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ARTICLE

Asthma Therapy in Pediatric


Patients: A Systematic
Review of Treatment With
Montelukast Versus Inhaled
Corticosteroids
Kristen Massingham, MS, CPNP, Shelley Fox, MS, FNP-BC,
& Arlene Smaldone, DNSc, CPNP, CDE

ABSTRACT
Introduction: Inhaled corticosteroids (ICS) are a first-line
treatment for mild persistent asthma, but montelukast
(MON) monotherapy also has been beneficial. The aim of
this review is to evaluate current evidence comparing MON
versus ICS monotherapy in pediatric patients.
Method: A systematic review was conducted of randomized
controlled trials evaluating treatment of mild to moderate
persistent asthma in which MON was compared with ICS
monotherapy in children aged 2 to 18 years. PubMed, the Cumulative Index to Nursing and Allied Health Literature, and
the Institute of Scientific Informations Web of Knowledge
Kristen Massingham, Pediatric Nurse Practitioner, Essex
Pediatrics, Doctor of Nursing Practice Program, Columbia
University School of Nursing, New York, NY.
Shelley Fox, Family Nurse Practitioner, Khasak Dermatology,
Doctor of Nursing Practice Program, Columbia University School
of Nursing, New York, NY.
Arlene Smaldone, Associate Professor of Clinical Nursing,
Columbia University School of Nursing, New York, NY.
Conflicts of interest: None to report.
Correspondence: Kristen Massingham, MS, CPNP, Columbia
University School of Nursing, 630 West 168th St, New York, NY
10032; e-mail: klm2158@columbia.edu.
0891-5245/$36.00
Copyright Q 2014 by the National Association of Pediatric
Nurse Practitioners. Published by Elsevier Inc. All rights
reserved.
Published online January 10, 2013.
http://dx.doi.org/10.1016/j.pedhc.2012.11.005

www.jpedhc.org

were searched using key words asthma, MON, and ICS. Studies that met inclusion criteria were appraised for quality.
Results: Of 214 identified studies, eight met inclusion criteria
and seven were deemed high quality. Study sample sizes
ranged from 62 to 994, 88% were multi-site, and the average
length of follow-up was 8.2 months. Asthma symptoms improved with both therapies. Four studies reported superiority of ICS compared with MON; the remaining studies
showed no differences between therapies.
Discussion: These results are consistent with the National
Asthma Education and Prevention Program (2007) recommendation that ICS therapy should be first-line treatment in
children with mild to moderate persistent asthma. J Pediatr
Health Care. (2014) 28, 51-62.

KEY WORDS
Asthma, inhaled corticosteroids, montelukast

Asthma affects approximately 7 million children


in the United States, accounting for 9.4% of the
pediatric population (Centers for Disease Control and
Prevention, 2010). Asthma prevalence in children has
increased considerably in recent years and currently is
at the highest level reported in the United States
(Akinbami, Moorman, & Liu, 2011). Asthma is associated with a high risk of morbidity. In children with
mild persistent asthma, 52% are at risk for adverse outcomes, including hospitalization or emergency department visits (Akinbami et al., 2011). Further, asthma
limits daily function. Approximately 60% of children
with asthma miss at least one day of school each year.
In 2008, more than 10 million school days were missed
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51

because of asthma exacerbations in children aged 5 to


17 years (Akinbami et al., 2011).
A higher prevalence of asthma exists in children compared with adults. Although asthma generally is more
common among women than among men in adulthood, in children younger than 17 years, boys have
a higher prevalence than do girls. Furthermore, racial
and socioeconomic disparities persist, with Black children and those with a family income below the federal
poverty level more likely to be affected by asthma
(Akinbami et al., 2011). African American children
have a 16% prevalence rate for asthma compared with
8% in non-Hispanic White children (U.S. Department
of Health & Human Services, 2011).
Effective management of persistent asthma in children can be extremely challenging. Asthma symptoms
can be managed by avoiding environmental stimuli,
monitoring disease progression, using controller medications, and/or using quick-relief medications (Fanta,
2009). Current recommendations by the American
Academy of Pediatrics and the National Asthma
Education and Prevention Program guidelines (2007) include using inhaled corticosteroids (ICS) as a first-line
controller medication (Rachelefsky, 2009). ICS work
by decreasing inflammation and hyperresponsiveness
of the bronchioles (Wolthers, 2009). A key component
to management of persistent asthma is prevention of
asthma exacerbations. Use of anti-inflammatory medication, including ICS, is an important tool in asthma
management. Because asthma varies in severity, treatment must be tailored to individual patients to best
manage symptoms. Montelukast (MON), a leukotriene
antagonist, is an alternative treatment option to ICS.
MON works by blocking cysteinyl leukotrienes, a class
of proinflammatory mediators, which decrease eosinophil migration, bronchoconstriction, and mucous hypersecretion (Harmanci, 2007). MON typically is used
as either second-line monotherapy or as combined therapy with ICS but can possibly be used as a first-line treatment option (Dahl
en, Dahl
en, & Drazen, 2011). One
published systematic review compared effectiveness
of monotherapy with MON versus ICS in children and
adults with mild to moderate persistent asthma
(Ducharme & di Salvio, 2004). However, only one trial
included in the systematic review was limited to children
with persistent asthma younger than 18 years, and the
results were inconclusive (Maspero et al., 2001), thus indicating a need for further investigation of this topic in
the pediatric population.
Although ICS are the recommended first-line
controller medication for mild to moderate persistent
asthma, equally effective alternative options may exist
(Dahl
en et al., 2011). One potential advantage of
MON is the ease of administration because it is
a once-daily oral medication compared with ICS, which
is a twice-daily inhaled medication and requires greater
cooperation from the child. In the pediatric population,
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a spacer is recommended when using medication delivered by a meter dose inhaler to increase the efficiency of
drug delivery. Proper delivery technique of aerosol
medications is extremely important to ensure that the
patient receives the full dose of the prescribed medication. Spacer devices have been shown to increase the
amount of delivered medication and improve lung delivery in children who may lack the ability to cooperate
with treatment because of limited developmental and
cognitive abilities (Myers & Tomasio, 2011). Administration via nebulization is beyond the scope of this review because this method of delivery typically is used
for acute exacerbations and is rarely indicated for
chronic use. Many children with asthma have concurrent rhinitis, a symptom that MON can address directly
(Dahlen, 2006). In addition, MON has fewer safety
concerns and is well tolerated (Knorr et al., 2001).
The most frequently reported adverse events include
headache, pharyngitis, gastrointestinal disorders, and
rash, although rates of these events are similar between
those receiving active medication and placebo
(Montella et al., 2012). Although ICS also have few adverse effects, particular concern exists about delayed
bone growth in children who take ICS on a long-term
basis (Pedersen et al., 2007). Until more is known about
the long-term effects of ICS, MON is considered a safe
alternative pharmacotherapy (Kazani, Ware, Drazen,
Taylor, & Sears, 2010).
This article seeks to systematically review the literature, following the Preferred Reporting Items for
Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Moher, Liberati, Tetzlaff, Altman, & the PRISMA
Group, 2009), to evaluate the effectiveness of asthma
management using MON monotherapy compared
with ICS monotherapy in children between 2 to 18 years
of age with mild to moderate persistent asthma.
METHODS
Search
Before beginning this review, searches of PubMed, the
Cochrane Library, and the Turning Research into Practice (TRIP) database (http://www.tripdatabase.com/)
were conducted to ensure that a comparable systematic
review had not been published. The search for randomized controlled trials (RCTs) on this topic was performed using PubMed, the Cumulative Index to
Nursing and Allied Health (CINAHL), and the Institute
of Scientific Informations Web of Knowledge. Searches
were conducted independently by two reviewers, using the following key words: asthma, MON, and ICS.
To reflect current treatment strategies, we restricted
studies to those published in the past 10 years (January
2002 to November 2011). The reference lists of studies
identified in the search were assessed for additional
studies that met the specified inclusion criteria. Only
RCTs that compared MON monotherapy with ICS
monotherapy were included; all other study designs
Journal of Pediatric Health Care

