Preventing Exacerbations in

Preschoolers With Recurrent

Wheeze: A Meta-analysis
Sunitha V. Kaiser, MD, MSc,a Tram Huynh,b Leonard B. Bacharier, MD,c Jennifer L. Rosenthal, MD,
d Leigh Anne Bakel, MD,e Patricia C. Parkin, MD, FRCPC,f Michael D. Cabana, MD, MPHa,g,h

CONTEXT: Half of children experience wheezing by age 6 years, and optimal strategies for abstract
preventing severe exacerbations are not well defined.
OBJECTIVE: Synthesize the evidence of the effects of daily inhaled corticosteroids (ICS),
intermittent ICS, and montelukast in preventing severe exacerbations among preschool
children with recurrent wheeze.
DATA SOURCES: Medline (1946, 2/25/15), Embase (1947, 2/25/15), CENTRAL.

STUDY SELECTION: Studies were included based on design (randomized controlled trials),
population (children ≤6 years with asthma or recurrent wheeze), intervention and
comparison (daily ICS vs placebo, intermittent ICS vs placebo, daily ICS vs intermittent ICS,
ICS vs montelukast), and outcome (exacerbations necessitating systemic steroids).
DATA EXTRACTION: Completed by 2 independent reviewers.

RESULTS: Twenty-two studies (N = 4550) were included. Fifteen studies (N = 3278) compared
daily ICS with placebo and showed reduced exacerbations with daily medium-dose ICS (risk
ratio [RR] 0.70; 95% confidence interval [CI], 0.61–0.79; NNT = 9). Subgroup analysis of
children with persistent asthma showed reduced exacerbations with daily ICS compared
with placebo (8 studies, N = 2505; RR 0.56; 95% CI, 0.46–0.70; NNT = 11) and daily ICS
compared with montelukast (1 study, N = 202; RR 0.59; 95% CI, 0.38–0.92). Subgroup
analysis of children with intermittent asthma or viral-triggered wheezing showed reduced
exacerbations with preemptive high-dose intermittent ICS compared with placebo
(5 studies, N = 422; RR 0.65; 95% CI, 0.51–0.81; NNT = 6).
LIMITATIONS: More studies are needed that directly compare these strategies.

CONCLUSIONS: There is strong evidence to support daily ICS for preventing exacerbations in
preschool children with recurrent wheeze, specifically in children with persistent asthma.
For preschool children with intermittent asthma or viral-triggered wheezing, there is strong
evidence to support intermittent ICS for preventing exacerbations.

aDepartment of Pediatrics, gPhillip Lee Institute for Health Policy Studies, and hDepartment of Epidemiology and Biostatistics, University of California, San Francisco, California; bSchool of

Public Health, University of California, Berkeley, California; cDepartment of Pediatrics, Washington University School of Medicine, St Louis, Missouri; dDepartment of Pediatrics, University of
California, Davis, California; eDepartment of Pediatrics, University of Colorado, Denver, Colorado; and fDepartment of Paediatrics, University of Toronto, Toronto, Ontario, Canada

Dr Kaiser conceptualized and designed the study, performed the systematic review and meta-analysis, drafted the initial manuscript, and reviewed and revised
the manuscript; Ms Huynh and Dr Rosenthal performed the systematic review and critically reviewed the manuscript; Drs Bacharier, Bakel, Parkin, and Cabana
conceptualized and designed the study, performed the systematic review, and critically reviewed the manuscript; and all authors approved the final manuscript as
submitted.

To cite: Kaiser SV, Huynh T, Bacharier LB, et al. Preventing Exacerbations in Preschoolers With Recurrent Wheeze: A Meta-analysis. Pediatrics. 2016;137(6):e20154496

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PEDIATRICS Volume 137, number 6, June 2016:e20154496 REVIEW ARTICLE
Half of all children experience one
or more episodes of wheezing by 6
years of age,1 and these wheezing
episodes lead to substantial
morbidity, caregiver burden, and
health care costs.2 In the United
States, annual direct health care costs
due to asthma in children exceed $50
billion,3 and rates of asthma-related
emergency department visits and
hospitalizations are highest among
preschool children.4
Optimal strategies for preventing
severe asthma exacerbations in this
population are not well defined. The
2007 National Asthma Education
and Prevention Program guidelines
recommend that preschool
children be classified in terms of
asthma severity, and for those with
persistent asthma, daily inhaled
corticosteroids (ICS) be initiated to
prevent severe exacerbations.5 Daily
ICS have been shown to significantly
reduce exacerbations in preschool
children, especially those with
persistent symptoms.6 However,
there are concerns about effects
on linear growth with prolonged
treatment,5 and ICS do not modify the
development of asthma or improve
lung function after discontinuation.7
The majority of preschool children
with recurrent wheezing have
intermittent, but sometimes severe,
exacerbations triggered by viral
upper respiratory tract infections
(URTIs) and minimal symptoms
between exacerbations.1 This
pattern of illness has been called
episodic viral wheeze (EVW)8 or
severe intermittent wheezing.9
Although wheezing patterns and
phenotypes in young children can
change over a short time,10 recent
studies have examined phenotype-
directed strategies for preventing
severe exacerbations, as well as
alternative strategies to daily ICS.
Two alternative strategies include
intermittent (started at the onset
of URTI) ICS and the leukotriene
inhibitor montelukast. Both of these
strategies offer potential advantages
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2 KAISER et al
to health care providers and
caregivers by mitigating the burden
and risks of daily ICS. The more
recent 2015 Global Initiative for
Asthma guideline, which integrates
these recent studies, recommends
considering intermittent ICS for
preschool children with EVW.11
Because of the complexity of
managing preschool children with
recurrent wheeze, substantial
practice variation exists regarding
choice of therapy for preventing
severe exacerbations.12 Given
the magnitude of disease burden
and health care costs of recurrent
wheezing in preschoolers, it is
paramount that we determine the
optimal therapeutic strategy for
preventing severe exacerbations in
these children. The primary objective
of this systemic review and meta-
analysis is to synthesize the evidence
of the effects of daily ICS, intermittent
ICS, and montelukast as strategies
for preventing severe exacerbations
in preschool children with recurrent
wheeze. Our secondary objective
is to synthesize the evidence of the
effects of these preventive strategies
in specific phenotypes of preschool
children with recurrent wheeze. Our
work is intended to update and build
on a recent review of the diagnosis,
management, and prognosis of
preschool wheeze by Ducharme
et al.13 These data should assist all
practitioners who provide primary
care to young children, provide
subspecialty care to children with
recurrent wheezing, and provide
care for children during acute
exacerbations.
METHODS
We conducted and reported this
systematic review in accordance
with the Preferred Reporting Items
for Systematic Reviews and Meta-
Analyses statement.14 We did not
register a protocol.
Literature Search
In consultation with a medical
librarian, we created search
strategies for 3 databases (Medline,
Embase, and CENTRAL) from
inception to February 2015.
The detailed search strategy for
Medline and Embase is outlined
in the Supplemental Appendix.
Briefly, the search used terms for
glucocorticoids (glucocorticoid/ and
detailed listing of all indexed drugs
within the glucocorticoid category),
montelukast, asthma (asthma/ or
status asthmaticus/ or asthma* or
reactive adj2 airway* or wheez*), and
inhaled (inhalational or nebulizer/
or vaporizer/ or inhaler/ and related
terms), limited to studies of humans
and children. We also searched
abstracts of the Pediatric Academic
Societies (2002–2014) and American
Academy of Allergy, Asthma, and
Immunology conference proceedings
(1996–2015), reference lists of all
included papers and relevant reviews
identified, and the top 200 citations
from Google Scholar (using terms
“asthma,” “wheeze,” “child,” “steroid,”
and “montelukast”).
Study Inclusion Criteria
Studies were considered eligible
for inclusion if they met criteria
regarding population, intervention
and comparator, outcomes, and
study design. Participants were
children ages ≤6 years with asthma
or recurrent wheezing (≥2 episodes
in last year). Studies that included
only children <2 years were excluded
because of the potential overlap with
bronchiolitis in this age group.15,16
We included studies comparing the
following interventions: daily ICS
versus placebo, intermittent ICS
versus placebo, daily ICS versus
intermittent ICS, or any regimen
of ICS versus any regimen of
montelukast. We included any studies
that reported on our outcome: severe
wheezing exacerbations necessitating
systemic (oral or intravenous)
corticosteroid. Severe exacerbations

