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Inhaled Corticosteroids and

Respiratory Infections in Children


With Asthma: A Meta-analysis
Cristine Cazeiro, BSN,a Cristina Silva, MD,b Susana Mayer,b Vanessa Mariany, MD,b
Claire Elizabeth Wainwright, MBBS, MD,c Linjie Zhang, MD, PhDa,b,d

CONTEXT: Inhaled corticosteroids (ICS) are associated with an increased risk of pneumonia in abstract
adult patients with chronic obstructive pulmonary disease.
OBJECTIVE: To assess the association between ICS use and risk of pneumonia and other
respiratory infections in children with asthma.
DATA SOURCES: We searched PubMed from inception until May 2015. We also searched
clinicaltrials.gov and databases of pharmaceutical manufacturers.
STUDY SELECTION: We selected randomized trials that compared ICS with placebo for at least 4
weeks in children with asthma.
DATA EXTRACTION: We included 39 trials, of which 31 trials with 11615 patients contributed data
to meta-analyses.
RESULTS: The incidence of pneumonia was 0.58% (44/7465) in the ICS group and 1.51%
(63/4150) in the placebo group. The meta-analysis of 9 trials that revealed at least 1 event
of pneumonia revealed a reduced risk of pneumonia in patients taking ICS (risk ratio [RR]:
0.65; 95% confidence interval [CI]: 0.44 to 0.94). Using risk difference as effect measure,
the meta-analysis including all 31 trials revealed no significant difference in the risk of
pneumonia between the ICS and placebo groups (risk difference: 0.1%; 95% CI: 0.3% to
0.2%). No significant association was found between ICS and risk of pharyngitis (RR: 1.01;
95% CI: 0.87 to 1.18), otitis media (RR: 1.07; 95% CI: 0.83 to 1.37), and sinusitis (RR: 0.89;
95% CI: 0.76 to 1.05).
LIMITATIONS: Lack of clearly defined criteria for respiratory infections and possible publication
bias.
CONCLUSIONS: Regular use of ICS may not increase the risk of pneumonia or other respiratory
infections in children with asthma.

aPostgraduate Program in Public Health, dPostgraduate Program in Health Science, and bFaculty of Medicine, Federal University of Rio Grande, Rio Grande, Brazil; and cDepartment of
Respiratory and Sleep Medicine, Lady Cilento Childrens Hospital and School of Medicine, The University of Queensland, Brisbane, Australia

Ms Cazeiro conceptualized and designed the study, participated in trial selection, quality assessment, data collection, data analysis and interpretation, and
drafted the protocol and the review article; Dr Silva, Ms Mayer, and Dr Mariany provided input for study conception and design, participated in trial selection,
quality assessment and data collection, and critically revised the manuscript; Dr Wainwright provided input for study conception and design and critically revised
the manuscript; Dr Zhang contributed to study conception and design, participated in trial selection, quality assessment, data collection, data analysis and
interpretation, and critically revised the review protocol and the manuscript; and all authors approved the nal manuscript as submitted.
DOI: 10.1542/peds.2016-3271

To cite: Cazeiro C, Silva C, Mayer S, et al. Inhaled Corticosteroids and Respiratory Infections in Children With Asthma: A Meta-analysis. Pediatrics. 2017;139(3):e20163271

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PEDIATRICS Volume 139, number 3, March 2017:e20163271 REVIEW ARTICLE
Inhaled corticosteroids (ICS) are link between use of ICS and the Central Register of Controlled Trials
widely used in the treatment of risk of other respiratory infections (CENTRAL), Literatura Latino-
asthma and chronic obstructive besides pneumonia in patients with Americana e do Caribe em Ciencias
pulmonary disease.1,2 They are asthma. Thus, we conducted this da Saude (LILACS), Scientific
generally considered safe and systematic review and meta-analysis Electronic Library OnLine (SciELO),
well tolerated in both adults and of randomized trials to assess the the Cochrane Library, and more than
children.3,4 However, recent studies association between regular use of 20 other databases.13 Reference lists
have raised concerns about increased ICS and risk of pneumonia, as well of primary studies and systematic
risk of pneumonia related to regular as other respiratory infections, reviews were screened for additional
use of ICS in adult patients with in children with asthma. We also relevant trials. We also conducted
chronic obstructive pulmonary investigated the potential effect searches on clinicaltrials.gov and the
disease.57 There have been few modifiers, such as drug molecules, databases of 2 main pharmaceutical
studies assessing the association daily doses, delivery devices, manufacturers of ICS (GSK and
between ICS and risk of pneumonia duration of treatment, and patients AstraZeneca) to identify unpublished
in patients with asthma. age. trials and to obtain unpublished
safety data of the trials.
The retrospective analysis of
individual patient data from 26 Study Selection
METHODS
AstraZeneca-sponsored randomized
trials revealed a reduced risk of We followed the recommendations To be included in this review,
pneumonia in patients (4 to 78 of the Preferred Reporting Items studies had to meet all of the
years) with asthma treated with for Systematic Reviews and Meta- following criteria: (1) study design:
budesonide.8 A recent meta-analysis Analyses statement11 for writing randomized controlled trials; (2)
of 10 randomized trials also revealed this systematic review. The participants: children up to 18 years
a protective effect of ICS against review protocol was registered old with diagnosis of asthma; (3)
pneumonia in patients with asthma.9 on PROSPERO (the International interventions and comparisons: daily
However, caution should be taken Prospective Register of Systemic use of ICS, delivered by any type of
in interpreting the results of this Reviews, CRD42015020656).12 inhalation device for at least 4 weeks,
review. Firstly, pneumonia and There are 2 differences between the compared with placebo delivered by
pneumonitis were used as the previously registered protocol and the same type of device; (4) outcome
search terms. Such search strategy this review: triamcinolone was measures: at least 1 of respiratory
might exclude a considerable added in addition as a search term, infections reported as adverse event.
number of relevant studies given that and 5 posthoc subgroup analyses and For this review, we defined clinically
pneumonia is not a well-established 2 posthoc sensitivity analyses were diagnosed pneumonia, with or
adverse event of ICS and is less likely also added. without radiological confirmation as
to be used as keyword or subject the primary outcome. The secondary
heading in clinical trials. Secondly, Search Strategy outcomes included other respiratory
the authors limited literature search infections, such as pharyngitis,
We searched PubMed from inception otitis media, sinusitis, bronchitis,
to adults, but the largest trial that
until May 2015 to identify clinical bronchiolitis, and influenza.
contributed with 83.1% of the
trials. The search strategy was as
weight included patients aged 5 to 66 We excluded cross-over trials,
follows: asthma AND (inhaled
years of age. No separate data were trials that compared ICS to other
corticosteroid OR inhaled steroid
available for pediatric patients. interventions without placebo, trials
OR beclomethasone OR budesonide
that used ICS plus other drugs, and
One recent study revealed an OR ciclesonide OR flunisolide
trials that included children but in
increased risk of oropharyngeal OR fluticasone OR mometasone
which pediatric patient data were not
colonization by Streptococcus OR triamcinolone). There was
identifiable.
pneumoniae in children with no restriction on language of
asthma regularly taking ICS.10 An publication. We also identified Four review authors (CC, CS, SM, VM),
increased microbial burden in the systematic reviews of randomized divided into 2 groups, independently
oropharyngeal area may lead to a trials that compared ICS with assessed the titles and abstracts of all
higher risk of respiratory infections, placebo, by searching PubMed and citations identified by the searches.
especially infections of neighborhood the Virtual Health Library of the We obtained the full articles when
sites such as pharyngitis, otitis Latin American and Caribbean Center they appeared to meet the inclusion
media, and sinusitis. Up until now, on Health Sciences Information, criteria or there were insufficient
no study has assessed the possible which contains Medline, Cochrane data in the title and abstract to make