were excluded. Studies that assessed effectiveness of


asthma treatment with the aforementioned medications
were included regardless of the outcomes measured.
Studies were restricted to pediatric trials of children between 2 and 18 years of age with mild to moderate persistent asthma; studies comparing treatment options for
children with severe persistent asthma were excluded
because these patients require more intensive treatment and are not eligible for monotherapy. Finally,
studies were restricted to those published in the English
language.
Two reviewers independently evaluated each study
identified by the literature search to determine eligibility for inclusion. Search engine results were screened
for full text availability. Each study identified by the
search was assessed based on the title and abstract in accordance with the inclusion/exclusion criteria. Studies
that met inclusion/exclusion criteria based on the initial
screening were further reviewed to verify that study
characteristics and procedures met the criteria for inclusion in the systematic review.
Quality Assessment
The PEDro scale was used to assess risk of bias and
validity of individual studies. A number of scales currently are available to assess the methodological
quality of RCTs. Using a Delphi technique, items of
the PEDro scale (Verhagen et al., 1998) were based on
a consensus of experts. The scale has face validity
(Verhagen et al., 1998) and good interrater reliability
(Maher, Sherrington, Herbert, Moseley, & Elkins,
2003). The PEDro scale evaluates 11 quality elements:
eligibility criteria specified; random allocation; allocation concealment; similarity of groups at baseline;
blinding of participants; blinding of therapists; blinding
of assessors; dropout rate; intention-to-treat analysis;
statistical analysis of outcomes measured; and differences in the treatment effects between outcome measures of each group. A point is awarded when a study
clearly satisfies a criterion, and if the criterion is not satisfied, no point is awarded. Two reviewers independently assessed the quality of each study. If the
category was satisfied, a score of 1 was assigned. If
the category was not satisfied, a score of 0 was assigned.
The maximum score was 11. If disagreement occurred
between reviewers on the assigned score, consensus
was achieved through discussion. Each study with a total score of 8 or higher was considered to be of high
methodological quality. After appraisal of individual
studies, risk of bias across studies was assessed by
examining sample size, length of follow-up, blinding,
assessment of asthma severity, and consistency of study
findings. The frequency of reported adverse events
were quantitatively synthesized across studies where
data were available; comparisons between groups
are reported as relative risks with a 95% confidence
interval.
www.jpedhc.org

RESULTS
Study Selection
After the initial search of three databases, 214 records
were identified and duplicates were eliminated, leaving
157 studies. After the initial screening of the title and abstract, 108 studies were eliminated. The primary reason
for exclusion was study design, including combination
therapy. The full text of 49 studies was further evaluated, and 41 studies were eliminated, primarily because
the study design was not an RCT. In total, 8 studies
met all inclusion/exclusion criteria and were included
in the review. The Figure provides detailed results of
the literature search.
Quality Assessment
Seven of the eight studies were deemed to be of high
quality with a score of 8 or higher on the PEDro scale.
Table 1 provides a detailed assessment of each study using the PEDro criteria. Risk of bias primarily was related
to dropout rates greater than 15% in three studies (Kooi
et al., 2008; Ostrom et al., 2005; Szefler, Baker, Uryniak,
Goldman, & Silkoff, 2007) and lack of intention-to-treat
analysis in two studies (Kumar, Ramesh, Lodha,
Pandey, & Kabra, 2007; Szefler et al., 2005). One study
did not use subject and investigator blinding by having
each participant take either a placebo oral tablet or inhaler in addition to the active medication (Szefler
et al., 2007). Four studies specified the method used
to blind patients to active versus placebo MON through
overencapsulated tablets (Sorkness et al., 2007), sugarcoated tablets (Maspero et al., 2008; Ostrom et al.,
2005), and similar appearance of tablets (Kooi et al.,
2008; Kumar et al., 2007), and three studies specified
use of identical diskus devices to blind patients to active
versus placebo ICS (Kooi et al., 2008; Kumar et al., 2007;
Sorkness et al., 2007). Patients lost to follow-up ranged
between 6.9% to 29% across studies. In three studies, attrition rates greater than 15% were reported (Kooi et al.,
2008; Ostrom et al., 2005; Szefler et al., 2007). The study
by Szefler and colleagues (2007) had the greatest dropout rate at 29%.
Study Findings
Table 2 summarizes each of the eight randomized trials included in the review. A total of 2,833 children
(62% male) participated in the studies. Four trials
were conducted in the United States (Ostrom et al.,
2005; Sorkness et al., 2007; Szefler et al., 2005;
Szefler et al., 2007). Of these, participant race and ethnicity characteristics were reported in three studies,
with a total of 70.1% of participants reported as White.
Study participants ranged in age from 2 to 17 years,
with a mean age of 8.6  1.9 years. Only two studies
included children younger than 5 years (Kooi et al.,
2008; Szefler et al., 2007). The sample sizes varied
greatly across studies, as did the study locations and
the length of follow-up. Sample size ranged from 62
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53