FIGURE 1
Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 flow diagram.
were chosen as our primary outcome
because they are a patient-important
outcome that have significant
consequences for children, caregivers,
and the health care system.17 Only
randomized controlled trials (RCTs)
were included. Guidelines, reviews,
commentaries, abstracts, and letters
to editors were reviewed to identify
any primary data; however, these
publication types were not included
because of lack of peer review and
inability to judge bias.
Study Selection Process
All titles and abstracts were pooled
in EndNote (Thompson Reuters,
Philadelphia, PA), and duplicates
were deleted. Two review authors
independently screened all titles
and abstracts to assess which
studies met the inclusion criteria.
We retrieved full-text copies of all
potentially relevant articles for
review. Unresolved disagreements
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PEDIATRICS Volume 137, number 6, June 2016
on inclusion were referred to a third
review author. The Supplemental
Appendix includes studies that were
excluded, and Fig 1 outlines the study
selection process.
Data Extraction and Management
Data were extracted via a standardized
data extraction form. Study design,
patient characteristics (age, gender,
atopy, family history), intervention
(dose, frequency, duration),
intervention and comparator groups,
methodological quality, and key
outcomes were noted. Corresponding
authors were contacted for information
not available in the journal article. This
process was not blinded to manuscript
origin (journal, authors, institution).
Assessment of Risk of Bias in
Included Studies
Methodological quality of all studies
was assessed with the Cochrane
Risk of Bias tool, which assesses
studies for risks of bias in selection,
performance, detection, attrition,
or reporting.18 This process was
not blinded to manuscript origin.
Study quality assessments were
incorporated into a sensitivity
analysis and the final conclusions.
Measures of Treatment Effect
For rates of severe wheezing
exacerbations necessitating systemic
steroids, we collected numbers of
participants in each group with
and without the outcome and
determined pooled risk ratios (RRs)
with 95% confidence intervals
(CIs). To determine whether to
pool results, we assessed for
clinical heterogeneity by detailed
consideration of each study (design,
patient characteristics, intervention,
comparison, outcomes, and conduct
of study) and assessed statistical
heterogeneity by visual inspection
of forest plots and calculation of
Cochran’s χ2 test of homogeneity
and I2 test statistic. A fixed-effects
model was used for the meta-analysis
unless statistical heterogeneity was
identified (Cochran’s χ2 test P ≤ .05
or I2 ≥50%). Analyses were done in
Review Manager 5.3 (Copenhagen,
Denmark). Publication bias was
assessed with funnel plots.
Subgroup and Sensitivity Analyses
To determine the efficacy of daily ICS,
intermittent ICS, and montelukast
for specific phenotypes of preschool
wheeze, we performed subgroup
analyses. Descriptions of each study
population’s baseline symptoms
were carefully reviewed to determine
phenotypic classification. We
performed 1 subgroup analysis
restricted to studies that described
inclusion only of children with
persistent asthma (symptoms >2
days/week, nighttime awakenings
1–2/month, short acting β-agonist
use >2 days/week, or minor
limitation with normal activity).5
We performed another subgroup
analysis that described inclusion
3
only of children with intermittent
asthma (symptoms ≤2 days/week,
no nighttime awakenings, short
acting β-agonist use ≤2 days/week,
and no limitation with normal
activity)5 or viral-triggered wheezing
and minimal symptoms between
exacerbations (EVW or severe
intermittent wheezing). Studies in
which the phenotypes of included
children were mixed or unclear were
analyzed as a separate subgroup. We
also performed a sensitivity analyses
in which we excluded studies with
high risk of bias in ≥1 domain or
crossover design to determine
whether effect size and direction was
consistent with our primary analysis.
RESULTS
Description of Studies
Results of Search
Our search identified 4290
references. After removing duplicates
and screening abstracts, we selected
123 for full-text review. Of these, 101
were excluded upon full-text review.
Reasons for exclusion are described
in the Supplemental Appendix.
Twenty-two studies met inclusion
criteria; all were included in the
quantitative synthesis and meta-
analysis (Fig 1).7,19–39
Included Studies
Characteristics of included studies
are described in Table 1.
Fifteen studies compared daily ICS
with placebo.7,20–22, 24–26, 28–32,35–37
All were double-blind RCTs. Thirteen
studies had a parallel design, and
2 had crossover designs: Gleeson
and Price28 and Webb et al36
(3-week washout period and no
washout, respectively). The studies
used several different delivery
systems and types of ICS, with most
studies using medium daily doses
(budesonide 0.4 mg/day, fluticasone
0.2 mg/day, beclomethasone 0.15
mg/day, ciclesonide 0.16 mg/day,
flucinolide 40 μg/kg/day). Study
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4 KAISER et al
durations ranged from 6 weeks
to 5 years, with most 12 weeks.
Eight of 15 studies focused on
preschool children with persistent
asthma.20–22,24,28, 31,32,35 Only 1 study
examined daily ICS for children
with intermittent asthma or viral-
triggered wheeze.37 A funnel plot
of these studies was symmetric,
suggesting no evidence of publication
bias.
Six studies compared intermittent
ICS with placebo.19,23,27, 30,33,38
All of these studies were double-blind
RCTs. Two had a crossover
design: Connett and Lenney23
(participants switched treatment
arms after each URTI) and Wilson
and Silverman38 (participants
switched treatment arms after 2
URTIs). The studies used several
different delivery systems and types
of ICS at high dosages (budesonide
1.6–2 mg/day, fluticasone 1.5 mg/day,
beclomethasone 2.3 mg/day).
Study durations ranged from
12 to 52 weeks. Five studies
focused on preschool children
with intermittent asthma or viral-
triggered wheeze.19,23, 27,33,38 A funnel
plot of these studies was symmetric,
suggesting no evidence of publication
bias.
Two studies directly compared daily
ICS with intermittent ICS.30,39 Both
were double-blind RCTs with parallel
designs. Papi et al30 compared high-
dose daily (0.4 mg twice daily [BID])
or intermittent beclomethasone
(0.8 mg as needed) to placebo for
12 weeks. Zeiger et al39 compared
high-dose daily (0.5 mg daily) with
intermittent budesonide (1 mg
BID) for 52 weeks in children with
viral-triggered asthma and positive
modified asthma predictive index.40
Two studies compared ICS with
montelukast.19,34 Both were RCTs
with parallel design. Bacharier
et al19 compared intermittent
ICS (budesonide 1 mg BID) with
intermittent montelukast (4 mg
daily) over 52 weeks in children with
intermittent wheezing. Szefler et al34
compared daily ICS (budesonide 0.5
mg BID) with daily montelukast (4
mg daily) over 52 weeks in children
with persistent asthma.
Risk of Bias and Quality
The risk of bias in all included studies
is illustrated in Fig 2. Twelve of 22
studies had low risk of bias. The
most common area of concern was
attrition bias due to incomplete
outcome data. Studies with >20%
loss to follow-up were rated as high
risk.19,25,27–29, 34,36,38,39 Most studies
did not describe how they handled
missing data. Szefler et al34 was
rated high risk of performance and
detection bias because of open-label
design. Wilson and Silverman38 was
rated high risk because of potential
confounding bias, because 13/24
participants were on daily controller
therapy during the study, which
could include ICS.
Outcomes
Risk of Severe Wheezing Exacerbations
Necessitating Systemic Steroids
Our meta-analyses of strategies for
preventing severe exacerbations in
preschool children with recurrent
wheeze are described in Fig 3.
Data from 15 studies (N = 3278)
showed a significant reduction in
rates of exacerbations with daily
ICS compared with placebo (12.9%
and 24.0%, respectively; RR 0.70;
95% CI, 0.61–0.79; P < .001; I2 =
42%). Treatment of 9 children
with daily ICS prevented 1 child
from experiencing an exacerbation
(number needed to treat [NNT] =
9; 95% CI, 7–12).
Data from 6 studies (N = 588)
showed a significant reduction
in rates of severe exacerbations
with intermittent ICS compared
with placebo (24.8% and 41.6%,
respectively; RR 0.64; 95% CI, 0.51–
0.81; P < .001; I2 = 0%). Treatment
of 6 children with intermittent ICS
therapy prevented 1 child from
experiencing an exacerbation
(NNT = 6; 95% CI, 4–11).
TABLE 1 Characteristics of Included Studies
Study Population Intervention (Dose Comparisons (Dose Study Outcomes
Category) Category) Duration
Bacharier et al Children 12–59 mo Intermittent ICS: 1) Intermittent 52 wk Primary outcome: SFDs (mean percentage):
2008 (parallel with intermittent budesonide 1 mg BID montelukast: intermittent ICS (76%), intermittent montelukast
RCT) asthma/EVW; mean via nebulizer (high) 4 mg daily × 7 d (73%), placebo (74%)
age 36 mo, 65% × 7 d started at first started at first
male, 34% with sign of URTI sign of a URTI
eczema, 45% with 2) Placebo Proportion of children with exacerbations:
parental asthma intermittent ICS (38.5%), intermittent
montelukast (46.8%), placebo (55.3%)
Change in height from baseline (cm): intermittent
ICS (7.8), intermittent montelukast (7.9), placebo
(7.5)
Bisgaard et al Children 12–47 mo Daily ICS: 2 doses Placebo 12 wk Primary outcome: mean increase in percentage of
1999 (parallel with persistent fluticasone cough-free days compared with placebo- 0.05 mg
RCT) asthma; mean age suspension via MDI, dose (8%), 0.1 mg dose (12%)
28 mo, 66% male, mask, and spacer Proportion of children with exacerbation: daily ICS
42% with eczema, used: 1) 0.05 mg BID (5%), placebo (16%)
72% with family (low), 2) 0.1 mg BID
history of asthma (medium)
Brand et al 2011 Children ages Daily ICS: 3 doses Placebo 24 wk Primary outcome: proportion of children with
(parallel RCT) 24–72 mo with ciclesonide via exacerbations: 40 μg (4.4%), 80 μg (7.3%), 160 μg
persistent asthma nebulizer used: 1) 40 (6.7%), placebo (10.2%)
and positive API, μg QHS (low), 2) 80
median age 48 mo, μg QHS (low), 3) 160
63% male μg QHS (medium)
Carlsen et al Children age 12–47 Daily ICS: fluticasone Placebo 12 wk Primary outcome: SFDs (mean percentage): daily
2005 (parallel mo with mild suspension 0.1 mg ICS (33%), placebo (20%)
RCT) persistent asthma, BID via pMDI/mask/ Proportion of children with exacerbations: daily ICS
mean age 28 mo, spacer (medium) (6%), placebo (12%)
68% male, 56%
with family history
of asthma
Connett and Children ages Intermittent ICS: Placebo 26 wk Primary outcome: mean symptom score (daytime
Lenney 1993 12–60 mo with budesonide solution wheeze): intermittent ICS (0.69), placebo (0.97),
(crossover intermittent 0.8 mg BID (high) P < .05
RCT) asthma/EVW; 56% via Nebuhaler or 1.6 Proportion of children with exacerbations:
male, 48% with mg BID (high) via intermittent ICS (8%), placebo (32%)
family history of Nebuhaler with mask
atopy × 7 d started at first
sign of URTI
Connett et al Children 12–36 mo Daily ICS: budesonide Placebo 26 wk Primary outcome: mean change in nighttime cough
1993 (parallel with persistent solution 0.2 mg symptom score: daily (−0.4), placebo (+0.1), P
RCT) asthma; mean age BID via Nebuhaler < .05
22 mo, 65% male, (medium) SFDs (mean percentage): daily (54%), placebo
58% with family (31%), P < .0001
history of asthma
de Benedictis Children ages 4–32 Daily ICS: flucinolide Placebo 12 wk Proportion of children with exacerbations: daily
et al 1996 mo, mean age 14 20 μg/kg BID via (62%), placebo (66%)
(parallel RCT) mo, 74% male, 18% nebulizer
with eczema
de Blic et al 1996 Children 6–30 mo, Daily ICS: budesonide 1 Placebo 12 wk Primary outcome: proportion of children with
(parallel RCT) mean age 17 mo, mg BID via nebulizer exacerbations: daily ICS (40%), placebo (83%)
87% male, 47% (high)
with parental
atopy

