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Steroids for Otitis Media With Effusion
A Systematic Review
Christopher C. Butler, BA, MB, ChB, DCh, MRCGP, CCH, MD;
Judith H. van der Voort, MRCP
Arch Pediatr Adolesc Med. 2001;155:641-647.
ABSTRACT
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Background Otitis media with effusion (OME) is common and may cause hearing loss
with associated delayed language development in children. Treatment remains
controversial.
Objective To examine evidence for or against treating OME with systemic or topical
nasal steroids.
Data Sources We searched the Cochrane Controlled Trials Register using the terms otitis media; otitis media with effusion; glue ear; or OME and steroids; glucocorticoids; glucocorticoids, synthetic; glucocorticoids, topical; or anti-inflammatory agents, steroidal; or various combinations
of these terms. EMBASE and MEDLINE were also searched.
Study Selection Randomized controlled trials of oral and topical nasal steroids, either
alone or in combination with another agent such as an antibiotic, were included.
Ten studies met the inclusion criteria.
Data Extraction Data extraction and methodological quality assessment were performed
by the 2 of us (C.C.B. and J.H.v.d.V.) independently, using standardized methods
described in the Cochrane Collaboration Handbook.
Data Synthesis The odds ratio for OME persisting after short-term follow-up in children
treated with oral steroids compared with a control was 0.22 (95% confidence
interval, 0.08 = 0.63), and was 0.32 (95% confidence interval, 0.20 = 0.52)
for children treated with oral steroids plus an antibiotic compared with a
control plus an antibiotic. Trends favored steroids for most other comparisons,
but confidence intervals included unity. Trends favored steroids for most
other comparisons, but confidence intervals included unity.
Conclusions Steroids alone or combined with an antibiotic lead to a quicker resolution
of OME in the short-term. However, there is no evidence for a long-term benefit
from treating hearing loss associated with OME with either oral or topical
nasal steroids. These treatments are, therefore, not recommended.
INTRODUCTION
OTITIS MEDIA with effusion (OME), or "glue ear," is characterized by
an accumulation of fluid in the middle ear, in the absence of acute inflammation.1 Otitis media with effusion is the most common cause
of acquired hearing loss (HL) in childhood and may negatively affect language
development.2, 3 The reason why
the condition develops is uncertain, but a low-grade infection, poor eustachian
tube function, and adenoidal infection or hypertrophy have all been implicated.4 Otitis media with effusion has a prevalence of about
20% at around the age of 2 years, with another peak at the age of 6 years,
and often resolves spontaneously.5 The prevalence
of recurrent otitis media may be increasing.6
The total annual cost of treating children younger than 5 years for
OME is more than $5 billion annually in the United States.7
The insertion of ventilation tubes is the second most common surgical procedure
performed on children in the United States. In England and Wales, expenditure
by the National Health Service on surgical treatment for OME is around $47.8
million.8 Otitis media with effusion is a common
reason for prescribing antibiotics, which contributes to the growing problem
of bacterial resistance. The optimal treatment strategy remains controversial,
and there is wide international variability in clinical practice.
There is in vitro and animal model evidence that steroids modulate effusions.9, 10, 11 It is hypothesized
that steroids could clear effusions by (a) stabilizing
membrane phospholipid breakdown and, thus, preventing the formation of arachidonic
acid and associated inflammatory mediators; (b) shrinking
peritubal lymphoid tissue; (c) enhancing secretion
of eustachian tube surfactant; and (d) reducing middle
ear fluid viscosity.12 Topical intranasal steroids
may be safer than systemic preparations because the glucocorticoid is rapidly
degraded in the nasal mucosa to less active metabolites and any unchanged
drug that is absorbed is metabolized in the first pass through the liver.13 Systemic adverse effects are, therefore, less likely,
while the desired anti-inflammatory effects may be similar. However, systemic
steroids may be able to gain access to the middle ear, while topical nasal
steroids would not be expected to reach the middle ear but may modulate eustachian
tube function. Clinicians may be concerned about using systemic steroids for
what may be a self-limiting condition.