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2 CAZEIRO et al
a clear decision for their inclusion. generally provide more detailed and over relative statistics (RR, OR) in
The definitive inclusion of trials was accurate information about drug that the RD is defined as zero when
made after reviewing the full-text adverse events. no events occur in either arm.14 Such
articles. Any disagreements about trials are therefore included in the
study selection were resolved by Assessment of Risk of Bias in pooled analysis.
discussion and, where necessary, a Included Studies
We assessed heterogeneity in results
senior reviewer (LZ) was consulted. Four reviewers (CC, CS, SM, VM) between trials by using the Cochrane
independently assessed the Q test (P < .1 considered significant)
Data Extraction and Management risk of bias in included trials by and the I2 statistic.15
examining the 6 key domains
Data from the included trials were according to the recommendations We conducted posthoc subgroup
extracted independently by 4 of the Cochrane Collaboration14: analyses on the basis of the type
review authors (CC, CS, SM, VM) (1) allocation sequence generation, of drugs, type of delivery devices
and cross-checked. A standardized (2) concealment of allocation, (metered-dose inhaler, dry powder
data extraction form was used to (3) blinding of participants and inhaler, nebulizer), duration of
extract the following data: (1) study investigators, (4) incomplete treatment (6 months, <6 months),
characteristics: year of publication, outcome data, (5) selective outcome patients age (<4 years, 4 to 18
country, and setting of study; (2) reporting, and (6) other sources of years), and data source (published
methods: study design, methods bias. We graded each potential source data, unpublished data). The 2 test
of random sequence generation, of bias as yes, no, or unclear, relating was used for subgroup comparison.
allocation concealment and to whether the potential for bias was To assess doseresponse effects of
blinding, description of withdrawal, low, high, or unknown. ICS, we conducted a meta-analysis
and adherence to treatment; (3) including only trials that compared
participants: sample size, age, sex, Any disagreements about assessment directly 2 or more daily doses. We
and inclusion and exclusion criteria; of risk of bias were resolved by conducted 2 posthoc sensitivity
(4) interventions: corticosteroid discussion and, where necessary, a analyses, excluding the trials in which
molecule, daily dose, interval senior reviewer (LZ) was consulted. adverse events were not collected by
of administration, duration of systematic assessment and the trials
treatment, drug delivery device, and
Data Synthesis and Statistical that contributed more than 50% of
Analysis the weight to the meta-analysis. All
cointerventions; (5) outcomes: we
extracted the number of participants We performed meta-analyses for meta-analyses were performed by
affected and the total number of quantitative data synthesis. The risk using Stata version 11.0 (Stata Corp,
participants in each treatment arm. ratios (RRs) and 95% confidence College Station, TX).
For trials that examined multiple intervals (CIs) were used to estimate
doses of ICS, we combined the active the risk of adverse events associated
treatment groups. Intention-to-treat with ICS. We used the random-effects RESULTS
(ITT) data sets were used whenever model for pooling RRs and 95%
Literature Search and Study
available. Given that it is likely that CIs, assuming that the patients and
Selection
outcomes for which no events occur interventions in clinical trials would
in either arm may not be mentioned have differed in ways that could The search strategy identified 2756
in reports of many randomized have impacted on the results, and unique records from PubMed. After
trials, we considered no events of therefore the trials would not share a screening the titles and abstracts,
pneumonia in both arms if the trial common effect size.14 For trials with we retrieved 227 potentially
had revealed at least 1 respiratory no events in 1 arm, 0.5 was added relevant full-text articles for further
infection event but not explicitly to each of the 4 cell counts of 2-by-2 evaluation. One hundred fifty-four
reported pneumonia. We obtained tables. Trials with no events in both articles were excluded for reasons
additional or unpublished safety arms were not included in the pooled shown in Fig 1. We identified 7
data through Clinical Trial Register analysis. Given that many outcomes unpublished trials from clinicaltrials.
(clinicaltrials.gov) and databases are rare events, we also undertook gov. Twelve additional trials were
of pharmaceutical manufacturers. meta-analyses by using Petos odds found by checking the reference
When there was inconsistency ratios (ORs) as effect size measure. lists of 9 systematic review articles.
between unpublished data and data For the primary outcome pneumonia, Thus, a total of 92 randomized
from published articles, we used we also used risk difference (RD) trials comparing ICS with placebo in
only unpublished data from above- as effect size measure because RD children with asthma were selected.
mentioned databases because they method appears to have advantage Thirty-seven trials did not reveal

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PEDIATRICS Volume 139, number 3, March 2017 3
safety data, and 16 trials did not
reveal respiratory infections as
adverse events. Thirty-nine trials1654
involving 13595 (8945 ICS-treated,
4650 placebo) children with
persistent asthma were therefore
included in the review. Thirty-
one trials1646 involving 11615
participants (7465 ICS-treated, 4150
placebo) contributed data to the
meta-analyses.