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PEDIATRICS Volume 137, number 6, June 2016 5
TABLE 1 Continued
Study Population Intervention (Dose Comparisons (Dose Study Outcomes
Category) Category) Duration
Ducharme et al Children 12–72 mo Intermittent ICS: Placebo 52 wk Primary outcome: proportion of children with
2009 (parallel with intermittent fluticasone exacerbations: intermittent ICS (39%), placebo
RCT) asthma/EVW; mean suspension 0.75 mg (64%)
age 32 mo, 60% BID (high) via mask/ Mean change in height from baseline (cm):
male, 43% with spacer started at intermittent ICS (6.23 ± 2.62), placebo (6.56 ±
eczema, 47% with first sign of URTI and 2.90), NS
family history of stopped after 48 h
asthma without symptoms
Gleeson and Children 24–72 mo Daily ICS: budesonide Placebo 6 wk in Primary outcome: mean change in peak expiratory
Price 1988 with persistent solution 0.2 mg each arm flow: daily ICS (112%), placebo (101%), P < .05
(crossover asthma; median BID via Nebuhaler (crossover) Proportion of children with exacerbations: daily
RCT) age 51 mo; 67% (medium) (2.6%), placebo (10.3%)
male, 38% with
asthma
Guilbert et al Children 24–36 mo Daily ICS: fluticasone Placebo 104 wk Primary outcome: SFDs (mean percentage): daily
2006 (parallel with positive API; suspension 88 μg BID (93%), placebo (88%), P = .006
RCT) mean age 36 mo, via MDI with mask/ Proportion of children with exacerbations: daily
62% male, 54% spacer (medium) (60%), placebo (65%)
with eczema, 65% Change in height: daily (12.6 cm), placebo (13.7 cm)
with parental
history of asthma
Murray et al Children ages 6–60 Daily ICS: fluticasone Placebo 260 wk Primary outcome: prevalence of asthma at 5 y of
2006 (parallel mo, mean age 22 suspension 0.1 mg age: daily ICS (61%), placebo (64%), P = .68
RCT) mo, 65% male, BID via MDI (medium) Proportion of children with exacerbations: daily ICS
47% with maternal (15.8%), placebo (14.1%)
asthma Change in height z score at 5 y: daily ICS (0.002),
placebo (0.066), P = .501
Papi et al 2009 Children 12–28 mo Daily ICS: 1) Intermittent ICS: 12 wk Primary outcome: SFDs (mean percentage): daily
(parallel RCT) recruited during beclomethasone 0.4 beclomethasone (69.6%), intermittent (64.9%), placebo (61.0)
acute wheezing mg BID via nebulizer 0.8 mg (high) Proportion of children with exacerbations: daily
exacerbation (high) and salbutamol (1.8%), intermittent (5.5%), placebo (9%)
during URTI; mean 1.6 mg PRN via
age 28 mo, 60% nebulizer during
male exacerbation; 2)
Placebo
Qaqundah et al Children age 12–48 Daily ICS: fluticasone Placebo 12 wk Primary outcome: percentage change in daily
2006 (parallel mo with persistent suspension 88 μg BID asthma symptom score: daily (−53.9%), placebo
RCT) asthma; mean age via MDI with mask/ (−44.1%), P = .036
30 mo, 62% male spacer (medium) Proportion of children with exacerbations: daily
(5%), placebo (12%)
SFDs (mean percentage): daily (36%), placebo (36%)
Roorda et al Children ages 12–47 Daily ICS: fluticasone Placebo 12 wk Primary outcome: SFDs (mean percentage): daily
2001 (parallel mo with persistent suspension 0.1 mg ICS (54%), placebo (36%)
RCT) asthma; mean age BID via mask/spacer proportion of children with exacerbations: daily ICS
29 mo, 66% male, (medium) (25%), placebo (36%)
47% with eczema,
71% with family
history of asthma
Svedmyr et al Children 12–36 mo Intermittent ICS: Placebo 52 wk Primary outcome: mean symptom score:
1999 (parallel with intermittent budesonide solution intermittent ICS (0.38 ± 0.21), placebo (0.55 ±
RCT) asthma/EVW. Mean 0.4 mg QID (high) 0.38), P = .028
age 26 mo, 69% × 3 d, then 0.4 mg Proportion of children with exacerbations:
male, 35% with BID (high) × 7 d intermittent ICS (35%), placebo (38%)
eczema, 24% with via mask/spacer
positive skin-prick (started at first sign
test of a URTI)

