preventing exacerbations in preschoolers with recurrent ...preschool children with recurrent wheeze,...

REVIEW ARTICLEPEDIATRICS Volume 137 , number 6 , June 2016 :e 20154496

Preventing Exacerbations in Preschoolers With Recurrent Wheeze: A Meta-analysisSunitha 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

abstractCONTEXT: Half of children experience wheezing by age 6 years, and optimal strategies for

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 fi nal 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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KAISER et al

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

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

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PEDIATRICS Volume 137 , number 6 , June 2016

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

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

FIGURE 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 fl ow diagram.


KAISER et al

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

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


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).


PEDIATRICS Volume 137 , number 6 , June 2016 5

TABLE 1 Characteristics of Included Studies

Study Population Intervention (Dose

Category)

Comparisons (Dose

Category)

Study

Duration

Outcomes

Bacharier et al

2008 (parallel

RCT)

Children 12–59 mo

with intermittent

asthma/EVW; mean

age 36 mo, 65%

male, 34% with

eczema, 45% with

parental asthma

Intermittent ICS:

budesonide 1 mg BID

via nebulizer (high)

× 7 d started at fi rst

sign of URTI

1) Intermittent

montelukast:

4 mg daily × 7 d

started at fi rst

sign of a URTI

52 wk Primary outcome: SFDs (mean percentage):

intermittent ICS (76%), intermittent montelukast

(73%), placebo (74%)

2) Placebo Proportion of children with exacerbations:

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

1999 (parallel

RCT)

Children 12–47 mo

with persistent

asthma; mean age

28 mo, 66% male,

42% with eczema,

72% with family

history of asthma

Daily ICS: 2 doses

fl uticasone

suspension via MDI,

mask, and spacer

used: 1) 0.05 mg BID

(low), 2) 0.1 mg BID

(medium)

Placebo 12 wk Primary outcome: mean increase in percentage of

cough-free days compared with placebo- 0.05 mg

dose (8%), 0.1 mg dose (12%)

Proportion of children with exacerbation: daily ICS

(5%), placebo (16%)

Brand et al 2011

(parallel RCT)

Children ages

24–72 mo with

persistent asthma

and positive API,

median age 48 mo,

63% male

Daily ICS: 3 doses

ciclesonide via

nebulizer used: 1) 40

μg QHS (low), 2) 80

μg QHS (low), 3) 160

μg QHS (medium)

Placebo 24 wk Primary outcome: proportion of children with

exacerbations: 40 μg (4.4%), 80 μg (7.3%), 160 μg

(6.7%), placebo (10.2%)

Carlsen et al

2005 (parallel

RCT)

Children age 12–47

mo with mild

persistent asthma,

mean age 28 mo,

68% male, 56%

with family history

of asthma

Daily ICS: fl uticasone

suspension 0.1 mg

BID via pMDI/mask/

spacer (medium)

Placebo 12 wk Primary outcome: SFDs (mean percentage): daily

ICS (33%), placebo (20%)

Proportion of children with exacerbations: daily ICS

(6%), placebo (12%)

Connett and

Lenney 1993

(crossover

RCT)

Children ages

12–60 mo with

intermittent

asthma/EVW; 56%

male, 48% with

family history of

atopy

Intermittent ICS:

budesonide solution

0.8 mg BID (high)

via Nebuhaler or 1.6

mg BID (high) via

Nebuhaler with mask

× 7 d started at fi rst

sign of URTI

Placebo 26 wk Primary outcome: mean symptom score (daytime

wheeze): intermittent ICS (0.69), placebo (0.97),

P < .05

Proportion of children with exacerbations:

intermittent ICS (8%), placebo (32%)

Connett et al

1993 (parallel

RCT)

Children 12–36 mo

with persistent

asthma; mean age

22 mo, 65% male,

58% with family

history of asthma

Daily ICS: budesonide

solution 0.2 mg

BID via Nebuhaler

(medium)

Placebo 26 wk Primary outcome: mean change in nighttime cough

symptom score: daily (−0.4), placebo (+0.1), P

< .05

SFDs (mean percentage): daily (54%), placebo

(31%), P < .0001

de Benedictis

et al 1996

(parallel RCT)

Children ages 4–32

mo, mean age 14

mo, 74% male, 18%

with eczema

Daily ICS: fl ucinolide

20 μg/kg BID via

nebulizer

Placebo 12 wk Proportion of children with exacerbations: daily

(62%), placebo (66%)

de Blic et al 1996

(parallel RCT)

Children 6–30 mo,

mean age 17 mo,

87% male, 47%

with parental

atopy

Daily ICS: budesonide 1

mg BID via nebulizer

(high)


exacerbations: daily ICS (40%), placebo (83%)


KAISER et al 6


Category)

Comparisons (Dose

Category)

Study

Duration

Outcomes

Ducharme et al

2009 (parallel

RCT)

Children 12–72 mo

with intermittent

asthma/EVW; mean

age 32 mo, 60%

male, 43% with

eczema, 47% with

family history of

asthma

Intermittent ICS:

fl uticasone

suspension 0.75 mg

BID (high) via mask/

spacer started at

fi rst sign of URTI and

stopped after 48 h

without symptoms


exacerbations: intermittent ICS (39%), placebo

(64%)