FIGURE. Flow diagram of study inclusion process. CINAHL, Cumulative Index to Nursing and Allied
Health Literature; ICS, inhaled corticosteroids; RCT, randomized controlled trial.
Identification

Studies identified through


database searching (n=214)
from
PubMed (n=105)
CINAHL(n= 0)
ISI Web of Knowledge (n=109)

Additional studies identified


through review of reference list
of included articles (n=22)

Screening

Studies after duplicates removed


(n=157)

Studies excluded (n=108)


Intermittent or severe persistent
asthma(n=19)
Age less than 2 or more than 18
years (n=16)
Combination therapy (n=35)
Outcome measure not control of
asthma symptoms (n=2)
Not comparing ICS (n=33)
Not RCT (n=3)

Eligibility

Studies screened
(n=157)

Full-text studies excluded (n=41)


Combination therapy (n=2)
Not ICS (n=10)
Age less than 2 or more than 18
years(n=10)
Not RCT (n=11)
Outcome measure not control of
asthma symptoms (n=2)
Intermittent or severe persistent
asthma (n=6)

Included

Full-text studies assessed for


eligibility (n=49)

Studies included in qualitative


synthesis (n=8)

to 994 participants, with most studies (n = 6) having


a sample greater than 100 participants. Most studies
(n = 7) were multi-site trials, with the number of study
sites ranging from 3 to 104. Length of follow-up
ranged from 2 months to 2 years with an average of
8.2 months; five trials were conducted over a period
of 3 months or less (Kooi et al., 2008; Kumar et al.,
2007; Maspero et al., 2008; Ostrom et al., 2005;
Szefler et al., 2005). The dose of ICS and MON also
varied across studies.
Outcome measures varied across studies. It is of interest that in all studies, subjects showed an improve-

ment in asthma symptoms from baseline regardless of


treatment assignment. Pulmonary function was an outcome of interest in seven studies, with results favoring
ICS over MON. These studies reported significant
changes in peak expiratory flow rate (Maspero et al.,
2008), forced expiratory volume in 1 second (FEV1;
Garcia et al., 2005; Maspero et al., 2008; Ostrom et al.,
2005; Sorkness et al., 2007; Szefler et al., 2005), and
asthma control days (Sorkness et al., 2007). Only one
study that measured an objective pulmonary function
parameter (change in FEV1) as its primary outcome detected no differences between groups (Kumar et al.,

TABLE 1. Assessment of potential bias in included randomized controlled trials using the PEDro
scoring system
Author

II

III

IV

VI

VII

VIII

IX

XI

Total

Garcia et al. (2005)


Kooi et al. (2008)
Kumar et al. (2007)
Maspero et al. (2008)
Ostrom et al. (2005)
Sorkness et al. (2007)
Szefler et al. (2005)
Szefler et al. (2007)

1
1
1
1
1
1
1
1

1
1
1
1
1
1
1
1

1
1
1
1
1
1
1
1

1
1
1
1
1
1
1
1

1
1
1
1
1
1
1
0

1
1
1
1
1
1
1
0

1
1
1
1
1
1
0
0

1
0
1
1
0
1
1
0

1
1
0
1
1
1
0
1

1
1
1
1
1
1
1
1

1
1
1
1
1
1
1
1

11
10
10
11
10
11
9
7

1, criteria fulfilled, low possibility of bias; 0, criteria not fulfilled, high possibility of bias.
Assessment criteria: I, Eligibility criteria specified; II, random allocation; III, allocation concealed; IV, groups similar at baseline; V, subject
blinding; VI, therapist blinding; VII, assessor blinding; VIII, less than 15% dropout rate; IX, intention-to-treat analysis; X, measurement of difference between groups in outcomes; XI, size of treatment effect and measures of variability (i.e., confidence intervals, standard errors, standard deviations, interquartile ranges, and minimum-maximum range).