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6 KAISER et al
TABLE 1 Continued
Study Population Intervention (Dose Comparisons (Dose Study Outcomes
Category) Category) Duration
Szefler et al 2013 Children ages 24–48 Daily ICS: budesonide Montelukast: 4 mg 52 wk Primary outcome: median time to first asthma
(parallel RCT) mo with persistent 0.5 mg QHS via or 5 mg daily exacerbation: daily ICS (183 d), montelukast (86
asthma; mean age nebulizer (high), for based on age d), P = .128
56 mo, 61% male mild exacerbations Proportion of children with exacerbations: daily ICS
escalation to (21.9%), montelukast (37.1%)
budesonide 0.5 mg
BID via nebulizer
Wasserman et al Children 24–47 mo Daily ICS: 2 doses Placebo 12 wk Primary outcome: mean change in asthma symptom
2006 (parallel with persistent fluticasone score: daily ICS 44 μg (−0.5), daily ICS 88 μg
RCT) asthma; mean age suspension via (−0.7), placebo (−0.5), P < .05 comparing 88 μg
36 mo, 61% male mask/spacer used: to placebo
1) 44 μg BID (low), 2) Proportion of children with exacerbations: daily ICS
88 μg BID (medium) 44 μg (14%), daily ICS 88 μg (13%), placebo (24%)
Change in height from baseline (cm): daily ICS 44 μg
(1.8), daily ICS 88 μg (1.8), placebo (1.8)
Webb et al 1986 Children 18–72 mo; Daily ICS: Placebo 8 wk Primary outcome: total symptom score (median):
(crossover mean age 41 mo, beclomethasone daily (182), placebo (182), NS
RCT) 88% male, 44% 0.15 mg daily via Proportion of children with exacerbations: daily
with eczema nebulizer (medium) (23%), placebo (23%)
Wilson and Children 12–60 mo Intermittent ICS: Placebo plus Proportion of children with exacerbations:
Silverman with intermittent beclomethasone bronchodilator intermittent ICS (29%), placebo (42%)
1990 asthma/EVW; mean solution 0.75 mg plus TID × 5 d started
(crossover age 42 mo, 71% bronchodilator TID at the first sign
RCT) male (high) via MDI and of asthma attack
spacer × 5 d started
at the first sign of
asthma attack
Wilson et al 1995 Children 8–72 mo Daily ICS: budesonide Placebo 16 wk Primary outcome: daily symptom score (median):
(parallel RCT) with intermittent solution 0.2 mg BID daily (0.6), placebo (0.63), NS
asthma/EVW; mean via MDI with mask/ Proportion of children with exacerbations: daily
age 1.9 y, 59% spacer (medium) (10%), placebo (10%)
male, 82% with SFDs (median): daily (73%), placebo (78%)
family history of
asthma
Zeiger et al 2011 Children 12–53 mo Daily ICS: budesonide Intermittent ICS: 52 wk Primary outcome: rate of exacerbations per patient-
(parallel RCT) with intermittent 0.5 mg daily via budesonide year: daily (0.97), intermittent (0.95), NS
asthma/EVW and nebulizer (high) 1 mg BID via Proportion of children with exacerbations: daily
positive API; 46% nebulizer (44.6%), intermittent (46.0%)
between 12–23 started at the SFDs (mean percentage): daily (78%), intermittent
mo, 69% male, onset of URTI × 7 (78%)
53% with eczema, d (high) Change in height: daily (7.8 cm), intermittent (8.0
64% with parental cm)
asthma
API, asthma predictive index; BID, 2 times daily; MDI, metered dose inhaler; NS, not significant; PRN, as needed; QHS, at bedtime; QID, 4 times daily; TID, 3 times daily.

