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 Cu-
mulative Index to Nursing and Allied Health Literature, and
the Institute of Scientific Information’s 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. Stud-
ies 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 im-
proved with both therapies. Four studies reported superior-
ity 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) recom-
mendation 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 associ-
ated with a high risk of morbidity. In children with
mild persistent asthma, 52% are at risk for adverse out-
comes, including hospitalization or emergency depart-
ment 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
January/February 2014 51
because of asthma exacerbations in children aged 5 to
17 years (Akinbami et al., 2011).
A higher prevalence of asthma exists in children com-
pared with adults. Although asthma generally is more
common among women than among men in adult-
hood, in children younger than 17 years, boys have
a higher prevalence than do girls. Furthermore, racial
and socioeconomic disparities persist, with Black chil-
dren 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 chil-
dren can be extremely challenging. Asthma symptoms
can be managed by avoiding environmental stimuli,
monitoring disease progression, using controller medi-
cations, 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) in-
clude 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 medi-
cation, including ICS, is an important tool in asthma
management. Because asthma varies in severity, treat-
ment 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 eosino-
phil migration, bronchoconstriction, and mucous hy-
persecretion (Harmanci, 2007). MON typically is used
as either second-line monotherapy or as combined ther-
apy with ICS but can possibly be used as a first-line treat-
ment 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 in-
dicating 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,
52 Volume 28  Number 1
a spacer is recommended when using medication deliv-
ered 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 medica-
tion. Spacer devices have been shown to increase the
amount of delivered medication and improve lung de-
livery in children who may lack the ability to cooperate
with treatment because of limited developmental and
cognitive abilities (Myers & Tomasio, 2011). Adminis-
tration via nebulization is beyond the scope of this re-
view because this method of delivery typically is used
for acute exacerbations and is rarely indicated for
chronic use. Many children with asthma have concur-
rent 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 ad-
verse 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 litera-
ture, following the Preferred Reporting Items for
Systematic Reviews and Meta-Analysis (PRISMA) guide-
lines (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 Prac-
tice (TRIP) database (http://www.tripdatabase.com/)
were conducted to ensure that a comparable systematic
review had not been published. The search for random-
ized controlled trials (RCTs) on this topic was per-
formed using PubMed, the Cumulative Index to
Nursing and Allied Health (CINAHL), and the Institute
of Scientific Information’s Web of Knowledge. Searches
were conducted independently by two reviewers, us-
ing 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 be-
tween 2 and 18 years of age with mild to moderate per-
sistent asthma; studies comparing treatment options for
children with severe persistent asthma were excluded
because these patients require more intensive treat-
ment 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 eligibil-
ity 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 ac-
cordance 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 inclu-
sion 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 cur-
rently 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; alloca-
tion 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 differ-
ences in the treatment effects between outcome mea-
sures of each group. A point is awarded when a study
clearly satisfies a criterion, and if the criterion is not sat-
isfied, no point is awarded. Two reviewers indepen-
dently 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 to-
tal 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 ab-
stract, 108 studies were eliminated. The primary reason
for exclusion was study design, including combination
therapy. The full text of 49 studies was further evalu-
ated, 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 us-
ing 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 in-
haler 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), sugar-
coated 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, at-
trition 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 drop-
out rate at 29%.
Study Findings
Table 2 summarizes each of the eight randomized tri-
als 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 eth-
nicity 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
January/February 2014 53
 FIGURE. Flow diagram of study inclusion process. CINAHL, Cumulative Index to Nursing and Allied
Health Literature; ICS, inhaled corticosteroids; RCT, randomized controlled trial.
Studies identified through

Identification
database searching (n=214)
Additional studies identified
from
through review of reference list
PubMed (n=105)
of included articles (n=22)
CINAHL(n= 0)
ISI Web of Knowledge (n=109)

Studies after duplicates removed

(n=157) Studies excluded (n=108)
Screening

•Intermittent or severe persistent

asthma(n=19)
•Age less than 2 or more than 18
years (n=16)
Studies screened •Combination therapy (n=35)
(n=157) •Outcome measure not control of
asthma symptoms (n=2)
•Not comparing ICS (n=33)
•Not RCT (n=3)
Eligibility

Full-text studies assessed for Full-text studies excluded (n=41)

eligibility (n=49) •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
Included

Studies included in qualitative asthma symptoms (n=2)

synthesis (n=8) •Intermittent or severe persistent
asthma (n=6)