Study Characteristics and Risk of


Bias
Table 1 summarizes the
characteristics of the 39 included
trials. Thirty-two were published
trials,1639,4754 but unpublished
safety data were obtained through
clinicaltrials.gov and databases of
pharmaceutical manufacturers in
7 trials.16,20,23,26,27,30,39 Seven were
unpublished trials identified through
clinicaltrials.gov.4046 All 39 studies
were randomized, double-blind,
placebo-controlled trials. Thirty-
five1620,2235,3746 were multicenter
trials. Only 6 trials1618,3537 were
designed to assess the safety of ICS,
whereas the remaining 33 trials aimed
mainly to assess the efficacy of ICS.
All but 4 trials24,28,48,50 were industry
funded. Five ICS (beclomethasone,
budesonide, ciclesonide, fluticasone,
and mometasone) given at low or
FIGURE 1
medium daily doses were used. Flow diagram of study selection.
Duration of intervention varied
from 4 weeks to 3 years. Adverse as ITT or quasi-ITT population was revealed at least 1 event of
events were collected by used for calculating rate of adverse pneumonia. The meta-analysis of 9
systematic assessment in 29 events in all 31 trials that contributed trials revealed that ICS significantly
trials,16,18,20,2225,2939,4143,4547,5054 but data to the meta-analyses. Given that reduced the risk of pneumonia
none of the trials explicitly defined the respiratory infections are not well- compared with placebo (RR: 0.65,
criteria for diagnosis of pneumonia established adverse events of ICS, 95% CI: 0.44 to 0.94, P = .02, I2 = 0%;
and other respiratory infections. All underreporting of some respiratory Petos OR: 0.63, 95% CI: 0.43 to 0.93,
39 trials were stated as randomized; infection outcomes might occur. We
however, only 9 published P = .02, I2 = 22.1%; Table 2). Posthoc
rated the risk of outcome reporting subgroup analyses did not reveal
trials18,20,28,29,31,33,35,50,51 described bias as high in the 3 trials21,28,35
the methods for random sequence significant effects of drug molecules,
because only 1 type of respiratory
generation and 228,35 described the delivery devices, treatment duration,
infection was reported.
methods for allocation concealment patients age, and data source on the
(Supplemental Table 4). The risk of size of risk of pneumonia related to
Use of ICS and Risk of Pneumonia
performance and detection bias was ICS (Table 3). The posthoc sensitivity
low in all 39 trials because matching Nine trials23,27,30,38,40,41,43,44,46 analysis excluding 1 trial38 that
placebos were used for blinding. The involving a total of 4617 participants contributed more than 50% of
risk of attrition bias was also low (2684 ICS-treated, 1933 placebo) the weight revealed no significant

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4 CAZEIRO et al
TABLE 1 Characteristics of Included Trials
Study ID, Country, Sponsor Participants Study Design Intervention and Control Primary Outcome Adverse Event Outcomes
RTI Reported Systematic Data
Collection
Allen et al 1998,16 USA, GSK Patients aged 4 to 11 y with persistent asthma 52-wk, multicenter, RDBPCT Fluticasone 100, 200 g/d, DPI Growth velocity, height Yes Yes
(ATS criteria) (FLD-220 trial) (n = 219)
Placebo, DPI (n = 106)
Baker et al 1999,47 USA, Patients aged 6 mo to 11 y with moderate 12-wk, multicenter, RDBPCT Budesonide 0.25, 0.5, 1.0 mg/d, Symptom score No Yes
AstraZeneca persistent asthma nebulizer (n = 386); Placebo,
nebulizer (n = 95)
Becker et al 2006,17 Boys (6.4 to 9.4 y) and girls (6.4 to 8.4 y) at 56-wk, multicenter, RDBPCT Beclomethasone 400 g/d, MDI Growth velocity, height Yes Unclear
USA, Canada, Hong Tanner stage I with mild persistent asthma (n = 119); Placebo, MDI (n = 121)
Kong, South Africa, (GINA criteria)

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7 countries in Latin
America, Merck
Berger et al 2005,18 USA, Infants aged 6 to 12 mo with mild to moderate 12-wk, multicenter, RDBPCT Budesonide 0.5, 1.0 mg/d, nebulizer Adrenal function Yes Yes
AstraZeneca persistent asthma or recurrent wheeze (n = 92); Placebo, nebulizer
(n = 49)
Berger et al 2006,19 USA, Children 4 to 11 y with persistent asthma 12-wk, multicenter, RDBPCT Mometasone 100, 200 g/d, DPI FEV1 Yes Unclear
Schering-Plough (n = 197); Placebo, DPI (n = 99)
Carlsen et al 2005,20 Children aged 12 to 47 mo with recurrent/ 12-wk, multicenter, RDBPCT Fluticasone 200 g/d, MDI (n = 79); Symptom-free Yes Yes
Australia, Canada, persistent asthma symptoms (FAS30007 trial) Placebo, MDI (n = 81)
Germany, Greece,
Italy, Latvia, Lithuania,
Norway, UK, GSK
Connett et al 1993,48 UK Children aged 1 to 3 y with persistent asthma 12-wk, unicenter, RDBPCT Budesonide 200 g/d, MDI (n = 20); Symptom score No Unclear
symptoms Placebo, MDI (n = 20)
de Blic et al 1996,21 France, Infants aged 6 to 30 mo with severe asthma 12-wk, unicenter, RDBPCT Budesonide 2 mg/d, nebulizer (n = Asthma exacerbations Yes Unclear
AstraZeneca 20); Placebo, nebulizer (n = 18)
FLTA2007 trial 2005,40 USA, Children aged 4 to 11 y with chronic asthma 12-wk, multicenter, RDBPCT Fluticasone 100 g/d, DPI (n = 179); FEV1, PEF Yes Unclear
GSK (ATS criteria) Placebo, DPI (n = 83)