Data from 2 studies (N = 498) directly (n = 202) showed a significant no differences comparing daily ICS
comparing daily with intermittent reduction in rates of severe versus intermittent ICS (1/2 studies
ICS showed no differences in rates exacerbations with daily ICS versus excluded, RR 0.33; 95% CI, 0.07–
of severe exacerbations (25.7% and daily montelukast (21.9% and 37.1%, 1.62). With the exclusion of 3 out of
28.1%, respectively; RR 0.91; 95% CI, respectively; RR 0.59; 95% CI, 6 studies comparing intermittent
0.71–1.18; P = .49, I2 = 43%). 0.38–0.92; P = .02). ICS with placebo, the benefit of
Bacharier et al19 (n = 190) showed We performed sensitivity analyses intermittent ICS was no longer
no significant differences in rates excluding studies with high risk of statistically significant (RR 0.61;
of severe exacerbations comparing bias in ≥1 domain. Findings were 95% CI, 0.35–1.07). Both studies
intermittent ICS to intermittent similar to our primary analysis for comparing ICS with montelukast
montelukast (38.5% and 46.8%, 2 comparisons, with daily ICS better had high risk of bias in ≥1 domains.
respectively; RR 0.82; 95% CI, 0.59– than placebo (5/15 studies excluded, We also performed a sensitivity
1.15; P = .25). Szefler et al34 RR 0.67; 95% CI, 0.58–0.77) and analysis excluding only the 4 studies

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PEDIATRICS Volume 137, number 6, June 2016 7

FIGURE 2
Risk of Bias Diagram.
with crossover design and found
very similar results to our primary
analysis.
Subgroup Analyses: Intermittent
Asthma or Viral-Triggered Wheeze
Our subgroup analyses of preschool
children with intermittent asthma or
viral-triggered wheeze are described
in Fig 4. There was only 1 study
(n = 41) examining daily ICS versus
placebo, which found no significant
benefit (RR 1.05; 95% CI, 0.16–6.76).
Most studies comparing intermittent
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8 KAISER et al
ICS with placebo were focused on
children with intermittent asthma
or viral-triggered wheeze (5/6).
Data from these 5 studies (N = 422)
showed significant reduction in
rates of severe exacerbations with
intermittent ICS (33.9% vs 51.3%,
respectively; RR 0.65; 95% CI, 0.51–
0.81; P = .0002; I2 = 0%). Treatment
of 6 children prevented 1 child
from experiencing an exacerbation
(NNT = 6; 95% CI, 4–12). There
was no difference in rates of severe
exacerbations with daily compared
with intermittent ICS (1 study, n =
278; RR 0.97; 95% CI, 0.75–1.25)
or intermittent ICS compared with
intermittent montelukast (1 study,
n = 190; RR 0.82; 95% CI, 0.59–1.15).
Subgroup Analyses: Persistent Asthma
Our subgroup analyses of preschool
children with persistent asthma
are described in Fig 5. Eight studies
comparing daily ICS with placebo
were focused on children with
persistent asthma (N = 2505), and
showed a reduction in rates of
severe exacerbations with daily
ICS (8.7% vs 18%, respectively; RR
0.56; 95% CI, 0.46–0.70; P < .001;
I2 = 0%). Treatment of 11 children
prevented 1 child from experiencing
an exacerbation (NNT = 11; 95% CI,
8–15). Data from Szefler et al34 (n =
202) showed that daily ICS reduced
rates of severe exacerbations
compared with daily montelukast
(RR 0.59; 95% CI, 0.38–0.92; P = .02).
There were no studies of intermittent
ICS for children with persistent
asthma.
Subgroup Analyses: Unclear or Mixed
Wheezing Phenotypes
Our subgroup analyses of preschool
children with unclear or mixed
phenotypes are described in Fig
6. Six studies compared daily ICS
with placebo (N = 732) and showed
no significant difference in rates
of severe exacerbations (30.8% vs
40.1%, respectively; RR 0.86; 95%
CI, 0.73–1.02; P = .08; I2 = 42%).
Data from Papi et al30 showed no
significant difference comparing
intermittent ICS with placebo
(RR 0.61; 95% CI, 0.19–1.91; P = .40)
or daily ICS with intermittent ICS
(RR 0.33; 95% CI, 0.07–1.62; P = .17).
Other Outcomes: Symptom-Free Days
and Linear Growth
Seven studies comparing daily
ICS with placebo (N = 1336)
reported on symptom-free days
(SFDs);7,22,24,30–32,37 however, few
provided adequate data for meta-
analysis. Six of these studies31
FIGURE 3
Meta-analyses of strategies for preventing severe exacerbations in preschoolers with recurrent wheeze. M-H, Mantel–Haenszel.