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Volume 28  Number 1

Journal of Pediatric Health Care

www.jpedhc.org

TABLE 2. Characteristics of individual studies


Study

Multisite (yes/no)

Sample size

Intervention groups

January/February 2014

Study duration

Study findings
Change in RFDs:
MON, 22.4%
ICS, 25.2%
p = NS
Mean change FEV1:
MON, 0.27 L
ICS, 0.30 L
p = .004
$ 3 School days missed:
MON, 1.9%
ICS, 2.1%
Treatment adherence:
MON, 98.1%
ICS, 98%
Change in eosinophils (103 cells per mL)
MON, 0.08
ICS: 0.06
p = NS
Daily symptom score:
Improvement with ICS and MON
p = NS
RFDs:
Significant decrease in both groups
p = NS
Oral corticosteroid use:
MON: 1 child
ICS: 1 child
Change in FEV1:
MON, 1.26 L
ICS, 1.44 L
p = NS
Oral corticosteroid use:
MON, none
ICS, none

Garcia et al. (2005)

Yes

N = 994
Age 6-14 years

MON, 5 mg daily, versus ICS, 100 mcg BID

12 months

Kooi et al. (2008)

Yes

N = 63
Age 2-5 years

MON, 4 mg daily and placebo inhaler, versus


ICS, 100 mcg BID and placebo oral tablet, versus
placebo oral tablet and placebo inhaler

3 months

Kumar et al. (2007)

No

N = 62
Age 5-15 years

MON, 5 mg tabs + placebo inhaler, versus


ICS, 200 mcg BID + placebo oral tablet

3 months

Continued on page 56

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TABLE 2. Continued.

Journal of Pediatric Health Care

Study

Multisite (yes/no)

Sample size

Intervention groups

Study duration

Maspero et al. (2008)

Yes

N = 548
Age 6-14 years

MON, 5 mg daily + placebo inhaler BID, versus


SFC, 50/100 mg inhaler BID + placebo tablet daily

3 months

Ostrom et al. (2005)

Yes

N = 342
Age 6-12 years

MON, 5 mg once daily + placebo inhaler, versus


ICS, diskus 50 mcg BID + placebo oral tablet

3 months

Sorkness et al. (2007)

Yes

N = 285
Age 6-14 years

MON, 5 mg in the evening + placebo diskus BID, versus


ICS inhaler, 100 mg BID + placebo oral tablet
Fluticasone 100 mg/salmeterol 50 mg diskus in morning
and 50 mg of salmeterol diskus in the evening
(PACT) + placebo oral tablet daily

11 months

Study findings
Change in evening PEFR:
MON, 28.0 L/min
SFC, 46.2 L/min
FEV1 improvement:
MON, 22.08%
ICS, 33.83%
RFDs:
MON, 15 days
ICS, 24 days
(p < .001)
Treatment adherence:
MON, 84%
ICS, 87%
Change in FEV1:
MON, 4.60%
ICS, 10.62%
RFDs:
MON, 35.0%
ICS, 45.1%
(p = .002)
Oral corticosteroid use:
MON, 4%
ICS, 3%
Treatment adherence:
MON, 97.8%
ICS, 92.8%
Change in asthma
control days:
MON, 52.5%
ICS, 64.2%
PACT, 59.6%
FEV1, % predicted:
MON, 0.58%
ICS, 6.32%
(p < .001)
PACT: 3.62%
Treatment adherence:
Capsule count (MON), 86%
Diskus (ICS and PACT), 90%

www.jpedhc.org

Szefler et al. (2005)

Yes

N = 144
Age 6-17 years
Crossover design

MON daily (5-10 mg) + placebo inhaler versus


ICS, 100 mg one puff BID + placebo oral tablet

2 months

Szefler et al. (2007)

Yes

N = 395
Age 2-8 years

MON, 4-5 mg versus


ICS, inhaled suspension 0.5 mg daily

12 months

FEV1, % predicted:
MON, .20%
ICS, 0.32%
(p = .05)
Oral corticosteroid use:
MON, 10 children
ICS, 2 children
Treatment adherence:
MON, 97% period 1
92% period 2
ICS, 94% period 1
89% period 2
Probability of having
an event:
MON, 9.6%
ICS, 6.6%
p = NS
FEV1:
MON, 0.05 L
ICS, 0.09 L
p = NS
RFDs:
MON, 37.24%
ICS, 38.74%
p = NS
Oral corticosteroid use:
MON, 32%
ICS, 25.5%
Treatment adherence:
MON, 82.8%
ICS, 82.9%

BID, Twice a day; EFD, episode-free day; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; MON, montelukast; RFD, rescue-free day; PEFR, peak expiratory flow rate; NS, no
significant difference; SFC, salmeterol/fluticasone propionate.

January/February 2014
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2007). Six studies measured rescue-free days, with the


majority reporting superiority of ICS over MON
(Garcia et al., 2005; Maspero et al., 2008; Ostrom
et al., 2005; Sorkness et al., 2007). In general, studies
that found no differences between treatment groups
measured more subjective patient outcomes: change
in daily symptom score (Kooi et al., 2008) and change
in the probability of asthma exacerbation (Szefler
et al., 2007).
Clinical adverse events were reported in all studies
and favored ICS versus MON. Asthma exacerbation
was the most frequently reported event and was reported in all eight studies. Across studies, 182 of 1,345
children (13.5%) assigned to MON and 128 of 1,468 children (8.7%) assigned to ICS experienced an asthma exacerbation; the risk of asthma exacerbation was 1.6
times higher (relative risk [RR] 1.56, 95% confidence interval [CI] 1.3-1.9) for children assigned to MON compared with ICS. Five studies reported the need for oral
corticosteroid use (Kooi et al., 2008; Kumar et al.,
2007; Ostrom et al., 2005; Szefler et al., 2005; Szefler
et al., 2007). Across studies, 81 of 488 children (16.6%)
assigned to MON and 58 of 498 children assigned to
ICS (11.6%) required oral corticosteroids, with the risk
of oral corticosteroid use 1.4 times higher (RR 1.43,
95% CI 1.04-1.9) for children assigned to MON versus
ICS. Other less frequently reported events were headache (Maspero et al., 2008; Ostrom et al., 2005), upper
respiratory infection (Kooi et al., 2008; Ostrom et al.,
2008), and skin rash (Kooi et al., 2008; Kumar et al.,
2007).
Six studies measured treatment adherence using selfreport (n = 3), pill counts (n = 4), diskus counts (n = 4),
and Electronic Drug Exposure Monitor (n = 2) methods.
Three studies used more than one method to measure
treatment adherence, such as measuring capsule counts
and diskus dose indicator in addition to either diary
cards or an electronic measure (Ostrom et al., 2005;
Sorkness et al., 2007; Szefler et al., 2005). On average,
self-reported adherence was high ($ 80%) across studies. Study findings were inconsistent across studies.
Two studies reported higher adherence in the MON
group (Ostrom et al., 2005; Szefler et al., 2005), two reported higher adherence in the ICS group (Maspero
et al., 2008; Sorkness et al., 2007), and two found no differences in adherence between the MON and ICS
groups (Garcia et al., 2005; Szefler et al., 2007).
Less frequently measured outcomes of interest were
school and parental work attendance, eosinophil
count, and linear growth. One study examined missed
school days (children) and missed work days (parents)
and found no differences between children in the ICS
group compared with the MON group (2.1% vs. 1.9%)
during the 12-month trial (Garcia et al., 2005). Three
studies measured serum eosinophil levels, and none
found differences between groups (Garcia et al.,
2005; Kooi et al., 2008; Szefler et al., 2005). Of these
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trials, only one study (Garcia et al., 2005) reported the