This review determines the beneficial and harmful effects of treatment
with steroids (systemic and intranasal) for children with OME. Our a priori
hypothesis was that steroids (systemic or intranasal), either alone or in
combination with another agent, are effective in treating the HL associated
with OME and in resolving effusions in children. A more detailed review is
published in the Cochrane Review on CD-ROM.14
CRITERIA FOR CONSIDERING STUDIES
Types of Studies
Randomized controlled trials of oral and intranasal steroids were included.
Randomized studies that used nonintervention controls were included, in which
blinding of outcome assessment was adequate. Excluded were publications in
abstract form, only because adequate appraisal was not possible15, 16;
uncontrolled nonrandomized17, 18
or retrospective studies; and studies reporting outcomes only with ears (rather
than children) as the unit of analysis,19, 20
because observations made on the ears of a single child cannot be regarded
as independent. Studies21 of treatment effect
on OME using the ear as the unit of analysis have found larger treatment effects
than studies analyzing at the level of the child. Studies (or data from arms
of studies)22, 23 comparing steroid
plus additional treatment with placebo plus placebo were excluded because
it was not possible to identify the "steroid effect" from such data.
Types of Participants
The focus was on studies of children up to the age of 12 years diagnosed
as having unilateral or bilateral OME and who had significant HL, however
defined. We report when older subjects were included.
The studies were divided into subgroups according to the following ways
of assessing exposure:
1. The diagnosis of OME was defined by (a) an air-bone gap of 10 dB or more, (b) 2 or more of otomicroscopy readings with or without pneumatic otoscopy
readings or tympanometry readings, (c) one of an
otoscopy reading or a tympanometry reading alone, or (d) poorly or not defined.
2. Significant HL was (a) defined by pure tone audiometric HL of more than 20 dB at 2 or more
times within 3 months; (b) defined, but less strict
than a; or (c) uncertain
or not defined.
Types of Interventions
The intervention was systemic or intranasal steroids compared with control
(placebo or nonintervention control). Additional treatments, such as antibiotics,
were included as long as they were identical in the treatment and the control
groups.
Types of Outcome Measures
We examined studies for data on the effect of steroid treatment over
time or at multiple points for (1) differences in hearing level, (2) degree
of conductive HL, (3) presence or absence of fluid in the middle ear cavity
(short- and longer-term), and (4) possible adverse effects.
We also examined studies for the effect of steroid treatment on secondary
development outcomes, such as language development and behavior.
DATA SOURCES
We searched the Cochrane Controlled Trials Register in February 2000
using the following search strategy: (1) otitis media
(MEDLINE Medical Subject Heading [MeSH] term, including all subheadings);
(2) otitis media with effusion (MeSH term, including
all subheadings); (3) glue ear (free-text term);
(4) OME (free-text term); (5) (1), (2), (3), or
(4); (6) steroids (MeSH
term, including all subheadings); (7) glucocorticoids
(MeSH term, including all subheadings); (8) glucocorticoids,
synthetic (MeSH term, including all subheadings); (9) glucocorticoids, topical (MeSH term, including all subheadings); (10) anti-inflammatory agents, steroidal (MeSH term, including
all subheadings); (11) (6), (7), (8), (9), or (10); or (12) (5) and (11).
Additional information was identified by searching MEDLINE and EMBASE,
using a similar search strategy. We also wrote to experts asking about knowledge
of additional studies. Previous systematic reviews and references of trials
identified by the search strategy were checked for additional relevant references.
There was no language restriction. Searches were carried out by the 2 of us
(C.C.B. and J.H.v.d.V.) independently. The full texts of all studies loosely
meeting the inclusion criteria were independently assessed by us, and differences
of opinion regarding inclusion were resolved by consensus.
DATA EXTRACTION
Data concerning methods, participants, interventions, and outcomes were
extracted from the published reports by the 2 of us (C.C.B. and J.H.v.d.V.)
independently, using standardized data extraction forms. Disagreement was
resolved by consensus after returning to the original publication. In studies
that provided data for various definitions of cure, data for the strictest
definition were used. In trials with a crossover design, data from the postcrossover
treatment period were not used because observations on patients in treatment
periods of these studies cannot be considered independent and carryover effects
of treatment periods are likely. Similarly, in multiarm studies (eg, steroid
vs antibiotic vs nonsteroidal anti-inflammatory vs control), only data for
the steroid-treated and control groups were used.