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FMS30059 trial 2005,46 Children aged 6 to 23 mo with asthma 12-wk, multicenter, RDBPCT Fluticasone 100, 200 g/d, MDI (n = PEF Yes Yes
USA, Puerto Rico, Chile, 142) ; Placebo, MDI (n = 69)
GSK
Gelfand et al 2006,22 USA, Children aged 4 to 11 y with persistent asthma 12-wk, multicenter, RDBPCT Ciclesonide 40, 80, 160 g/d, MDI FEV1 Yes Yes
Aventis (NIH criteria) (n = 768); Placebo, MDI (n = 257)
Hofstra et al 2000,49 The Children aged 6 to 14 y with asthma 6-wk, multicenter, RDBPCT Fluticasone 200, 500 g/d, MDI Lung function No Unclear
Netherlands, GSK (n = 25) Placebo, MDI (n = 12) measurements
Jnasson et al 1998,50 Patients aged 7 to 16 y with mild asthma 12-wk, unicenter, RDBPCT Budesonide 100, 200 g/d, DPI (n = Lung function No Yes
Norway 123); Placebo, DPI (n = 40) measurements
Katz et al 1998,23 Finland, Patients aged 1 to 5 y with persistent asthma 12-wk, multicenter, RDBPCT Fluticasone 100, 200 g/d, DPI PEF Yes Yes
France, Hong Kong, (FLIT85 trial) (n = 171) Placebo, DPI (n = 92)
Israel, Italy, Portugal,
Singapore, Spain, United
Arab Emirates, GSK

5
6
TABLE 1 Continued
Study ID, Country, Sponsor Participants Study Design Intervention and Control Primary Outcome Adverse Event Outcomes
RTI Reported Systematic Data
Collection
Kerwin et al 2008,51 Patients 6 to 17 y with mild asthma 12-wk, multicenter, RDBPCT Budesonide 180, 200, 720, 800 g/d, FEV1 No Yes
Indonesia, Philippines, DPI (n = 410); Placebo, DPI
Thailand, Singapore, (n = 106)
USA, AstraZeneca
Kooi et al 2008,24 The Children aged 2 to 5 y with asthmalike 6-mo, multicenter, RDBPCT Fluticasone 200 g/d, MDI (n = 25); Symptom score Yes Yes
Netherlands symptoms Placebo, MDI (n = 20)
LaForce et al 2000,25 USA, Children aged 4 to 11 y with persistent asthma 12-wk, multicenter, RDBPCT Fluticasone 200 g/d, DPI (n = 164); FEV1, PEF Yes Yes
GSK Placebo, DPI (n = 78)
Levy et al 2006,26 USA, GSK Children aged 4 to 11 y with 6-mo history of 12-wk, multicenter, RDBPCT Fluticasone 200 g/d, MDI (n = PEF Yes Unclear
asthma requiring pharmacotherapy (FAP30010 trial) 160); Placebo, MDI (n = 81)
MacKenzie et al 1993,27 Children aged 6 to 12 y with asthma 4-wk, multicenter, RDBPCT Fluticasone 100 g/d, DPI (n = 128); Symptom score Yes Unclear
Austria, Belgium, (FLIP20 trial) Placebo, DPI (n = 130)
Finland, Germany,
Greece, Ireland, Israel,
Italy, the Netherlands,
Norway, South Africa,
UK, GSK
Martinez et al 2011,28 USA Patients aged 5 to 18 y with mild persistent 44-wk, multicenter, RDBPCT Beclomethasone 100 g/d, MDI (n = PEF Yes Unclear
asthma (US NAEPP criteria) (NCT00394329 trial) 72); Placebo, MDI (n = 74)
Nayak et al 2002,29 USA, 3M Children aged 5 to 12 y with moderate 12-wk, multicenter, RDBPCT Beclomethasone 100, 200 g/d, MDI FEV1 Yes Yes
Pharmaceuticals symptomatic asthma (n = 237); Placebo, MDI (n = 116)
NCT00163293 trial 2012,41 Children aged 4 to 11 y with mild persistent 12-mo, multicenter, RDBPCT Ciclesonide 200, 400 g/d, MDI (n = Asthma exacerbations Yes Yes
Canada, Hungary, South asthma. 155); Placebo, MDI (n = 85)
Africa, Takeda
NCT00392288 trial 2012,42 Children aged 4 to <12 y with persistent 12-wk, multicenter, RDBPCT Ciclesonide 100, 200 g/d, MDI (n = FEV1 Yes Yes
USA, Hungary, Mexico, asthma 349); Placebo, MDI (n = 172)
Poland, Russian
Federation, South

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Africa, Nycomed, Sano
NCT00569192 trial 2013,43 Children aged 12 mo to 8 y with mild to 12-wk, multicenter, RDBPCT Budesonide 0.27, 0.50 mg/d, Symptom score Yes Yes
India, Allergan moderate persistent asthma (NIH criteria) nebulizer (n = 246); Placebo,
nebulizer (n = 110)
NCT00920959 trial, 2013,44 Children were aged between 4 and 11 y with 12-wk, multicenter, RDBPCT Fluticasone 100 g/d, DPI (n = 304); PEF Yes Unclear
USA, 11 centers in Latin asthma Placebo, DPI (n = 300)
America, GSK
NCT01136382 trial 2014,45 Children aged 6 to <12 y with asthma 6-wk, multicenter, RDBPCT Budesonide 400 g/d, MDI (n = PEF Yes Yes
USA, Bulgaria, Hungary, 152); Placebo, MDI (n = 152)
Latvia, Poland, Romania,
Slovakia, South Africa,
AstraZeneca
Peden et al 1998,30 USA, Children aged 4 to 11 y with persistent asthma 12-wk, multicenter, RDBPCT Fluticasone 100, 200 g/d, DPI FEV1, PEF Yes Yes
GSK (ATS criteria) (FLTA2006 trial) (n = 351) Placebo, DPI (n = 86)

CAZEIRO et al
TABLE 1 Continued
Study ID, Country, Sponsor Participants Study Design Intervention and Control Primary Outcome Adverse Event Outcomes
RTI Reported Systematic Data
Collection
Pedersen et al 2010,31 Children aged 6 to 11 y with persistent asthma 12-wk, multicenter, RDBPCT Ciclesonide 50, 100, 200 g/d, MDI PEF Yes Yes
Bulgaria, Germany, (RAINBOW trial) (n = 930); Placebo, MDI (n = 150)
Hungary, Poland,
Romania, Russia, South
Africa, Spain, Ukraine,
Nycomed
Qaqundah et al 2006,32 Children aged 1 to <4 y with asthma 12-wk, multicenter, RDBPCT Fluticasone 200 g/d, MDI (n = Symptom score Yes Yes
Argentina, Chile, USA, 239); Placebo, MDI (n = 120)
GSK