change in eosinophil level in the MON and ICS groups
before and after intervention ( 0.08  103 vs. 0.06 
103, p = .411). Three studies measured the childs linear
growth over the duration of the study. One study found
that children in the MON group demonstrated greater
annual height increase compared with the ICS group
(6.18 vs. 5.81 cm, p = .018; Garcia et al., 2005). The remaining two studies found no differences between
groups (Sorkness et al., 2007; Szefler et al., 2007).
Several areas of bias were noted across studies. Two
studies had sample sizes of less than 100 subjects and
may have lacked statistical power to detect treatment
differences; thus the results may be subject to type II error (Kooi et al., 2008; Kumar et al., 2007). Furthermore,
five of the studies were conducted for a 3-month duration or less (Kooi et al., 2008; Maspero et al., 2008;
Ostrom et al., 2005; Szefler et al., 2005), a period that
may have been too short to fully evaluate treatment response and maintenance of asthma control.
DISCUSSION
Summary of Evidence
Eight RCTs comparing the effects of ICS and MON in the
treatment of pediatric patients with mild to moderate
persistent asthma were included in this systematic review. All studies demonstrated that, regardless of treatment assignment, asthma symptoms improved from
baseline. This improvement may be
.although four
related to several facstudies favored ICS
tors, including response to the assigned
and four studies
treatment medication
found no
or the Hawthorne efdifferences
fect, where subjects
may change their bebetween groups,
havior because they
no study found
are aware that they are
MON monotherapy
in a clinical trial. Importantly,
although
superior to
four studies favored
monotherapy with
ICS and four studies
ICS.
found no differences
between groups, no
study found MON monotherapy superior to monotherapy with ICS. In addition, the two studies that reported
no differences between groups had small samples and
may have lacked statistical power to detect differences
between treatments, leading to type II error.
Most studies restricted their inclusion criteria to children with mild persistent asthma. Only three studies included children with moderate persistent asthma
(Ostrom et al., 2005; Sorkness et al., 2007; Szefler
et al., 2005). Therefore the ability to generalize the study
findings must be considered cautiously in treatment of
patients with moderate asthma. In addition, the ability
Journal of Pediatric Health Care

to generalize findings is limited in patients younger


than 5 years because only two studies examined this
population (Kooi et al., 2008; Szefler et al., 2007). Interestingly, the two studies that included children younger
than 5 years found no differences between treatment
groups (Kooi et al., 2008; Szefler et al., 2007), suggesting that MON may be of equal benefit in young children. One possible explanation for this finding may
be that asthma in young children is frequently virally induced and therefore may not require maintenance therapy with inhaled corticosteroids (Bisgaard et al., 2005;
Knorr et al., 2001). On the other hand, an alternative explanation for this finding could be that asthma exacerbations in this population were mild and ICS did not
provide increased benefit at reducing inflammation
compared with MON. Further research is needed in
management and best treatment options for young children with mild to moderate persistent asthma.
FEV1 was a physiologic outcome of several of the included studies, with most studies favoring ICS. This
finding reinforces the current recommendation that
ICS be used as first-line pharmacotherapy for persistent
asthma (Rachelefsky, 2009). Previous research has
demonstrated that a clinically relevant change in FEV1
is a 10% improvement from baseline (Santanello,
Zhang, Seidenberg, Reiss, & Barber, 1999). In the study
by Garcia and colleagues (2005), the absolute FEV1 difference between groups was only 2.2% and, although
statistically significant, may not be clinically important.
The large sample size in this study (N = 994) may have
provided statistical power to detect very small differences between groups.
Asthma exacerbations occurred more frequently in
the MON group. This finding is a significant consideration; however, it is important to note that the criterion
for exacerbation was subjective assessment of symptoms, which may have had an impact on the differences
identified between groups. Interestingly, only one study
evaluated missed days of school and work and found no
differences between those assigned to ICS versus MON
(Garcia et al., 2005). We include these findings in this
systematic review because both school and work attendance is important to the quality of life of both children
with asthma and their parents. However, when interpreting this finding, it is important to consider this result
as the outcome of one study only. More studies are
needed to determine the relationship between ICS
and MON monotherapy treatment and missed school
or work days. Other adverse effects were comparable
between groups across all studies. Although one trial
found a clinically significant difference in linear growth
in the MON group compared with the ICS group (Garcia
et al., 2005), the mean difference in annual growth
velocity between groups was very small and most likely
not clinically important. Although concern has been expressed about using ICS in prepubertal children with
asthma because of the potential for decreased skeletal
www.jpedhc.org