The methodological quality of the included studies was independently
assessed by the 2 of us (C.C.B. and J.H.v.d.V.) using the scheme described
in the Cochrane Collaboration Handbook.24
This involved assessing studies for (1) selection bias, (2) performance bias,
(3) attrition bias, and (4) detection bias. A 3-point rating scale for overall
validity was used, with the grading as follows: (a)
low risk of bias—plausible bias is unlikely to alter the results seriously,
(b) moderate risk of bias—plausible bias raises
some doubt about the results, and (c) high risk of
bias—plausible bias seriously weakens confidence in the results.
DATA SYNTHESIS
We used the statistical methods for dichotomous outcomes described by
Yusuf and colleagues.25 Results were expressed
as an odds ratio for achieving the outcome in question at a given point together
with the 95% confidence intervals for this estimate. Continuous data were
analyzed using the weighted mean difference in a fixed-effects model. Tests
for heterogeneity between studies were performed using a Mantel-Haenszel approach.
Description of Studies
Regarding ascertainment of the presence of OME, most studies documented
effusions by a combination of pneumatic otoscopy and tympanometry (1b). No study documented HL from OME 2 or more times in
the 3 months before study enrollment (2a). (Explanations
of 1b and 2a are given in
the "Types of Participants" subsection of the "Criteria for Considering Studies"
section.) Only one study26 required documented
HL for all children before study enrollment. One trial27
was open, comparing children treated with steroids with nonintervention controls.
Four included studies26, 28, 29, 30
provided audiometric data at follow-up. However, only one26
provided data that could be used in this review (numbers of children improving
their HL by at least 10 dB). Audiometric data otherwise used ears as the unit
of analysis or were unclear. No study reported effects on language or other
aspects of development.
The adverse effects of steroid treatment were reported in 5 studies.13, 23, 27, 31, 32
In cases in which the same data are apparently published twice,27, 33, 34, 35 these
data are used only once in this review.
Studies fell into 4 categories (oral steroid vs control, oral steroid
plus antibiotic vs control plus antibiotic, intranasal steroid vs control,
and intranasal steroid plus antibiotic vs control plus antibiotic or antibiotic
alone) (Table 1). The study13 of intranasal steroid plus antibiotic vs control
plus antibiotic also reported on symptoms in the form of a scale, which was
considered as continuous data. This was the only study13
to report symptoms as an outcome, but validation of their symptom scale was
not described.
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Table 1. Comparison and Results*
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Methodological Quality of Included Studies
Of the 10 included studies,13, 26, 27, 28, 29, 30, 31, 32, 34, 36
there were 313, 26, 28
that were rated A for quality. All other studies were rated B, apart from
227, 30 that were rated C for quality
(Table 2).
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Table 2. Characteristics of Included Studies
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Results
Overall, the number of studies for each comparison was small (Table 1). The number of participants available
for each comparison ranged from 15 to 274. For the 4 groups of studies, a
total of 10 comparisons were made. This reflects the use of various points
and methods to measure outcomes. Three included studies26, 27, 36
provided data for 108 patients randomized to treatment with oral steroid vs
control. The odds ratio for OME persisting after short-term follow-up ( 2
weeks) was 0.22. Four included studies28, 29, 31, 34
provided data on a total of 274 patients randomized to treatment with oral
steroid plus antibiotic vs control plus antibiotic. The odds ratio for OME
persisting after short-term follow-up (2 weeks) was 0.32. There was significant
heterogeneity between the studies involving steroids plus antibiotics (P<.01). Only one of these studies31
reported longer-term outcomes and provided data for only 15 patients. Seven
comparisons across the study groups included only one study, so they offer
no new information. Overall, 7 comparisons favored steroids, 2 favored controls,
and 1 favored neither. However, the confidence intervals were generally wide
and included unity for all but 2 comparisons. Because of the small number
of studies in many of the comparisons, we did not perform sensitivity analyses.
No serious or lasting adverse effects were reported in the 4 studies
mentioning adverse effects.