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Schokker et al 2008,33 Children 1 to 5 y with asthmalike symptoms 6-mo, multicenter, RDBPCT Fluticasone 200 g/d, MDI (n = 48); Symptom score Yes Yes
The Netherland, (ASTERISK trial) Placebo, MDI (n = 48)
GSK and Stichting
Astmabestrijding
Shapiro et al 1998,52 USA, Children aged 6 to 18 y with moderate to severe 12-wk, multicenter, RDBPCT Budesonide 100, 200, 400 g/d, DPI PEF, FEV1 No Yes
AstraZeneca persistent asthma (n = 301); Placebo, DPI (n = 103)
Shapiro et al 1998,53 USA, Children aged 4 to 8 y with persistent asthma 12-wk, multicenter, RDBPCT Budesonide 0.5, 1.0, 2.0 mg/d, Symptom score No Yes
AstraZeneca (NHI criteria) nebulizer (n = 134); Placebo,
nebulizer (n = 44)
Shapiro et al 2001,34 USA, Children aged 6 to 17 y with persistent asthma 12-wk, multicenter, RDBPCT Budesonide 200, 400 g/d, DPI (n = FEV1 Yes Yes
AstraZeneca (ATS criteria) 183); Placebo, DPI (n = 91)
Silverman et al 2006,38 UK Children aged 5 to 10 y with mild persistent 3-y, multicenter, RDBPCT Budesonide 200 g/d, DPI (n = Severe asthma-related Yes Yes
and other 31 countries asthma (START trial) 1004); Placebo, DPI (n = 977) event
throughout the world,
AstraZeneca
Simons 1997,54 Canada, Children aged 6 to 14 y with asthma 1-y, multicenter, RDBPCT Beclomethasone 400 g/d, DPI (n = Airway responsiveness No Yes
GSK 81); Placebo, DPI (n = 80)
Skoner et al 2008,35 Children aged 5 to 18 y with mild persistent 1-y, multicenter, RDBPCT Ciclesonide 50, 100 g/d, MDI (n = Growth velocity Yes Yes
Argentina, Chile, USA, asthma 440); Placebo, MDI (n = 221)

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Venezuela, Sano-
aventis, Altana Pharma
US, Nycomed
Skoner et al 2010,36 USA, Children aged 6 to 11 y with mild asthma 4-wk, unicenter, RDBPCT Mometasone 200, 400, 800 g/d, DPI Plasma cortisol Yes Yes
Schering-Plough (n = 38); Placebo, DPI (n = 12)
Skoner et al 2011,37 USA, Children aged 4 to 9 y with mild persistent 52-wk, multicenter, RDBPCT Mometasone 100, 200 g/d, DPI Growth velocity Yes Yes
Merck asthma (n = 142); Placebo, DPI (n = 45)
Wasserman et al 2006,39 Children aged 2 to 4 y with asthma requiring 12-wk, multicenter, RDBPCT Fluticasone 100, 200 g/d, MDI (n = Symptom score Yes Yes
USA, GSK regular maintenance therapy (FMS30058 trial) 219); Placebo, MDI (n = 113)
ATS, American Thoracic Society; DPI, dry powder inhaler; FEV1, forced expiratory volume in the rst second; GINA, global initiative for asthma; MDI, metered-dose inhaler; NAEPP, National Asthma Education and Prevention Program; NIH, National
Institutes of Health; PEF, peak expiratory ow; RDBPCT, randomized double-blind placebo controlled trial; RTI, respiratory tract infection.