growth, several studies assessing linear growth over


time in children treated with ICS have shown a temporary decrease in growth velocity but no effect on final
adult height (Agertoft & Pedersen, 2000; Stefanovic,
Verona, Cicak, & Vrsalovic, 2011; The Childhood
Asthma Management Program Research group, 2000).
However, one recent study found that decreased skeletal growth in prepubertal children treated with ICS persisted as decreased adult height (Kelly et al., 2012).
Blinding of study medication may have been problematic in some of the included RCTs. Most studies implemented use of either a placebo oral tablet or inhaler
in addition to active medication. However, only three of
the studies specified the techniques used to make the
active medication and placebo similar in taste or odor
(Ostrom et al., 2005; Sorkness et al., 2007; Szefler
et al., 2005). Without this detail, it is difficult to assess
the adequacy of blinding in the remaining studies. Further, the lack of attempting to blind the study medication in the additional studies may have led to bias that
affected the results.
Enrollment of minority children at higher risk for
asthma was limited. Only four studies reported race
and ethnicity characteristics of their samples. Of these,
most subjects reported their race as white (Garcia et al.,
2005; Maspero et al., 2008; Szefler et al., 2005; Szefler
et al., 2007). In the remaining studies, one in the Netherlands, one in India, and two in the United States, race
and ethnicity were not reported. This lack of information is particularly important in studies conducted in
the United States because of the diversity of the population. There is a higher prevalence of asthma in Black
children compared with White children and a lower
prevalence among Asian children (Akinbami et al.,
2011). Failure to include minority children in the trials
may limit the ability to generalize findings to these populations.
Of note, all studies included a higher percentage of
male participants and reflect the higher prevalence of
asthma in male youth. However, it is unclear if children
of families with income below the federal poverty level,
known to be at higher risk of asthma (Akinbami et al.,
2011), were included in the research because socioeconomic status was not reported in any of the included
studies.
All studies included in this review used medication
dosages within the recommended range by specific
age categories of the children enrolled (Taketomo,
Hodding, & Kraus, 2010). Interestingly, although differences in dosing occurred across studies, the variability
in dosing did not seem to have affected the results.
For example, ICS was not superior to MON when
a high dose (200 mcg) of ICS was used (Kumar et al.,
2007). Furthermore, no decrease in efficacy was reported when a lower dose of either MON or ICS was
used (Kooi et al., 2008; Ostrom et al., 2005; Szefler
et al., 2007).
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59

Adherence to the assigned medication was generally


high across studies, with comparable compliance rates
between MON and ICS groups. This finding is surprising because a large body of research documents the
problem of poor adherence with controller medication
in children with asthma (McQuaid, Kopel, Klein, &
Fritz, 2003). Parental report, used to measure adherence, has been shown to overestimate medication adherence compared with other measurement methods
such as canister weight or pharmacy refill (Burgess,
Sly, & Devadason, 2010). Bukstein, Luskin, and
Bernstein (2003) reported higher medication refill rates
over a 12-month period for MON (7.7  3) compared
with ICS (5.5  3). Adherence with ICS may be poorer
because of twice-per-day dosing and the need to rinse
the mouth after inhalation to prevent oropharyngeal
candidiasis and systemic absorption of the medication
(Makino, Ohta, Nishima, & Morikawa, 2005). The
high adherence rates identified in this review may
have been influenced by the method of measurement,
because several studies used parental report, which
may have overestimated medication adherence. However, it is important to note that all studies that measured
adherence via self-report used validated measures such
as The Pediatric Asthma Diary (Santanello et al., 1999).
Further, only one study used self-report as the only
method of measuring adherence, with most using
a combined approach such as diskus and pill counts
in addition to parental self-report. Using combinations
of indirect measures of adherence such as these have
been shown to improve measurement (Osterberg &
Blaschke, 2005).
Study duration varied across studies and warrants
special mention because greater duration allows examination of response to asthma therapy over time. Five of
the eight studies were conducted over 3 months or less.
Because asthma is associated with exacerbations that
fluctuate across seasons, the short follow-up period
may have limited the ability to identify true differences
in response to asthma management (Kooi et al., 2008;
Kumar et al., 2007; Maspero et al., 2008; Ostrom et al.,
2005; Szefler et al., 2005). Larger sample sizes and
more sufficient follow-up times are needed to better
understand the long-term effects of ICS compared
with MON.
Motivation of participants to continue in clinical trials
often is challenging and tends to decline over time. Attrition rates varied across studies, and three studies had
attrition rates greater than 15%. The study with the highest attrition rate included in this review (Szefler et al.,
2007) had a follow-up length of 11 months, which
may have added to the attrition because of the length
of follow-up. Participants with chronic illnesses such
as asthma have been identified as having associated
psychosocial factors, such as depression, which may
add to dropout rates (Bender et al., 2003). Furthermore,
asthma is a chronic illness in which patients experience
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Volume 28  Number 1

exacerbations that require more intensive management. One of the primary reasons for patient withdrawal in the studies included in this review was
asthma exacerbation. High dropout rates can affect validity; however, it is important to note that each study
reporting a high rate of attrition conducted an
intention-to-treat analysis that minimized
MON may be
bias by including data
particularly
of all enrolled participants in the analysis.
beneficial for
The evidence sumtreatment of
marized in this review
asthma in certain
supports the current
guidelines that ICS
populations such
should be prescribed
as children younger
as first-line for treatthan 5 years.
ment of persistent
asthma (Rachelefsky,
2009). However, MON may be particularly beneficial
for treatment of asthma in certain populations such as
children younger than 5 years. Because most studies included in this review did not include young children in
their samples, this question remains unanswered and
requires further research. In addition, the ability to generalize these findings to African American and Hispanic
children is limited because these children were not well
represented in the included clinical trials.
Limitations
Our systematic review has several limitations. The literature search only included studies published in the English language. Only three large databases were
searched, and thus additional studies not identified
via use of these particular databases potentially were
not included. Although in four of the studies included
in this review no differences were found between treatment groups, it is possible that publication bias may
have led to a failure to publish other studies finding
no significant differences between ICS and MON.
CONCLUSION
In children ages 2 to 18 years with mild to moderate persistent asthma, both MON and ICS monotherapies are
effective options in improving asthma symptoms,
with a somewhat more favorable response to ICS
monotherapy. The findings of this systematic review
are consistent with the recommendation of the
National Asthma Education and Prevention Program
(2007) that ICS therapy should be first-line for all pediatric patients with mild to moderate persistent asthma.
Further studies are needed that include minority children at higher risk for asthma. Examination of the use of
MON and ICS also is needed in preschool children
younger than 5 years, because this population may particularly benefit from MON treatment. Additionally, further research is needed to compare the effectiveness of
Journal of Pediatric Health Care

