
ear
Agirdir et al., Italy NA (3–10) 30 Randomized trial CLO test/HP COME Myringotomy with OME þ adenoid
2005 (12) tube placemen hypertrophy versus
adenoid hypertrophy
Yılmaz et al., Turkey NA 18 Cross-sectional PCR/HP COME Adenoid hypertrophy OME þ adenoid
2004 (13) b and/or chronic hypertrophy versus
OME adenoid hypertrophy
Yılmaz et al., Turkey 5 (2–13) 22 Randomized trial PCR/HP OME Adenoid hypertrophy Adenoidectomy/
2006 (14) and/or OME tonsillectomy
Melake et al,2012 Egypt NA (2–14) 60 Cross-sectional PCR and culture /HP OME myringotomy with versus dry ear
(15),c tube placement
Z-H. WU ET AL.

Saki et al., 2014 Iran NA (1–10) 84 Cross-sectional PCR/HP OME Adenoidectomy and Adenoidectomy and
(16) myringotomy myringotomy versus
adenoidectomy
Abdel-aziz et al., Egypt 2.8 (1–10) 31 Cross-sectional 24-hour pH monitoring COME Myringotomy with Surgical group versus
2013 (17) tube placement medical group
Sone et al., 2010 Japan 63.4 (29–91) 186 Cross-sectional Questionnaire OME OME of unknown OME group versus without
(18) etiology OME
Velepic et al., Croatia 7 (2–13) 30 Cross-sectional 24-hour pH monitoring COME Tubotympanal COME versus ROM
2000 (19) and ROM disorders
Keles et al., 2004 Turkey 6.8 (3–12) 37 Case–control 24-hour pH monitoring COME Standard examination COME versus healthy
(20) children
a
Middle ear samples (dry ears and effusion ears).
b
Data from middle ear effusions and adenoid tissue.

Copyright © 2021 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited.
c
Data from PCR and culture results.
CLO indicates Campylobacter-like organism test; COME, chronic otitis media with effusion; ELISA, enzyme-linked immunosorbent assay; ENT, ear, nose, and throat; GERD, gastroesophageal
reflux disease; HP, Helicobacter pylori; OM, otitis media; PCR, polymerase chain reaction; ROM, recurrent acute otitis media.
 RELATIONSHIP BETWEEN OTITIS MEDIA WITH EFFUSION e249

FIG. 2. Relationship of OME and GERD. The results indicated that OME was significantly associated with risk of GERD (OR ¼ 4.52, 95%
CI ¼ 2.42–8.44). CI indicates confidence interval; GERD, gastro-esophageal reflux disease; OME, otitis media with effusion; OR, odds ratio.

FIG. 3. The forest plot of pepsin subgroup analysis.

FIG. 4. The forest plot of antireflux therapy subgroup analysis.

FIG. 5. The forest plot of Helicobacter pylori subgroup analysis.

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e250 Z-H. WU ET AL.

FIG. 6. The forest plot of 24-hour pH monitoring subgroup analysis.

FIG. 7. The Begg’s tests and Egger’s tests funnel plots.

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 RELATIONSHIP BETWEEN OTITIS MEDIA WITH EFFUSION e251
TABLE 2. Methodological assessment according to the Newcastle–Ottawa scale
Selection Outcome
Representa- Outcome of FU Adequacy Total
Study tiveness Selection Ascertainment Interest Comparability Assessment of FU Scorea

He et al., 2007 (8)   –   –  – 6

O’Reilly et al., 2008 (9)         8
Ardehali et al., 2008 (10)     – – –  5
Serra et al., 2007 (11)      – – – 6
Agirdir et al., 2005 (12) –    – – – – 3
Yılmaz et al., 2004 (13)   –   –  – 5
Yılmaz et al., 2006 (14)      –   7
Melake et al., 2012 (15) –        8
Saki et al., 2014 (16)  –     –  6
Abdel-aziz et al., 2013 (17)   –   –  – 5
Sone et al., 2010 (18) –    – –  – 4
Velepic et al., 2000 (19)         8
Keleş et al., 2004 (20)   –    –  7
a
We considered a study to be of high quality when the total score was eight or nine stars, moderate quality when the total score was six or
seven stars, and low quality when the total score was five stars or fewer.
– indicates no stars; FU, follow-up.