7
TABLE 2 Risk of Pneumonia Associated With Use of ICS in Children With Asthma Using RD as effect estimate, we
Study ID Participants Affected/ Treatment Effect (95% CI) conducted the meta-analysis including
Participants Randomly all 31 trials that revealed at least 1
Assigned respiratory infection event. Twenty-
ICS Placebo RR Petos OR RD three trials1622,2426,28,29,3137,39,42,45,46
Allen et al 199816 0/219 0/106 UC UC 0 (0.01 to 0.01) did not explicitly reveal pneumonia as
Becker et al 200617 0/119 0/121 UC UC 0 (0.02 to 0.02) adverse events, and we considered no
Berger et al 200518 0/92 0/49 UC UC 0 (0.03 to 0.03) events of pneumonia in both treatment
Berger et al 200619 0/197 0/99 UC UC 0 (0.02 to 0.02) arms. Thus, 44 patients in the
Carlsen et al 200520 0/79 0/81 UC UC 0 (0.02 to 0.02)
de Blic et al 199621 0/20 0/18 UC UC 0 (0.09 to 0.09)
corticosteroid group (44/7465, 0.58%)
FLTA2007 200540 0/179 2/83 0.09 (0.01 to 0.04 (0.002 to 0.024 (0.06 to 0.01) and 63 patients in the placebo group
1.92) 0.83) (63/4150, 1.51%) had pneumonia
FMS30059 200546 2/142 0/69 2.45 (0.12 to 4.45 (0.23 to 0.01 (0.02 to 0.04) as adverse events. The summary RD
50.29) 85.99)
between the corticosteroid and placebo
Gelfand et al 200622 0/764 0/254 UC UC 0 (0.01 to 0.01)
Katz et al 199823 1/172 0/93 1.63 (0.07 to 4.67 (0.08 to 0.01 (0.01 to 0.03) groups was 0.1% (95% CI: 0.3% to
39.62) 283.50) 0.2%, P = .72, I2 = 0%; Table 2). The
Kooi et al 200824 0/25 0/20 UC UC 0 (0.08 to 0.08) posthoc sensitivity analysis excluding
LaForce et al 0/164 0/78 UC UC 0 (0.02 to 0.02) 8 trials17,19,21,2628,40,44 in which
200025
adverse events were not collected by
Levy et al 200626 0/160 0/81 UC UC 0 (0.02 to 0.02)
Mackenzie et al 0/128 3/130 0.15 (0.01 to 0.14 (0.01 to 0.02 (0.05 to 0.01) systematic assessment yielded the
199327 2.78) 1.31) similar results.
Martinez et al 0/143 0/74 UC UC 0 (0.02 to 0.02)
201128 Use of ICS and Risk of Other
NCT00163293 1/155 0/84 1.64 (0.07 to 4.67 (0.07 to 0.01 (0.02 to 0.03) Respiratory Infections
201241 39.69) 283.50)
Figure 2 reveals the results of meta-
NCT00392288 0/174 0/172 UC UC 0 (0.01 to 0.01)
201242 analyses of secondary outcomesother
NCT00569192 1/249 0/111 1.34 (0.06 to 4.25 (0.06 to 0.004 (0.01 to 0.02) respiratory infections. No significant
201343 32.74) 295.90) association was found between use of
NCT00920959 0/304 1/300 0.33 (0.01 to 0.13 (0.003 to 0.003 (0.01 to 0.01) ICS and risk of pharyngitis (23
201344 8.04) 6.73)
trials,16,1820,22,23,26,27,29,31,3342,4446
NCT01136382 0/152 0/152 UC UC 0 (0.01 to 0.01)
201445 RR: 1.01, 95% CI: 0.87 to
Nayak et al 200229 0/237 0116 UC UC 0 (0.01 to 0.01) 1.18, I2 = 19%), otitis media
Peden et al 199830 1/351 0/86 0.74 (0.03 to 3.48 (0.03 to 0.003 (0.01 to 0.02) (17 trials,16,1820,23,26,27,30,32,33,3741,44,46
18.05) 480.40) RR: 1.07, 95% CI: 0.83 to 1.37,
Pedersen et al 0/927 0/146 UC UC 0 (0.01 to 0.01)
201031
I2 = 34.2%), sinusitis (15
Qaqundah et al 0/239 0/120 UC UC 0 (0.01 to 0.01) trials,16,18,22,25,26,29,30,34,3741,44,46 RR:
200632 0.89, 95% CI: 0.76 to 1.05, I2 = 0%),
Schokker et al 0/48 0/48 UC UC 0 (0.04 to 0.04) bronchitis (9 trials,16,23,27,28,32,3739,46
200833 RR: 0.89, 95% CI: 0.75 to 1.05, I2 =
Shapiro et al 0/183 0/91 UC UC 0 (0.02 to 0.02)
200134
0%), and influenza (4 trials,16,23,41,45
Silverman et al 38/1004 57/977 0.65 (0.43 to 0.64 (0.43 to 0.02 (0.04 to RR: 1.12, 95% CI: 0.65 to 1.93, I2 =
200638 0.97) 0.96) 0.00) 0%). Posthoc subgroup analyses did
Skoner et al 200835 0/440 0/221 UC UC 0 (0.01 to 0.01) not reveal significant effects of drug
Skoner et al 201036 0/38 0/12 UC UC 0 (0.11 to 0.11) molecules, delivery devices, treatment
Skoner et al 201137 0/142 0/45 UC UC 0 (0.03 to 0.03)
Wasserman et al 0/219 0/113 UC UC 0 (0.01 to 0.01)
duration, patients age, and data source
200639 on the treatment effect size of ICS
All trials combined 44/7465 63/4150 0.65 (0.44 to 0.63 (0.43 to 0.001 (0.003 to (Table 3).
0.94) 0.93) 0.002)
Use of ICS and Risk of Respiratory
UC, unable to calculate using RR and Petos OR because no events in either group.
Infections: DoseResponse
Relationship
association between use of ICS and sensitivity analysis, excluding 3
risk of pneumonia (RR: 0.62, 95% CI: trials27,40,44 in which adverse events Seventeen trials16,18,19,22,23,2931,
0.21 to 1.86, P = .39, I2 = 0%; Petos were not collected by systematic 3437,39,4143,46 in which 2 or more

OR: 0.57, 95% CI: 0.17 to 1.89, P = assessment did not significantly daily doses of ICS were compared
.36, I2 = 31.6%). In another posthoc change the results. had contributed data to the

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8 CAZEIRO et al
TABLE 3 Risk of Respiratory Infections Associated With Use of ICS in Children With Asthma: Subgroup Analyses
Subgroups Pneumonia Bronchitis Otitis media Sinusitis Pharyngitis Upper Respiratory
Infection
RR (95% CI) Trial, RR (95% CI) Trial, n RR (95% CI) Trial, n RR (95% CI) Trial, n RR (95% CI) Trial, RR (95% CI) Trial, n
n n
Type of ICS P = .71* P = .94 P = .80 P = .61 P = .11 P = .65
Beclomethasone 0 1.56 (0.06 to 37.89) 1 0 1.96 (0.22 to 17.32) 1 0.83 (0.43 to 1.59) 1 1.09 (0.73 to 1
1.64)
Fluticasone 0.43 (0.11 to 1.71) 5 0.88 (0.74 to 1.04) 6 1.12 (0.76 to 1.64) 12 0.84 (0.65 to 1.08) 7 1.42 (1.01 to 1.84) 10 1.09 (0.93 to 13
1.27)
Budesonide 0.66 (0.44 to 0.97) 3 1.14 (0.45 to 2.90) 1 1.08 (0.86 to 1.34) 2 0.96 (0.56 to 1.65) 3 0.93 (0.82 to 1.06) 4 0.87 (0.60 to 5
1.27)
Mometasone 0 0.90 (0.27 to 3.02) 1 0.72 (0.11 to 4.76) 2 1.45 (0.66 to 3.18) 2 0.92 (0.61 to 1.40) 3 0.90 (0.69 to 2