MON to ICS in moderate persistent asthma, because this


review included only three studies examining patients
with asthma categorized as moderate severity.
RELEVANCE TO CLINICAL PRACTICE
This systematic review examined monotherapy with
MON compared with ICS in children with mild to moderate persistent asthma. The results reinforce the current National Asthma Education and Prevention
Program (2007) guidelines that ICS should be used as
first-line therapy in patients with mild to moderate persistent asthma. MON may be considered as a therapeutic
agent for patients when ICS therapy does not provide
adequate symptom management or for persons who
have difficulty using inhalers or adhering to the twicedaily dosing regimen. An appropriate therapeutic regimen must be developed for each individual patient.
Because this review focuses on treatment for mild to
moderate asthma, it is important to consider the severity
of symptoms. Because only three studies in this review
included subjects with asthma of moderate severity,
findings of this systematic review should be used with
caution in patients with moderate severity symptoms.
Furthermore, because only two studies included children younger than 5 years, the results of this review
must be used carefully with this population.
REFERENCES
Agertoft, L., & Pedersen, S. (2000). Effect of long-term treatment with
inhaled budesonide on adult height in children with asthma.
New England Journal of Medicine, 343, 1064-1069.
Akinbami, L. J., Moorman, J. E., & Liu, X. (2011). Asthma prevalence,
health care use, and mortality: United States, 2005-2009
(Report No. 32). Retrieved from http://www.cdc.gov/nchs/
data/nhsr/nhsr032.pdf
Bender, B. G., Ellison, M. C., Gleason, M., Murphy, J. R., Sundstrom,
D. A., & Szefler, S. J. (2003). Minimizing attrition in a long-term
clinical trial of pediatric asthma. Annals of Allergy, Asthma & Immunology, 91, 168-176.
Bisgaard, H., Zielen, S., Garcia-Garcia, M. L., Johnston, S. L., Gilles,
L., Menten, J., . Polos, P. (2005). Montelukast reduces
asthma exacerbations in 2- to 5-year-old children with intermittent asthma. American Journal of Respiratory and Critical Care
Medicine, 171(4), 315-322.
Bukstein, D., Luskin, A., & Bernstein, A. (2003). Real-world effectiveness of daily controller medicine in children with mild persistent asthma. Annals of Allergy, Asthma, & Immunology, 90,
543-549.
Burgess, S., Sly, P., & Devadason, S. (2010). Adherence with
preventive medication in childhood asthma. Pulmonary Medicine, 2011, 973849.
Centers for Disease Control and Prevention. (2010). Asthma.
Retrieved from http://www.cdc.gov/nchs/fastats/asthma.htm
n, S. E. (2006). Treatment of asthma with antileukotrienes: First
Dahle
line or last resort therapy? European Journal of Pharmacology,
533, 40-56.
n, S. E., Dahle
n, B., & Drazen, J. M. (2011). Asthma treatment
Dahle
guidelines meet the real world. New England Journal of Medicine, 364(18), 1769-1770.
Ducharme, F., & di Salvio, F. (2004). Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent

www.jpedhc.org

and/or chronic asthma in adults and children. Cochrane Database of Systematic Reviews, 1, CD002314.
Fanta, C. (2009). Asthma. New England Journal of Medicine,
360(10), 1002-1014.
Garcia, G. M. L., Wahn, U., Gilles, L., Swern, A., Tozzi, C. A., & Polos,
P. (2005). Montelukast, compared with fluticasone, for control
of asthma among 6- to 14-year-old patients with mild asthma:
The MOSAIC study. Pediatrics, 116(2), 360-369.
Harmanci, K. (2007). Montelukast: Its role in the treatment of children
with asthma. Journal of Therapeutics and Clinical Risk Management, 3(5), 885-892.
Kazani, S., Ware, J. H., Drazen, J. H., Taylor, D. R., & Sears, M. R.
(2010). The safety of long-acting beta-agonists: More evidence
is needed. Respirology, 15(6), 881-886.
Kelly, H. W., Sternberg, A. L., Lescher, R., Fuhlbrigge, A. L., Williams,
P., Zeiger, R. S., . Strunk, R. C. (2012). Effect of inhaled glucocorticoids in childhood on adult height. New England Journal
of Medicine, 367(10), 904-912.
Knorr, B., Franchi, L. M., Bisgaard, H., Vermeulen, J. H., LeSouef, P.,
Santanello, N., . Bratton, D. L. (2001). Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma
in children aged 2 to 5 years. Pediatrics, 108(3), e48-e58.
Kooi, E. M. W., Schokker, S., Boezen, M., de Vries, T. W., VaessenVerbern, A. A. P. H., van der Molen, T., & Duiverman, E. J.
(2008). Fluticasone or montelukast for preschool children with
asthma-like symptoms: Randomized controlled trial. Pulmonary
Pharmacology & Therapeutics, 21(5), 798-804.
Kumar, V., Ramesh, P., Lodha, R., Pandey, R. M., & Kabra, S. K.
(2007). Montelukast vs. inhaled low-dose budesonide as monotherapy in the treatment of mild persistent asthma: A randomized double blind controlled trial. Journal of Tropical
Pediatrics, 53(5), 325-330.
Maher, C. G., Sherrington, C., Herbert, R. D., Moseley, A. M., &
Elkins, M. (2003). Reliability of the PEDro scale for rating quality
of randomized controlled trials. Physical Therapy, 83(8),
713-721.
Makino, S., Ohta, K., Nishima, S., & Morikawa, A. (2005). Pharmacologic control of asthma. International Archives of Allergy and
Immunology, 136, 14-49.
Maspero, J. F., Duenas-Meza, E., Volovitz, B., Daza, C. P., Kosa, L.,
Vrijens, F., & Leff, J. A. (2001). Evaluating long-term safety,
satisfaction, and adherence with therapy. Current Medical
Research and Opinion, 17(2), 96-104.
Maspero, J., Guera, F., Cuevas, F., Gutierrez, J. P., Soto-Ramos, M.,
Anderton, S., . Pedersen, S. (2008). Efficacy and tolerability
of salmeterol/fluticasone versus montelukast in childhood
asthma: A prospective, randomized, double-blind, double
dummy, parallel-group study. Clinical Therapeutics, 30(8),
1492-1504.
McQuaid, E. L., Kopel, S. J., Klein, R. B., & Fritz, G. K. (2003).
Medication adherence in pediatric asthma: Reasoning, responsibility, and behavior. Journal of Pediatric Psychology, 28(5),
323-333.
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G. & the PRISMA
Group. (2009). Preferred reporting items for systematic review
and meta-analyses: The PRISMA statement. PloS Medicine,
6(7), e1000097.
Montella, S., Maglione, M., De Stefano, S., Manna, A., Di Giorgio, A.,
& Santamaria, F. (2012). Update on leukotriene receptor antagonists in preschool children wheezing disorders. Italian Journal
of Pediatrics, 38(1), 29-46.
Myers, T. R., & Tomasio, L. (2011). Asthma: 2105 and beyond.
Respiratory Care, 56(9), 1389-1407.
National Asthma Education and Prevention Program. (2007). Guidelines for the diagnosis and management of asthma (NIH Publication No. 085846). Retrieved from http://www.nhlbi.nih.
gov/guidelines/asthma/asthsumm.pdf