Mean change in height from baseline (cm):

intermittent ICS (6.23 ± 2.62), placebo (6.56 ±

2.90), NS

Gleeson and

Price 1988

(crossover

RCT)

Children 24–72 mo

with persistent

asthma; median

age 51 mo; 67%

male, 38% with

asthma


solution 0.2 mg

BID via Nebuhaler

(medium)

Placebo 6 wk in

each arm

(crossover)

Primary outcome: mean change in peak expiratory

fl ow: daily ICS (112%), placebo (101%), P < .05

Proportion of children with exacerbations: daily

(2.6%), placebo (10.3%)

Guilbert et al

2006 (parallel

RCT)

Children 24–36 mo

with positive API;

mean age 36 mo,

62% male, 54%

with eczema, 65%

with parental

history of asthma


suspension 88 μg BID

via MDI with mask/

spacer (medium)


(93%), placebo (88%), P = .006


(60%), placebo (65%)

Change in height: daily (12.6 cm), placebo (13.7 cm)

Murray et al

2006 (parallel

RCT)


mo, mean age 22

mo, 65% male,

47% with maternal

asthma


suspension 0.1 mg

BID via MDI (medium)

Placebo 260 wk Primary outcome: prevalence of asthma at 5 y of

age: daily ICS (61%), placebo (64%), P = .68


(15.8%), placebo (14.1%)

Change in height z score at 5 y: daily ICS (0.002),

placebo (0.066), P = .501

Papi et al 2009

(parallel RCT)

Children 12–28 mo

recruited during

acute wheezing

exacerbation

during URTI; mean

age 28 mo, 60%

male

Daily ICS:

beclomethasone 0.4

mg BID via nebulizer

(high)

1) Intermittent ICS:

beclomethasone

0.8 mg (high)

and salbutamol

1.6 mg PRN via

nebulizer during

exacerbation; 2)

Placebo

12 wk Primary outcome: SFDs (mean percentage): daily

(69.6%), intermittent (64.9%), placebo (61.0)


(1.8%), intermittent (5.5%), placebo (9%)

Qaqundah et al

2006 (parallel

RCT)

Children age 12–48

mo with persistent

asthma; mean age

30 mo, 62% male


suspension 88 μg BID

via MDI with mask/

spacer (medium)

Placebo 12 wk Primary outcome: percentage change in daily

asthma symptom score: daily (−53.9%), placebo

(−44.1%), P = .036


(5%), placebo (12%)

SFDs (mean percentage): daily (36%), placebo (36%)

Roorda et al

2001 (parallel

RCT)


mo with persistent

asthma; mean age

29 mo, 66% male,

47% with eczema,

71% with family

history of asthma


suspension 0.1 mg

BID via mask/spacer

(medium)


ICS (54%), placebo (36%)

proportion of children with exacerbations: daily ICS

(25%), placebo (36%)

Svedmyr et al

1999 (parallel

RCT)

Children 12–36 mo

with intermittent

asthma/EVW. Mean

age 26 mo, 69%

male, 35% with

eczema, 24% with

positive skin-prick

test

Intermittent ICS:

budesonide solution

0.4 mg QID (high)

× 3 d, then 0.4 mg

BID (high) × 7 d

via mask/spacer

(started at fi rst sign

of a URTI)

Placebo 52 wk Primary outcome: mean symptom score:

intermittent ICS (0.38 ± 0.21), placebo (0.55 ±

0.38), P = .028



TABLE 1 Continued



Data from 2 studies (N = 498) directly

comparing daily with intermittent

ICS showed no differences in rates

of severe exacerbations (25.7% and

28.1%, respectively; RR 0.91; 95% CI,

0.71–1.18; P = .49, I2 = 43%).

Bacharier et al19 (n = 190) showed

no significant differences in rates

of severe exacerbations comparing

intermittent ICS to intermittent

montelukast (38.5% and 46.8%,


1.15; P = .25). Szefler et al34

(n = 202) showed a significant

reduction in rates of severe

exacerbations with daily ICS versus

daily montelukast (21.9% and 37.1%,

respectively; RR 0.59; 95% CI,

0.38–0.92; P = .02).

We performed sensitivity analyses

excluding studies with high risk of

bias in ≥1 domain. Findings were

similar to our primary analysis for

2 comparisons, with daily ICS better

than placebo (5/15 studies excluded,

RR 0.67; 95% CI, 0.58–0.77) and

no differences comparing daily ICS

versus intermittent ICS (1/2 studies

excluded, RR 0.33; 95% CI, 0.07–

1.62). With the exclusion of 3 out of

6 studies comparing intermittent

ICS with placebo, the benefit of

intermittent ICS was no longer

statistically significant (RR 0.61;

95% CI, 0.35–1.07). Both studies

comparing ICS with montelukast

had high risk of bias in ≥1 domains.