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PEDIATRICS Volume 137, number 6, June 2016 9
FIGURE 4
Meta-analyses of strategies for preventing severe exacerbations in preschoolers with intermittent asthma or viral-triggered wheeze (subgroup analysis).
M-H, Mantel–Haenszel.
found a benefit with daily ICS, with
mean differences in percentage of
SFDs ranging from 5% to 23%. Two
studies that compared daily and
intermittent ICS30,39 (N = 498) found
no difference in SFDs. Bacharier
et al19 found no differences in SFDs
comparing intermittent ICS with
intermittent montelukast or placebo.
We also reviewed linear growth
effects, because this is the major
concerning side effect with ICS.5
We were unable to meta-analyze
these data given the small number
of studies reporting growth data and
the varied growth metrics reported.
Six studies reported on linear growth
outcomes7,19,27, 29,35,39 (N = 1461).
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10
Three studies compared daily ICS
with placebo.7,29,35 Wasserman
et al35 found no differences in growth
velocity during their 12-week study.
Guilbert et al7 found that children
treated with daily ICS had a 1.1
cm lower mean increase in height
at 2 years (12.6 ± 1.9 cm vs 13.7 ±
1.9 cm, P < .001), but 1 year after
discontinuation of ICS, the difference
in height increase was reduced to
0.7 cm (19.2 ± 2.2 cm vs 19.9 ± 2.2
cm, P = .008). Murray et al29 found
a significantly smaller change in
mean height z score after 6 months
of daily ICS but no differences at 1,
2, or 5 years of follow-up. In studies
comparing intermittent ICS with
placebo,19,27,39 Bacharier et al19
found no significant differences in
mean change in height comparing
intermittent ICS with montelukast
or placebo over 1 year. Ducharme
et al27 found that intermittent ICS
compared with placebo led to smaller
mean change in height (6.23 ± 2.62
cm vs 6.56 ± 2.90 cm) and height z
score (−0.19 ± 0.42 vs 0.00 ± 0.48)
over 1 year. Zeiger et al39 found
no significant differences in mean
change in height, height percentile,
or z score comparing daily with
intermittent ICS over 1 year.
DISCUSSION
With this analysis, we aimed to
synthesize the evidence of the effects
KAISER et al
FIGURE 5
Meta-analyses of strategies for preventing severe exacerbations in preschoolers with persistent asthma (subgroup analysis). M-H, Mantel–Haenszel.
of daily ICS, intermittent ICS, and
montelukast in preventing severe
exacerbations among preschool
children with recurrent wheeze.
In our primary analysis, we found
that both daily and intermittent ICS
were effective in preventing severe
exacerbations. Daily ICS reduced
the risk of exacerbations by 30%,
intermittent ICS reduced risk by
36%, and there were no significant
differences when these strategies
were compared directly. Given
the varying patterns of recurrent
wheezing in preschool children, we
performed subgroup analyses by
wheezing phenotype. In line with
the 2007 National Asthma Education
and Prevention Program guideline,
we found strong evidence to support
daily ICS for preschool children with
persistent asthma. For preschool
children with intermittent asthma or
viral-triggered wheeze, we found strong
evidence to support intermittent ICS.
In our primary analysis of preschool
children with recurrent wheeze, we
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PEDIATRICS Volume 137, number 6, June 2016
found that daily ICS was effective in
reducing the risk of severe wheezing
exacerbations (NNT = 9), in line
with a meta-analysis done in 2009.6
Daily ICS also led to an increase in
SFDs. These findings are in line with
studies in older children and adults
that have established ICS as the most
potent and consistently effective
long-term control medication
for asthma.5 The broad action of
ICS on the inflammatory process
probably accounts for their efficacy
as preventive therapy.5 Overall, the
growth-suppressive effects of ICS
in preschool children improved
over time in most children.7,29,
35 A follow-up study by Guilbert
et al41 found that children started
on daily ICS at a younger age (<2
years) or lower weight (<15 kg) may
experience greater effects on linear
growth. A Cochrane meta-analysis
found dose–response effects of ICS
on growth.42 Consequently,
children on ICS should have regular
monitoring of growth, and health
care providers should titrate ICS
dosing to the lowest dose that is
effective.
Our subgroup analyses by wheezing
phenotype showed that most
studies of daily ICS in preschool
children have focused on children
with persistent asthma. For these
children, we found strong evidence
to support daily ICS, with data from
>1600 children demonstrating 44%
reduced risk of severe exacerbations
(NNT = 11). In addition, most studies
that reported on symptom-free days
found significant improvements
with daily ICS compared with
placebo.22,24,32 We also found that daily
ICS reduced risk of exacerbations more
than montelukast, but these data
were limited to a single study. These
findings support current national and
international guidelines,5,8,11 which
recommend daily ICS as first-line
therapy for preschool children with
persistent asthma.
We also performed a subgroup
analysis of preschool children
11
FIGURE 6
Meta-analyses of strategies for preventing severe exacerbations in preschoolers with unclear or mixed wheezing phenotypes (subgroup analysis). M-H,
Mantel–Haenszel.
with intermittent asthma or viral-
triggered wheeze, because this is
the most common wheezing pattern
in this age group.1 Most studies
evaluated intermittent ICS. We
found strong evidence to support
intermittent ICS, with a 35% risk
reduction in severe exacerbations
(NNT = 6). In these studies, children
generally received high-dose ICS
started at the first sign of a URTI
for 7 to 10 days. The children
studied had minimal wheezing
between URTIs, but the majority
had a history of moderate to severe
wheezing exacerbations with URTI
necessitating systemic steroids,
emergency department visits, and
hospitalizations (severe intermittent
wheezing).19,27,33,38 There were
limited data for daily ICS in this
population, with only 1 small study
comparing daily ICS with placebo
(N = 41) that found no difference.
Zeiger et al39 directly compared
daily ICS with intermittent ICS and
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12
found no differences; they also
found that intermittent ICS led to a
lower cumulative dose than daily
ICS. Ducharme et al27 found slower
linear growth in children treated
with intermittent ICS compared with
placebo. However, Bacharier et al19
(intermittent ICS versus placebo) and
Zeiger et al39 (intermittent versus
daily ICS) found no differences
in linear growth. Overall, there is
strong evidence to support the safety
and efficacy of intermittent ICS for
preschool children with intermittent
asthma or viral-triggered wheeze,
including those with severe
intermittent wheezing, in line with
the 2015 Global Initiative for Asthma
guideline.11 We found limited data
directly comparing montelukast with
ICS, and a recent Cochrane meta-
analysis comparing montelukast
with placebo for preschool children
with viral-triggered wheezing found
no benefit with montelukast.43 More
studies are needed that directly
compare the efficacy of intermittent
ICS, daily ICS, and montelukast for
this population.
Previous systematic reviews of these
therapies have either not focused on
preschool children or not compiled
data on multiple therapeutic
strategies (daily ICS, intermittent
ICS, and montelukast). Our findings
are in line with previous studies
that combined pediatric and adult
data or examined a single therapy.
A 2009 meta-analysis compared
daily ICS with placebo in preschool
children with recurrent wheeze
and found a similar reduction in
wheezing exacerbations (RR 0.59;
95% CI, 0.52–0.67; P = .0001;
I2 = 10%).6 A 2015 Cochrane meta-
analysis comparing intermittent
ICS with placebo found a reduction
in wheezing exacerbations with
intermittent ICS in a subgroup
analysis of preschool children
(odds ratio 0.48; 95% CI, 0.31–0.73;