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 in-
terest that in all studies, subjects showed an improve-
ment in asthma symptoms from baseline regardless of
treatment assignment. Pulmonary function was an out-
come 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 de-
tected no differences between groups (Kumar et al.,

TABLE 1. Assessment of potential bias in included randomized controlled trials using the PEDro
scoring system
Author I II III IV V VI VII VIII IX X XI Total
Garcia et al. (2005) 1 1 1 1 1 1 1 1 1 1 1 11
Kooi et al. (2008) 1 1 1 1 1 1 1 0 1 1 1 10
Kumar et al. (2007) 1 1 1 1 1 1 1 1 0 1 1 10
Maspero et al. (2008) 1 1 1 1 1 1 1 1 1 1 1 11
Ostrom et al. (2005) 1 1 1 1 1 1 1 0 1 1 1 10
Sorkness et al. (2007) 1 1 1 1 1 1 1 1 1 1 1 11
Szefler et al. (2005) 1 1 1 1 1 1 0 1 0 1 1 9
Szefler et al. (2007) 1 1 1 1 0 0 0 0 1 1 1 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 dif-
ference between groups in outcomes; XI, size of treatment effect and measures of variability (i.e., confidence intervals, standard errors, stan-
dard deviations, interquartile ranges, and minimum-maximum range).

54 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 Study duration Study findings
Garcia et al. (2005) Yes N = 994 MON, 5 mg daily, versus ICS, 100 mcg BID 12 months Change in RFDs:
Age 6-14 years 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
Kooi et al. (2008) Yes N = 63 MON, 4 mg daily and placebo inhaler, versus 3 months Daily symptom score:
Age 2-5 years ICS, 100 mcg BID and placebo oral tablet, versus Improvement with ICS and MON
placebo oral tablet and placebo inhaler p = NS
RFDs:
Significant decrease in both groups
p = NS
Oral corticosteroid use:
MON: 1 child
ICS: 1 child
Kumar et al. (2007) No N = 62 MON, 5 mg tabs + placebo inhaler, versus 3 months Change in FEV1:
Age 5-15 years ICS, 200 mcg BID + placebo oral tablet MON, 1.26 L
ICS, 1.44 L
p = NS
Oral corticosteroid use:
MON, none
January/February 2014

ICS, none

Continued on page 56
55
56
Volume 28  Number 1

TABLE 2. Continued.
Study Multisite (yes/no) Sample size Intervention groups Study duration Study findings
Maspero et al. (2008) Yes N = 548 MON, 5 mg daily + placebo inhaler BID, versus 3 months Change in evening PEFR:
Age 6-14 years SFC, 50/100 mg inhaler BID + placebo tablet daily 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%
Ostrom et al. (2005) Yes N = 342 MON, 5 mg once daily + placebo inhaler, versus 3 months Change in FEV1:
Age 6-12 years ICS, diskus 50 mcg BID + placebo oral tablet 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%
Sorkness et al. (2007) Yes N = 285 MON, 5 mg in the evening + placebo diskus BID, versus 11 months Change in asthma
ICS inhaler, 100 mg BID + placebo oral tablet
Journal of Pediatric Health Care

Age 6-14 years control days:

Fluticasone 100 mg/salmeterol 50 mg diskus in morning MON, 52.5%
and 50 mg of salmeterol diskus in the evening ICS, 64.2%
(PACT) + placebo oral tablet daily 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 MON daily (5-10 mg) + placebo inhaler versus 2 months FEV1, % predicted:
Age 6-17 years ICS, 100 mg one puff BID + placebo oral tablet MON, .20%
Crossover design 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
Szefler et al. (2007) Yes N = 395 MON, 4-5 mg versus 12 months Probability of having
Age 2-8 years ICS, inhaled suspension 0.5 mg daily 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
57
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 re-
ported in all eight studies. Across studies, 182 of 1,345
children (13.5%) assigned to MON and 128 of 1,468 chil-
dren (8.7%) assigned to ICS experienced an asthma ex-
acerbation; the risk of asthma exacerbation was 1.6
times higher (relative risk [RR] 1.56, 95% confidence in-
terval [CI] 1.3-1.9) for children assigned to MON com-
pared 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 head-
ache (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 self-
report (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 stud-
ies. Study findings were inconsistent across studies.
Two studies reported higher adherence in the MON
group (Ostrom et al., 2005; Szefler et al., 2005), two re-
ported higher adherence in the ICS group (Maspero
et al., 2008; Sorkness et al., 2007), and two found no dif-
ferences 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
58 Volume 28  Number 1
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 child’s 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 re-
maining 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 er-
ror (Kooi et al., 2008; Kumar et al., 2007). Furthermore,
five of the studies were conducted for a 3-month dura-
tion 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 re-
sponse 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 re-
view. All studies demonstrated that, regardless of treat-
ment assignment, asthma symptoms improved from
baseline. This im-
provement may be .although four
related to several fac-
tors, including re- studies favored ICS
sponse to the assigned and four studies
treatment medication found no
or the Hawthorne ef-
fect, where subjects differences
may change their be- between groups,
havior because they no study found
are aware that they are
in a clinical trial. Im- MON monotherapy
portantly, although superior to
four studies favored monotherapy with
ICS and four studies
found no differences ICS.
between groups, no
study found MON monotherapy superior to monother-
apy 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 chil-
dren with mild persistent asthma. Only three studies in-
cluded 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). Inter-
estingly, the two studies that included children younger
than 5 years found no differences between treatment
groups (Kooi et al., 2008; Szefler et al., 2007), suggest-
ing that MON may be of equal benefit in young chil-
dren. One possible explanation for this finding may
be that asthma in young children is frequently virally in-
duced and therefore may not require maintenance ther-
apy with inhaled corticosteroids (Bisgaard et al., 2005;
Knorr et al., 2001). On the other hand, an alternative ex-
planation for this finding could be that asthma exacer-
bations 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 chil-
dren with mild to moderate persistent asthma.
FEV1 was a physiologic outcome of several of the in-
cluded 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 dif-
ference 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 differ-
ences between groups.
Asthma exacerbations occurred more frequently in
the MON group. This finding is a significant consider-
ation; however, it is important to note that the criterion
for exacerbation was subjective assessment of symp-
toms, 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 atten-
dance is important to the quality of life of both children
with asthma and their parents. However, when inter-
preting 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 ex-
pressed 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 tempo-
rary 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 skele-
tal growth in prepubertal children treated with ICS per-
sisted as decreased adult height (Kelly et al., 2012).
Blinding of study medication may have been prob-
lematic in some of the included RCTs. Most studies im-
plemented 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. Fur-
ther, the lack of attempting to blind the study medica-
tion 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 Nether-
lands, one in India, and two in the United States, race
and ethnicity were not reported. This lack of informa-
tion is particularly important in studies conducted in
the United States because of the diversity of the popula-
tion. 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 pop-
ulations.
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 socioeco-
nomic 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 differ-
ences 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 re-
ported when a lower dose of either MON or ICS was
used (Kooi et al., 2008; Ostrom et al., 2005; Szefler
et al., 2007).
January/February 2014 59
 Adherence to the assigned medication was generally
high across studies, with comparable compliance rates
between MON and ICS groups. This finding is surpris-
ing 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 adher-
ence, has been shown to overestimate medication ad-
herence 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. How-
ever, 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 exam-
ination 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. At-
trition rates varied across studies, and three studies had
attrition rates greater than 15%. The study with the high-
est 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
60 Volume 28  Number 1
exacerbations that require more intensive manage-
ment. One of the primary reasons for patient with-
drawal in the studies included in this review was
asthma exacerbation. High dropout rates can affect val-
idity; however, it is important to note that each study
reporting a high rate of attrition conducted an
intention-to-treat anal-
ysis that minimized
bias by including data
MON may be
of all enrolled partici- particularly
pants in the analysis. beneficial for
The evidence sum-
marized in this review
treatment of
supports the current asthma in certain
guidelines that ICS populations such
should be prescribed
as first-line for treat-
as children younger
ment of persistent than 5 years.
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 in-
cluded in this review did not include young children in
their samples, this question remains unanswered and
requires further research. In addition, the ability to gen-
eralize 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 liter-
ature search only included studies published in the En-
glish 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 treat-
ment 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 per-
sistent 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 pedi-
atric patients with mild to moderate persistent asthma.
Further studies are needed that include minority chil-
dren 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 par-
ticularly benefit from MON treatment. Additionally, fur-
ther 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 mod-
erate persistent asthma. The results reinforce the cur-
rent National Asthma Education and Prevention
Program (2007) guidelines that ICS should be used as
first-line therapy in patients with mild to moderate per-
sistent 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 twice-
daily dosing regimen. An appropriate therapeutic regi-
men 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 chil-
dren younger than 5 years, the results of this review
must be used carefully with this population.
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