We also performed a sensitivity

analysis excluding only the 4 studies

7


Category)

Comparisons (Dose

Category)

Study

Duration

Outcomes

Szefl er et al 2013

(parallel RCT)


mo with persistent

asthma; mean age

56 mo, 61% male


0.5 mg QHS via

nebulizer (high), for

mild exacerbations

escalation to

budesonide 0.5 mg

BID via nebulizer

Montelukast: 4 mg

or 5 mg daily

based on age

52 wk Primary outcome: median time to fi rst asthma

exacerbation: daily ICS (183 d), montelukast (86

d), P = .128


(21.9%), montelukast (37.1%)

Wasserman et al

2006 (parallel

RCT)

Children 24–47 mo

with persistent

asthma; mean age

36 mo, 61% male

Daily ICS: 2 doses

fl uticasone

suspension via

mask/spacer used:

1) 44 μg BID (low), 2)

88 μg BID (medium)

Placebo 12 wk Primary outcome: mean change in asthma symptom

score: daily ICS 44 μg (−0.5), daily ICS 88 μg

(−0.7), placebo (−0.5), P < .05 comparing 88 μg

to placebo


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

(crossover

RCT)

Children 18–72 mo;

mean age 41 mo,

88% male, 44%

with eczema

Daily ICS:

beclomethasone

0.15 mg daily via

nebulizer (medium)

Placebo 8 wk Primary outcome: total symptom score (median):

daily (182), placebo (182), NS


(23%), placebo (23%)

Wilson and

Silverman

1990

(crossover

RCT)

Children 12–60 mo

with intermittent

asthma/EVW; mean

age 42 mo, 71%

male

Intermittent ICS:

beclomethasone

solution 0.75 mg plus

bronchodilator TID

(high) via MDI and

spacer × 5 d started

at the fi rst sign of

asthma attack

Placebo plus

bronchodilator

TID × 5 d started

at the fi rst sign

of asthma attack



Wilson et al 1995

(parallel RCT)

Children 8–72 mo

with intermittent

asthma/EVW; mean

age 1.9 y, 59%

male, 82% with

family history of

asthma


solution 0.2 mg BID

via MDI with mask/

spacer (medium)

Placebo 16 wk Primary outcome: daily symptom score (median):

daily (0.6), placebo (0.63), NS


(10%), placebo (10%)

SFDs (median): daily (73%), placebo (78%)

Zeiger et al 2011

(parallel RCT)

Children 12–53 mo

with intermittent

asthma/EVW and

positive API; 46%

between 12–23

mo, 69% male,

53% with eczema,

64% with parental

asthma


0.5 mg daily via

nebulizer (high)

Intermittent ICS:

budesonide

1 mg BID via

nebulizer

started at the

onset of URTI × 7

d (high)

52 wk Primary outcome: rate of exacerbations per patient-

year: daily (0.97), intermittent (0.95), NS


(44.6%), intermittent (46.0%)

SFDs (mean percentage): daily (78%), intermittent

(78%)

Change in height: daily (7.8 cm), intermittent (8.0

cm)

API, asthma predictive index; BID, 2 times daily; MDI, metered dose inhaler; NS, not signifi cant; PRN, as needed; QHS, at bedtime; QID, 4 times daily; TID, 3 times daily.

TABLE 1 Continued


KAISER et al

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

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%,


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


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


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

8

FIGURE 2Risk of Bias Diagram.


PEDIATRICS Volume 137 , number 6 , June 2016 9

FIGURE 3Meta-analyses of strategies for preventing severe exacerbations in preschoolers with recurrent wheeze. M-H, Mantel–Haenszel.


KAISER et al

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).

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

10

FIGURE 4Meta-analyses of strategies for preventing severe exacerbations in preschoolers with intermittent asthma or viral-triggered wheeze (subgroup analysis). M-H, Mantel–Haenszel.



of daily ICS, intermittent ICS, and

montelukast in preventing severe

exacerbations among preschool


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

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 5Meta-analyses of strategies for preventing severe exacerbations in preschoolers with persistent asthma (subgroup analysis). M-H, Mantel–Haenszel.


KAISER et al


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

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;

12

FIGURE 6Meta-analyses of strategies for preventing severe exacerbations in preschoolers with unclear or mixed wheezing phenotypes (subgroup analysis). M-H, Mantel–Haenszel.



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

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


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.

13

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


KAISER et al

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14

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: [email protected]

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 fi nancial 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 confl icts of interest to disclose.



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DOI: 10.1542/peds.2015-4496 originally published online May 26, 2016; 2016;137;Pediatrics

Anne Bakel, Patricia C. Parkin and Michael D. CabanaSunitha V. Kaiser, Tram Huynh, Leonard B. Bacharier, Jennifer L. Rosenthal, Leigh

Meta-analysisPreventing Exacerbations in Preschoolers With Recurrent Wheeze: A

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DOI: 10.1542/peds.2015-4496 originally published online May 26, 2016; 2016;137;Pediatrics

Anne Bakel, Patricia C. Parkin and Michael D. CabanaSunitha V. Kaiser, Tram Huynh, Leonard B. Bacharier, Jennifer L. Rosenthal, Leigh

Meta-analysisPreventing Exacerbations in Preschoolers With Recurrent Wheeze: A

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