January/February 2014

61

Osterberg, L., & Blaschke, T. (2005). Adherence to medication. New


England Journal of Medicine, 353, 487-497.
Ostrom, N. D., Decotiis, B. A., Lincourt, W. R., Edwards, L. D., Hanson, K. M., Rosenzweig, C., & Crim, C. (2005). Comparative efficacy and safety of low-dose fluticasone propionate and
montelukast in children with persistent asthma. Journal of Pediatrics, 147(2), 213-220.
Pedersen, S., Agertoft, L., Williams-Herman, D., Kuznetsova, O., Reiss, T., Knorr, B., . Wolthers, O. D. (2007). Placebo-controlled
study of montelukast and budesonide on short-term growth in
prepubertal asthmatic children. Pediatric Pulmonology, 42,
838-843.
Rachelefsky, G. (2009). Inhaled corticosteroids and asthma control in
children: Assessing impairment and risk. Pediatrics, 123(1),
353-366.
Santanello, N. C., Davies, G., Galant, S. P., Pedinoff, A., Sveum, R.,
Seltzer, J., . Knorr, B. A. (1999). Validation of an asthma symptom diary for interventional studies. Archives of Diseases in
Childhood, 80(5), 414-420.
Santanello, N. C., Zhang, J., Seidenberg, B., Reiss, T. F., & Barber,
B. L. (1999). What are minimal important changes for asthma
measures in a clinical trial? European Respiratory Journal, 14,
23-27.
Sorkness, C. A., Lemanske, R. F. J., Mauger, D. T., Boehmer, S. J.,
Chinchilli, V. M., Martinez, F. D., . Taussig, L. M. (2007).
Long-term comparison of 3 controller regimens for mildmoderate persistent childhood asthma: The Pediatric Asthma
Controller Trial. Journal of Allergy and Clinical Immunology,
119(1), 64-72.
Stefanovic, I. M., Verona, E., Cicak, B., & Vrsalovic, R. (2011).
No effect of fluticasone proprionate on linear growth in pre-

62

Volume 28  Number 1

school children with asthma. Pediatrics International, 53(5),


672-676.
Szefler, S. J., Baker, J. W., Uryniak, T., Goldman, M., & Silkoff, P. E.
(2007). Comparative study of budesonide inhalation suspension and montelukast in young children with mild persistent
asthma. Journal of Allergy and Clinical Immunology, 120(5),
1043-1050.
Szefler, S. J., Phillips, B. R., Martinez, F. D., Chinchilli, V. M.,
Lemanske, R. F., Strunk, R. C., . Taussig, L. M. (2005). Characterization of within-subject responses to fluticasone and
montelukast in childhood asthma. Journal of Allergy and Clinical
Immunology, 115(2), 233-242.
Taketomo, C. K., Hodding, J. H., & Kraus, D. M. (2010). Pediatric
dosage handbook (17th ed.). Hudson, OH: Lexi-Comp.
The Childhood Asthma Management Program Research Group.
(2000). Long-term effects of budesonide or nedocromil in children with asthma. New England Journal of Medicine, 343,
1054-1063.
U.S. Department of Health & Human Services. (2011). Summary
health statistics for U.S. children: National health interview survey, 2010 (DDH Publication No. 2012-1578). Retrieved from
http://www.cdc.gov/nchs/data/series/sr_10/sr10_250.pdf
Verhagen, A. P., de Vet, H. C., de Bie, R. A., Kessels, A. G., Boers,
M., Bouter, L. M., & Knipschild, P. G. (1998). The Delphi
list: A criteria list for quality assessment of randomized clinical
trials for conducting systematic reviews developed by Delphi
consensus. Journal of Clinical Epidemiology, 51(12),
1235-1241.
Wolthers, O. D. (2009). Anti-inflammatory treatment of asthma:
Differentiation and trial-and-error. Acta Paediatrica, 98,
1237-1241.

Journal of Pediatric Health Care