PEDIATRICS Volume 139, number 3, March 2017


1.18)
Ciclesonide 1.64 (0.07 to 39.69) 1 0 2.17 (0.47 to 9.98) 1 1.08 (0.68 to 1.72) 2 0.83 (0.56 to 1.22) 5 0.94 (0.61 to 4
1.44)
Type of devices P = .52 P = .92 P = .21 P = .69 P = .61 P = .87
MDI 2.02 (0.23 to 18.41) 2 0.86 (0.45 to 1.63) 4 1.57 (0.94 to 2.60) 7 0.97 (0.59 to 1.61) 6 0.91 (0.67 to 1.22) 12 1.00 (0.83 to 13
1.21)
DPI 0.62 (0.42 to 0.91) 6 0.89 (0.75 to 1.06) 5 0.92 (0.63 to 1.36) 9 0.86 (0.72 to 1.03) 8 1.00 (0.89 to 1.12) 10 1.02 (0.88 to 9
1.20)
Nebulizer 1.34 (0.06 to 32.74) 1 0 0.93 (0.61 to 1.43) 1 1.33 (0.44 to 4.03) 1 1.86 (0.40 to 8.63) 1 0.87 (0.50 to 3
1.53)
Duration of P = .75 P = .85 P = .54 P = .32 P = .72 P = .93
treatment
<6 mo 0.54 (0.17 to 1.76) 7 0.84 (0.47 to 1.48) 5 1.00 (0.66 to 1.52) 12 0.79 (0.63 to 1.06) 4 0.98 (0.76 to 1.27) 18 1.01 (0.87 to 21
1.17)
6 mo 0.66 (0.44 to 0.98) 2 0.89 (0.75 to 1.06) 4 1.16 (0.93 to 1.44) 5 1.20 (0.89 to 1.61) 11 1.04 (0.85 to 1.26) 5 1.00 (0.84 to 4
1.20)
Patients age P = .38 P = .87 P = .97 P = .60 P = .25 P = .66
<4 y 2.45 (0.12 to 50.29) 1 0.84 (0.43 to 1.61) 3 1.04 (0.78 to 1.39) 5 1.06 (0.57 to 1.97) 3 1.68 (0.70 to 3.97) 5 1.08 (0.78 to 5

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1.49)
4 to 18 y 0.63 (0.43 to 0.92) 8 0.89 (0.75 to 1.06) 6 1.05 (0.73 to 1.52) 12 0.89 (0.74 to 1.07) 12 1.00 (0.85 to 1.15) 18 1.00 (0.88 to 20
1.12)
Data source P = .94 P = .84 P = .66 P = .84 P = .51 P = .74
Published 0.64 (0.43 to 0.95) 4 0.89 (0.74 to 1.08) 4 1.15 (0.78 to 1.69) 6 0.94 (0.76 to 1.16) 7 0.94 (0.84 to 1.06) 11 0.99 (0.82 to 11
1.19)
Unpublished 0.68 (0.17 to 2.78) 5 0.85 (0.57 to 1.26) 5 1.01 (0.68 to 1.50) 10 0.90 (0.62 to 1.29) 8 1.07 (0.74 to 1.51) 12 1.03 (0.89 to 14
1.19)
DPI, dry powder inhaler; MDI, metered-dose inhaler. , no data.
* P value for subgroup comparison using 2 test.

9
FIGURE 2
Use of ICS and risk of other respiratory infections. RR > 1 favors placebo, suggesting a higher risk of respiratory infections in the ICS group. Weights are
from random effects analysis. ES, effect size; RTI, respiratory tract infection. a Rate: cases/participants at risk.

meta-analyses. Five trials16,23,30,39,46 associated with lower risk of otitis of pneumonia. The meta-analysis of
used fluticasone (100 vs 200 g/ media (9 trials, RR: 0.73, 95% CI: 9 trials using RR as effect measure
day), 3 trials18,34,43 used budesonide 0.57 to 0.93, I2 = 0%). reveals that use of ICS could result
(200 to 500 vs 400 to 1000 g/ in a 35% reduction in the risk of
day), 1 trial29 used beclomethasone pneumonia when compared with
(100 vs 200 g/day), 3 trials19,36,37 DISCUSSION placebo. The meta-analysis using
used mometasone (100 vs 200 g/ Petos OR as effect measure yields
This systematic review and meta-
day), and 5 trials22,31,35,41,42 used a similar result. These results are
analysis of randomized trials suggests
ciclesonide (50 to 100 vs 100 to 200 consistent with those found in a
that regular use of ICS is unlikely
g/day). Three trials compared 3 meta-analysis9 of 10 trials in which
to increase the risk of pneumonia
daily doses, of which 2 trials22,31 the majority of participants were
or other respiratory infections in
used ciclesonide (50, 100, and adults with asthma. However, caution
children with asthma. Drug molecules,
200 g/day), and 1 trial36 used daily doses, delivery devices, should be taken when interpreting
mometasone (200, 400, and 800 g/ treatment duration, and patients age these results. Firstly, meta-analysis
day). In these 3 trials, we combined appear to have no significant impact may overestimate the incidence of
2 higher doses into a single group. on the size of risk of respiratory pneumonia if excluding the trials in
The meta-analyses did not reveal infections related to use of ICS. which no events of pneumonia were
a significant doseresponse reported in either arm. Secondly,
relationship between ICS and risk In this review, we used 2 data sets 1 trial38 contributed with 89% of
of respiratory infections (Fig 3). and 3 different effect size measures the weight to the meta-analysis
Moreover, an inverse relationship (RR, Petos OR, and RD) to estimate and the results were no longer
was observed between dose of ICS the risk of pneumonia due to ICS. statistically significant when this
and risk of otitis media, that is, The first data set includes only 9 trial was excluded in the sensitivity
higher dose of ICS was significantly trials that revealed at least 1 event analysis. However, exclusion

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10 CAZEIRO et al
FIGURE 3
Use of ICS and risk of respiratory infections: doseresponse relationship. RR > 1 favors lower doses, suggesting a greater risk of respiratory infections
in subgroup higher doses. Weights are from random effects analysis. ES, effect size; RTI, respiratory tract infection.

of this trial changed the upper arms if pneumonia had not been that the method used for dealing with
limit of 95% CI from 0.94 to 1.86, explicitly reported. The rationale possibly no events in both arms is
suggesting a potential increase of for this strategy is that no events of not yet validated, but no other better
risk of pneumonia on the basis of pneumonia in either treatment arm method is currently available.
the results of smaller trials. Thirdly, were likely not to be mentioned in
asthma exacerbations could be easily the trial reports because the majority ICS may affect local immunity
misclassified as pneumonia given of trials were designed to assess the and microbial community in the
the lack of clearly defined criteria for efficacy of ICS and pneumonia was respiratory tract.55 One cross-
pneumonia in the trials and similar rarely considered an a priori safety sectional study demonstrates that
clinical manifestations between end point. children with asthma regularly taking
pneumonia and asthma exacerbation. ICS are almost 4 times more likely
On the other hand, if the trial to have oropharyngeal colonization
The second data set consists of all revealed at least 1 respiratory by S pneumoniae than those not
31 trials that revealed at least 1 infection event, it is unlikely taking such drugs when adjusted
respiratory infection event, even that pneumonia, a more severe for potential confounders.10 It could
if pneumonia was not explicitly respiratory infection, could be be expected that children with an
mentioned. Using RD as effect ignored. Taking all together, we increased microbial burden in the
measure, the meta-analysis of believe that the meta-analysis on the oropharyngeal area may be at higher
31 trials reveals no significant basis of second data set may provide risk for respiratory infections, not
association between use of ICS more accurate estimates, suggesting only pneumonia but also other
and risk of pneumonia in children no significant association between respiratory infections. However,
with asthma. In this database, use of ICS and risk of pneumonia in this systematic review does not
we considered no events in both children with asthma. We recognize find a significantly increased risk