CONCLUSIONS
Steroids alone or together with an antibiotic appear to improve resolution
of effusion in the short-term. However, there was significant heterogeneity
between studies involving steroids plus antibiotics. This could be explained
by differences between studies in pharmacological interventions, including
steroid formulation, steroid dose, duration of steroid treatment, and type
and duration of concomitant antibiotic. Also, studies differed in terms of
study population, including age, setting, proportion with bilateral OME, and
duration of OME at study enrollment. The clinical significance of this finding
is uncertain because we were not able to evaluate the effect of steroid treatment
on hearing from these studies. Few data are available for longer-term outcomes,
and no study assessed the effect of steroids on language in the longer-term.
One study27 did assess hearing at 12 months,
but this assessment was made on only 35% of the patients, so the results are
difficult to interpret and were, therefore, not presented. Given concern about
treating what is often a self-limiting condition with systemic steroids, we
were particularly interested to examine evidence for the effect of topical
nasal steroids. The one study32 we included
of intranasal steroid vs placebo showed no benefit. The one study13 of intranasal steroid in combination with an antibiotic
demonstrated an effect in clearing effusions in the short-term, but by 3 months,
differences between study groups were no longer statistically significant.
Adverse effects of steroid treatment were mentioned in a few studies. No study
documented HL prospectively before study enrollment. Only one study13 attempted to measure the effect of steroids on subjective
symptoms.
Previous reviews1, 37, 38
were published before the trial by Hemlin and colleagues.31
Some used different inclusion criteria (eg, Nuss and Berman37
included trials published in abstract form only and a nonrandomized open study).
However, conclusions were similar to ours in that despite evidence for a short-term
steroid effect, the general use of steroids for OME was not recommended. A
cost-effectiveness review concluded that steroid plus antibiotic was the most
cost-effective intervention for children found to have OME at a first follow-up
visit 6 weeks after the diagnosis of acute otitis media.39
However, adverse effects were not considered.
Implications for Practice
There is imperfect evidence demonstrating short-term improvement in
OME from oral steroids alone or combined with an antibiotic. However, we found
no evidence for lasting benefit from oral or topical nasal steroid treatment
of HL associated with OME. Based on the research we identified, these treatments
are, therefore, not recommended.
Implications for Research
Otitis media with effusion may be present without significant HL. Positive
predictive values range from 49% to 66.4% for an HL of 25 dB or greater after
an abnormal tympanogram.40, 41, 42
Given the high rate of spontaneous remission, future studies should
document HL associated with OME for a period before beginning study treatment
and at follow-up. In the absence of evidence that unilateral OME influences
language development, the practice of enrolling children with unilateral OME
into treatment studies is questionable. Follow-up should be longer and ideally
include symptom, hearing, and language development outcome assessments. Audiometric
data should be presented not as mean hearing levels for groups but as numbers
of children with defined levels of HL in their best hearing ear. Data should
not be presented only with ears as the unit of analysis because observations
on the different ears of the same child cannot be regarded as independent.
Assessors of outcomes should be blinded to the treatment condition. Improvement
should be clearly defined (eg, researchers should present data for children
with bilateral OME resolving in one but not both ears). Analysis should be
based on the intention to treat. A short course of oral steroids followed
by longer-term intranasal steroids has so far not been evaluated.
AUTHOR INFORMATION
Accepted for publication December 1, 2000.
This study was supported by a fellowship from the Wales Office of Research
and Development for Health and Social Care, National Health Service (Dr Butler).
We thank the editorial staff and the editorial group of the Cochrane
Ear, Nose and Throat Disorder Group for their help and comments. Comments
from external and internal reviewers of the Cochrane Ear, Nose and Throat
Disorder Group on the longer version of this review, which appears in the
Cochrane Database of Systematic Reviews, are gratefully acknowledged.
From the Departments of Family Medicine (Dr Butler) and Pediatrics
(Dr van der Voort), McMaster University Medical Centre, Hamilton, Ontario.
Corresponding author: Christopher C. Butler, BA, MB, ChB, DCh, MRCGP,
CCH, MD, Department of Family Medicine, McMaster University, Faculty of Health
Sciences, 1200 Main St W, HSC–2V14, Hamilton, Ontario, Canada L8N 3Z5
(e-mail: cbutler{at}mcmaster.ca).
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