KAISER et al
P < .001).44 In addition, a 2013
Cochrane meta-analysis comparing
intermittent and daily ICS found no
significant differences in a subgroup
analysis of preschool children (RR
1.09; 95% CI, 0.85–1.41; P = .49).45
In 2015, Ducharme et al13 published
a nonsystematic review of preschool
wheeze with meta-analyses of
newer studies; they reported similar
results comparing daily ICS with
placebo (relative risk 0.57; 95% CI,
0.40–0.80) and daily and intermittent
ICS (relative risk 0.91; 95% CI,
0.71–1.18). The conclusions of a 2016
nonsystematic review by Castro-
Rodriguez et al46 were also in line
with our findings.
One limitation to our study is
heterogeneity among the included
studies. We found moderate
heterogeneity in our primary analyses
of daily ICS versus placebo and daily
versus intermittent ICS. Sources of
heterogeneity likely include variations
in clinical factors (population, study
duration, cointerventions) and study
design (parallel vs crossover). As
expected, when we narrowed to more
homogenous studies in our subgroup
analyses, heterogeneity improved.
Another limitation was the inclusion
of studies that had a high risk of bias
in ≥1 domain, usually because of
incomplete outcome data. To address
the influence of this potential bias, we
ran sensitivity analyses that excluded
these studies, which were in line with
our primary findings. Additionally,
the majority of studies included
children <2 years, so they may
include some children with
bronchiolitis. However, all studies
required children to have recurrent
wheezing, and many additionally
required other criteria that should
have minimized recruitment
of children with bronchiolitis
(bronchodilator response, risk factors
for asthma).
Our subgroup analyses highlighted
that most studies of daily ICS focused
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PEDIATRICS Volume 137, number 6, June 2016
on children with persistent asthma,
and most studies of intermittent ICS
focused on children with intermittent
asthma or viral-triggered wheezing.
Studies of intermittent ICS may
have also preferentially recruited
children with higher baseline risk,
because rates of exacerbations
in placebo groups were higher in
studies comparing intermittent
ICS with placebo (41.6%) than in
studies comparing daily ICS with
placebo (24.0%). The differences in
study groups recruited for testing
these strategies may correlate with
treatment response, given that
we found treatment benefits in
phenotypically homogenous groups
and did not find benefits in a group
with mixed or unclear phenotypes.
However, phenotypic classification
of recurrent wheezing in preschool
children has limitations. Although the
pattern of episodic viral wheeze has
been well described in the literature
and advocated as a management tool
by a European Respiratory Society
Task Force,8 recent studies have
demonstrated that most preschool
children quickly change from 1
phenotype to another.47 Given these
limitations, therapeutic decisions
remain challenging until more
studies are conducted that clearly
describe the disease pattern and
baseline risk of enrolled children
and directly compare daily ICS,
intermittent ICS, and montelukast.
Our findings show significant
reductions in risk of moderate to
severe exacerbations with ICS, and
they support initiation of ICS therapy
in preschool children with symptoms
of persistent asthma or those with
high risk of severe exacerbations
(>1 course of systemic steroids
per year).5 Reasonable therapeutic
strategies include initiation of daily
ICS5 or intermittent ICS11 and should
be based on symptom pattern, risk
of severe exacerbations,5 and risk
of developing chronic asthma.40
Therapy should be reevaluated
frequently and adjusted based on
symptom pattern.
This is the first study to our
knowledge to systematically review
and meta-analyze the effects of
daily ICS, intermittent ICS, and
montelukast in preventing severe
exacerbations among preschool
children with recurrent wheeze.
We performed a thorough and
extensive search of the literature.
Our overall study population was
large, including 4756 children from
centers across the world. We found
strong evidence to support daily ICS
for preventing severe exacerbations
in preschool children with recurrent
wheeze, specifically in children with
persistent asthma. For preschool
children with intermittent asthma
or viral-triggered wheeze, we
found strong evidence to support
intermittent ICS for preventing
exacerbations. With either
treatment strategy, we recommend
frequent reassessment of wheezing
symptoms and pattern, close
monitoring of growth, and active
titration to the lowest ICS dose
that is effective. More studies are
needed that directly compare these
therapies.
ACKNOWLEDGMENTS
We thank Elizabeth M. Uleryk for
helping develop our search strategy
and Dr Prakesh S. Shah for technical
guidance with the design and analysis
of this study.
ABBREVIATIONS
BID: twice daily
CI: confidence interval
EVW: episodic viral wheeze
ICS: inhaled corticosteroids
NNT: number needed to treat
RR: risk ratio
RCT: randomized controlled
trial
SFDs: symptom-free days
URTI: upper respiratory tract
infection
13
DOI: 10.1542/peds.2015-4496
Accepted for publication Mar 16, 2016
Address correspondence to Sunitha V. Kaiser, MD, MSc, 550 16th St, Box 3214, San Francisco, CA 94158. E-mail: sunitha.kaiser@ucsf.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr Bacharier has received consulting fees from Merck and Teva and payment for lectures from Astra Zeneca and Teva; Dr
Cabana has served as a consultant for Genentech (Data Registry Safety Board) and Merck (Speaker’s Bureau); and the other authors have indicated they have no
potential conflicts of interest to disclose.
REFERENCES
1. Martinez FD, Wright AL, Taussig LM,
Holberg CJ, Halonen M, Morgan
WJ; The Group Health Medical
Associates. Asthma and wheezing in
the first six years of life. N Engl J Med.
1995;332(3):133–138
2. Laforest L, Yin D, Kocevar VS, et al.
Association between asthma control
in children and loss of workdays
by caregivers. Ann Allergy Asthma
Immunol. 2004;93(3):265–271
3. American Lung Association. Asthma
& children fact sheet. 2014. Available
at: www.lung.org/lung-health-and-
diseases/lung-disease-lookup/asthma/
learn-about-asthma/asthma-children-
facts-sheet.html?referrer=https://
www.google.com/
4. Centers for Disease Control and
Prevention. National surveillance
of asthma. Atlanta, GA: Centers for
Disease Control and Prevention;
2012:2001–2010
5. National Asthma Education and
Prevention Program. Expert panel
report 3 (EPR-3): guidelines for
the diagnosis and management of
asthma—summary report 2007.
[Erratum appears in J Allergy
Clin Immunol. 2008;121(6):1330] J
Allergy Clin Immunol. 2007;120(5
suppl):S94–S138
6. Castro-Rodriguez JA, Rodrigo GJ.
Efficacy of inhaled corticosteroids
in infants and preschoolers with
recurrent wheezing and asthma: a
systematic review with meta-analysis.
Pediatrics. 2009;123(3). Available at:
www.pediatrics.org/cgi/content/full/
123/3/e519
7. Guilbert TW, Morgan WJ, Zeiger
RS, et al. Long-term inhaled
Downloaded from by guest on March 7, 2017
14
corticosteroids in preschool children
at high risk for asthma. N Engl J Med.
2006;354(19):1985–1997
8. Brand PL, Baraldi E, Bisgaard H, et al.
Definition, assessment and treatment
of wheezing disorders in preschool
children: an evidence-based approach.
Eur Respir J. 2008;32(4):1096–1110
9. Bacharier LB, Phillips BR, Bloomberg
GR, et al; Childhood Asthma Research
and Education Network, National Heart,
Lung, and Blood Institute. Severe
intermittent wheezing in preschool
children: a distinct phenotype. J Allergy
Clin Immunol. 2007;119(3):604–610
10. Chipps BE, Bacharier LB, Harder JM.
Phenotypic expressions of childhood
wheezing and asthma: implications for
therapy. J Pediatr. 2011;158:878–84 e1
11. Global Initiative for Asthma. Global
Strategy for Asthma Management
and Prevention. Available at: www.
ginasthma.org
12. Sawicki GS, Smith L, Bokhour B, et
al. Periodic use of inhaled steroids
in children with mild persistent