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PEDIATRICS Volume 139, number 3, March 2017 11
of other respiratory infections occur equally in both treatment arms. an effect. Use of antibiotic and
such as pharyngitis, otitis media, To minimize outcome reporting bias, oral steroids may have acted as
sinusitis, bronchitis, and influenza we obtained additional data for 7 a potential confounder because
in children with asthma taking ICS. published trials through clinicaltrials. patients taking placebo were more
These findings suggest that impaired gov. Another inherent methodological likely to receive these medications
local immunity and increased shortcoming of primary trials is than those taking ICS due to poorer
oropharyngeal bacterial colonization lack of clearly defined criteria for asthma control. Unfortunately, there
related to use of ICS may not be diagnosis of respiratory infections was no available data from the trials
associated with an increased risk and this should be considered as the to assess the effect of potential
of respiratory infections in children other main limitation of this review. confounding.
with asthma. Publication bias is always a concern The quality of evidence provided
We also explored other potential in meta-analysis and there is no by this systematic review could
effect modifiers through subgroup standard method for detecting it.56 be graded only as low for primary
analyses, and we did not find To minimize the potential publication outcome (pneumonia) and moderate
significant impact of drug molecules, bias, we have attempted to identify for secondary outcomes (other
delivery devices, treatment duration, the maximum number as possible respiratory infections), according to
and patients age on the effect size of of published and unpublished trials the Grading of Recommendations,
ICS. through the following strategies: Assessment, Development and
building an effective search strategy Evaluations57 criteria (Supplemental
The meta-analysis of 17 trials that by using only 2 types of search terms
compared different doses of ICS Table 5). Further prospective
(asthma and inhaled corticosteroids); studies examining the safety of ICS
does not reveal a doseresponse checking the references of retrieved
relationship between ICS and risk in children with asthma including
articles including systematic reviews well-defined pneumonia and other
of respiratory infections in children to find additional relevant trials;
with asthma. However, only low to respiratory infections as a priori
searching clinicaltrials.gov and the outcomes are still needed.
medium doses of ICS were used in databases of GSK and AstraZeneca
the trials. to identify unpublished trials.
Most of the included trials did not Moreover, the subgroup analysis CONCLUSIONS
describe the methods for random on the basis of data source did not The evidence provided by this
sequence generation and allocation find significant difference in the systematic review suggests that
concealment. This may raise a results between published and regular use of ICS is unlikely to
concern about the potential selection unpublished data, suggesting that increase the risk of pneumonia
bias. However, these potential biases the potential publication bias might or other respiratory infections in
may have no significant impact on the not substantially affect the results of children with asthma. These data add
trial results given that the baseline the review. Given that this review did to the already considerable body of
characteristics were similar between not include trials that used ICS plus evidence suggesting a good safety
treatment groups in all included other drugs, caution should be taken profile of ICS in children with asthma.
trials. Underreporting of adverse when extrapolating the findings of
events of treatment is common this review to patients taking ICS plus
in clinical trials. This inherent long-acting 2 agonist or other drugs. ABBREVIATIONS
methodological shortcoming of Children aged 12 to 16 through 18
CI:confidence interval
primary trials is the main limitation years might be underrepresented
ICS:inhaled corticosteroids
of all systematic review of safety because only 6 trials of this review
ITT:intention-to-treat
data. It may underestimate the rate included children in this age group.
OR:odds ratio
of adverse events; however, the risk Some posthoc subgroup analyses
RD:risk difference
estimation could not be substantially and meta-analysis of doseresponse
RR:risk ratio
affected because underreporting may might be underpowered to detect

Accepted for publication Dec 2, 2016


Address correspondence to Linjie Zhang, MD, PhD, Associate Professor, Faculty of Medicine, Federal University of Rio Grande, Rua Visconde de Paranagua 102,
Centro, Rio Grande-RS, Brazil. E-mail: lzhang@furg.br
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2017 by the American Academy of Pediatrics

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12 CAZEIRO et al
FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr Wainwright declared the following relationships/conditions/circumstances that may present a potential conict of
interest: income on a per patient basis derived from pharmaceutical studies (Vertex Pharmaceuticals, Inc; Boehringer Ingelheim; and Ablynx NV); epidemiological
research support from GlaxoSmithKline (analysis of bronchoalveolar lavage [BAL] uid from children with respiratory disorders, 20102012); research grant
from Novo Nordisk Pharmaceuticals P/L- CF-IDEA Study, 20122013; and honorarium and travel reimbursement from Vertex Pharmaceuticals, Inc, Gilead Sciences,
Inc, Medscape, and Novartis Pharmaceuticals; the other authors have indicated they have no potential conicts of interest to disclose.

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PEDIATRICS Volume 139, number 3, March 2017 15
Inhaled Corticosteroids and Respiratory Infections in Children With Asthma: A
Meta-analysis
Cristine Cazeiro, Cristina Silva, Susana Mayer, Vanessa Mariany, Claire Elizabeth
Wainwright and Linjie Zhang
Pediatrics 2017;139;; originally published online February 24, 2017;
DOI: 10.1542/peds.2016-3271
Updated Information & including high resolution figures, can be found at:
Services /content/139/3/e20163271.full.html
Supplementary Material Supplementary material can be found at:
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at:
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Asthma
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly


publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2017 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Inhaled Corticosteroids and Respiratory Infections in Children With Asthma: A
Meta-analysis
Cristine Cazeiro, Cristina Silva, Susana Mayer, Vanessa Mariany, Claire Elizabeth
Wainwright and Linjie Zhang
Pediatrics 2017;139;; originally published online February 24, 2017;
DOI: 10.1542/peds.2016-3271

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/139/3/e20163271.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly


publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2017 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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