(OR ¼ 4.52; 95% CI: 2.42–8.44; p < 0.001). Credibility
of our results was confirmed by the lack of bias in the
subgroup analyses. In addition, Begg’s and Egger’s tests
also revealed a lack of publication bias in our study. After
observing moderate heterogeneity among the studies
(I2 > 50, p < 0.001), we further performed subgroup
analysis to determine the heterogeneity sources. We
therefore think that the strong relationship between
OME and GERD, as revealed by our results is accurate.
In addition, sensitivity analysis results demonstrated that
neither study omission nor conversion of effects model
from random to fixed, could not affect the results.
A lot of research geared towards developing methods
of detecting pepsin/pepsinogen concentrations in the
middle ear effusions have been conducted since it was
first described by Tasker et al. (5). Although a recent
systematic review reported a very high pepsin/pepsino-
gen marker prevalence (60–100%) in OME patients (21),
while it was lower in our meta-analysis because He et al.
(8) and O’Reilly et al. (9) collected samples from dry
ears, and the prevalence of markers was 10 and 20%,
respectively. Many studies investigating the presence of
pepsin/pepsinogen in MEE have since been reported,
with very few focusing on its association with GERD.
Our meta-analysis therefore sought to examine this asso-
ciation. Summary odds ratio (OR) for pepsin subgroup
analysis under the fixed-effects model was 16.30 (95%
CI: 8.01–33.17), indicating that the presence of pepsin/
pepsinogen in the middle ear effusions is positively
correlated with OME development.
These findings agreed with other studies that adminis-
tered anti-reflux therapy to participants with GERD
symptoms. For instance, after administering standard
anti-reflux therapy to patients for two consecutive 12-
week periods, Mccoul et al. (22) used GERD question-
naire and fiberoptic laryngoscopy to assess the outcome.
Seven patients returned to type A tympanogram (33%)
after the therapy. Additionally, all patients (21)
responded positively to anti-reflux therapy in a separate
study conducted by Poelmans et al. (23). Our findings
supported these two studies since we found a summary
OR of 2.57 (95% CI: 1.13–5.84) for anti-reflux therapy
subgroup analysis under the fixed-effects model. This
further confirmed that GERD might be indirectly
involved in the pathophysiology of OME. In addition,
other studies have found H. pylori to be an important
factor in the association between OME and GERD.
However, the contribution of Hp to such relationship
remains controversial with different studies reporting
conflicting results. For instance, a systematic review
(24) found poor evidence for Hp associated otitis media
with effusion and recommended further research on such
association. Conversely, a recent study (25) found strong
association between Hp in middle ear effusions and
GERD. In this meta-analysis, results from Hp subgroup
analysis suggested that Hp plays an important role in
OME pathogenesis.
Due to its ability to detect episodes of laryngophar-
yngeal and gastroesophageal refluxes, 24-hour dual-
probe esophageal pH monitoring is presently the standard
diagnostic method for GERD. However, our meta-anal-
ysis only included data from gastroesophageal reflux.
Thus far, there is no consensus among researchers with
respect to the number of probes, the positioning of the
proximal and distant probe, or the interpretation of results
obtained from the 24-hour dual-probe esophageal pH
monitoring (26). Most studies however have used the
24-hour dual-probe esophageal pH monitoring to detect
episodes of GERD. For example, El-Fattah et al. (27)
used the ambulatory 24-hour dual-probe pH monitoring
and detected most physiologic reflux episodes in all
included studies. Similarly, our 24-hour pH monitoring
subgroup analysis showed a significant positive correla-
tion between OME and GERD.

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e252 Z-H. WU ET AL.
From our results, we conclude that GERD is a signifi-
cant predisposing factor in OME pathogenesis. There-
fore, patients with OME and GERD should undergo anti-
reflux treatment, e.g., proton pump inhibitors, or anti-
bacterial treatment; and lifestyle modifications, e.g.,
dietary; sleep position. In addition, we also suggest that
OME patients should be evaluated for GERD before
undergoing myringotomy with tube placement or any
other surgical treatment. If GERD is present, its treatment
should be first administered for a period of time before
resorting to any surgical procedure (28). Further, upon
exhibition of GERD’s signs and symptoms (such as
frequent throat clearing, reflux laryngitis, sore throat
and posterior laryngitis with hoarseness, laryngeal and
subglottic stenosis, and chronic cough (29)), fiberoptic
laryngoscopy or 24-hour dual-probe esophageal pH mon-
itoring should be performed on the OME patients. This
would ensure high-risk patients with GERD disease are
identified and first treated for GERD to limit abuse
of antibiotics.
To the best of our knowledge, this is the first meta-
analysis to elucidate the association between GERD and
OME. It however has the following limitations that
should be considered when interpreting our results. First,
the sample size was relatively small; therefore large-
sample studies should be conducted to validate our
results. Secondly, although we explored the source of
heterogeneity by subgroup analysis in our study, we
could not explore other heterogeneity aspects due to
the insufficient clinical data and the limited number of
included studies. Thirdly, the results may be biased since
inconsistent measurement techniques were used to detect
pepsin (enzyme assay/Western blot), or Hp (campylo-
bacter-like organism test/polymerase chain reaction/cul-
ture), different anti-reflux treatments (proton pump
inhibitors/omeprazole) were administered to patients in
different studies. Additionally, the study population was
mainly composed of children; hence these results may
not apply to adult population.
CONCLUSIONS
This meta-analysis provided direct evidence that the
GERD participation in OME pathogenesis and suggest us
that treatment of OME should not be neglect the GERD
in clinical practice.
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Otology & Neurotology, Vol. 42, No. 3, 2021

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