asthma: what are pediatricians
recommending? Clin Pediatr (Phila).
2008;47(5):446–451
13. Ducharme FM, Tse SM, Chauhan
B. Diagnosis, management, and
prognosis of preschool wheeze. Lancet.
2014;383(9928):1593–1604
14. Moher D, Liberati A, Tetzlaff J, Altman
DG, Group P; PRISMA Group. Preferred
reporting items for systematic reviews
and meta-analyses: the PRISMA
statement. BMJ. 2009;339:b2535
15. Hasegawa K, Tsugawa Y, Brown DF,
Camargo CA, Jr. Childhood asthma
hospitalizations in the United States,
2000–2009. J Pediatr. 2013;163:1127–
1133 e3
16. Davies BR, Carroll WD. The use of
inhaled corticosteroids in the wheezy
under 5-year-old child. Arch Dis Child
Educ Pract Ed. 2011;96(2):61–66
17. Gionfriddo MR, Hagan JB, Hagan CR,
Volcheck GW, Castaneda-Guarderas
A, Rank MA. Stepping down inhaled
corticosteroids from scheduled to as
needed in stable asthma: Systematic
review and meta-analysis. Allergy
Asthma Proc. 2015;36(4):262–267
18. Higgins JPAD, Gøtzsche PC, Jüni P, et
al; Cochrane Bias Methods Group.
Cochrane Statistical Methods Group.
The Cochrane Collaboration’s tool for
assessing risk of bias in randomised
trials. BMJ. 2011;343:d5928
19. Bacharier LB, Phillips BR, Zeiger RS, et
al; CARE Network. Episodic use of an
inhaled corticosteroid or leukotriene
receptor antagonist in preschool
children with moderate-to-severe
intermittent wheezing. J Allergy Clin
Immunol. 2008;122(6):1127–1135.e8
20. Bisgaard H, Gillies J, Groenewald
M, Maden C. The effect of inhaled
fluticasone propionate in the
treatment of young asthmatic children:
a dose comparison study. Am J Respir
Crit Care Med. 1999;160(1):126–131
21. Brand PLP, Luz García-García M,
Morison A, Vermeulen JH, Weber
HC. Ciclesonide in wheezy preschool
children with a positive asthma
predictive index or atopy. Respir Med.
2011;105(11):1588–1595
22. Carlsen KCL, Stick S, Kamin W, Cirule
I, Hughes S, Wixon C. The efficacy and
safety of fluticasone propionate in
very young children with persistent
KAISER et al
 asthma symptoms. Respir Med.
2005;99(11):1393–1402
23. Connett G, Lenney W. Prevention of
viral induced asthma attacks using
inhaled budesonide. Arch Dis Child.
1993;68(1):85–87
24. Connett GJ, Warde C, Wooler E, Lenney
W. Use of budesonide in severe
asthmatics aged 1-3 years. Arch Dis
Child. 1993;69(3):351–355
25. de Benedictis FM, Martinati LC,
Solinas LF, Tuteri G, Boner AL.
Nebulized flunisolide in infants
and young children with asthma:
a pilot study. Pediatr Pulmonol.
1996;21(5):310–315
26. de Blic J, Delacourt C, Le Bourgeois M,
et al. Efficacy of nebulized budesonide
in treatment of severe infantile
asthma: a double-blind study. J Allergy
Clin Immunol. 1996;98(1):14–20
27. Ducharme FM, Lemire C, Noya FJD,
et al. Preemptive use of high-dose
fluticasone for virus-induced wheezing
in young children. N Engl J Med.
2009;360(4):339–353
28. Gleeson JG, Price JF. Controlled trial of
budesonide given by the nebuhaler in
preschool children with asthma. BMJ.
1988;297(6642):163–166
29. Murray CS, Woodcock A, Langley SJ,
Morris J, Custovic A; IFWIN Study Team.
Secondary prevention of asthma by the
use of Inhaled Fluticasone Propionate
in Wheezy Infants (IFWIN): double-blind,
randomised, controlled study. Lancet.
2006;368(9537):754–762
30. Papi A, Nicolini G, Baraldi E, et al;
Beclomethasone and Salbutamol
Treatment (BEST) for Children
Study Group. Regular vs prn
nebulized treatment in wheeze
preschool children. Allergy.
2009;64(10):1463–1471
31. Qaqundah PY, Sugerman RW, Ceruti E,
et al. Efficacy and safety of fluticasone
propionate hydrofluoroalkane
Downloaded from by guest on March 7, 2017
PEDIATRICS Volume 137, number 6, June 2016
inhalation aerosol in pre-school-age
children with asthma: a randomized,
double-blind, placebo-controlled study.
J Pediatr. 2006;149(5):663–670
32. Roorda RJ, Mezei G, Bisgaard H, Maden
C. Response of preschool children
with asthma symptoms to fluticasone
propionate. J Allergy Clin Immunol.
2001;108(4):540–546
33. Svedmyr J, Nyberg E, Thunqvist
P, Asbrink-Nilsson E, Hedlin G.
Prophylactic intermittent treatment
with inhaled corticosteroids of
asthma exacerbations due to airway
infections in toddlers. Acta Paediatr.
1999;88(1):42–47
34. Szefler SJ, Carlsson LG, Uryniak T,
Baker JW. Budesonide inhalation
suspension versus montelukast in
children aged 2 to 4 years with mild
persistent asthma. J Allergy Clin
Immunol Pract. 2013;1(1):58–64
35. Wasserman RL, Baker JW, Kim
KT, et al. Efficacy and safety of
inhaled fluticasone propionate
chlorofluorocarbon in 2- to 4-year-
old patients with asthma: results of
a double-blind, placebo-controlled
study. Ann Allergy Asthma Immunol.
2006;96(6):808–818
36. Webb MS, Milner AD, Hiller EJ, Henry
RL. Nebulised beclomethasone
dipropionate suspension. Arch Dis
Child. 1986;61(11):1108–1110
37. Wilson N, Sloper K, Silverman M. Effect
of continuous treatment with topical
corticosteroid on episodic viral wheeze
in preschool children. Arch Dis Child.
1995;72(4):317–320
38. Wilson NM, Silverman M. Treatment of
acute, episodic asthma in preschool
children using intermittent high dose
inhaled steroids at home. Arch Dis
Child. 1990;65(4):407–410
39. Zeiger RS, Mauger D, Bacharier LB, et
al; CARE Network of the National Heart,
Lung, and Blood Institute. Daily or
intermittent budesonide in preschool
children with recurrent wheezing. N
Engl J Med. 2011;365(21):1990–2001
40. Castro-Rodríguez JA, Holberg CJ,
Wright AL, Martinez FD. A clinical index
to define risk of asthma in young
children with recurrent wheezing. Am
J Respir Crit Care Med. 2000;162(4 pt
1):1403–1406
41. Guilbert TW, Mauger DT, Allen DB,
Zeiger RS, Lemanske RF, Jr., Szefler
SJ, et al Growth of preschool children
at high risk for asthma 2 years after
discontinuation of fluticasone. J Allergy
Clin Immunol. 2011;128:956–63 e1–7
42. Pruteanu AI, Chauhan BF, Zhang L,
Prietsch SO, Ducharme FM. Inhaled
corticosteroids in children with
persistent asthma: dose–response
effects on growth. Cochrane Database
Syst Rev. 2014;7:CD009878
43. Brodlie M, Gupta A, Rodriguez-Martinez
CE, Castro-Rodriguez JA, Ducharme
FM, McKean MC. Leukotriene receptor
antagonists as maintenance and
intermittent therapy for episodic
viral wheeze in children. Cochrane
Database Syst Rev. 2015;10:CD008202
44. Chong J, Haran C, Chauhan BF, Asher
I. Intermittent inhaled corticosteroid
therapy versus placebo for persistent
asthma in children and adults.
Cochrane Database Syst Rev.
2015;7:CD011032
45. Chauhan BF, Chartrand C, Ducharme
FM. Intermittent versus daily inhaled
corticosteroids for persistent asthma
in children and adults. Cochrane
Database Syst Rev. 2013;2:CD009611
46. Castro-Rodriguez JA, Custovic A,
Ducharme FM. Treatment of asthma
in young children: evidence-based
recommendations. Asthma Res Pract.
2016;2:5
47. van Wonderen KEGR, Geskus RB, van
Aalderen WM, et al. Stability and
predictiveness of multiple trigger and
episodic viral wheeze in preschoolers.
Clin Exp Allergy. 2015. 10.1111/cea.12660
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 Preventing Exacerbations in Preschoolers With Recurrent Wheeze: A
Meta-analysis
Sunitha V. Kaiser, Tram Huynh, Leonard B. Bacharier, Jennifer L. Rosenthal, Leigh
Anne Bakel, Patricia C. Parkin and Michael D. Cabana
Pediatrics 2016;137;; originally published online May 26, 2016;
DOI: 10.1542/peds.2015-4496
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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 © 2016 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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 Preventing Exacerbations in Preschoolers With Recurrent Wheeze: A
Meta-analysis
Sunitha V. Kaiser, Tram Huynh, Leonard B. Bacharier, Jennifer L. Rosenthal, Leigh
Anne Bakel, Patricia C. Parkin and Michael D. Cabana
Pediatrics 2016;137;; originally published online May 26, 2016;
DOI: 10.1542/peds.2015-4496

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/137/6/e20154496.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 © 2016 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from by guest on March 7, 2017