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Asthma Therapy in Pediatric

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

ABSTRACT were searched using key words asthma, MON, and ICS. Stud-
Introduction: Inhaled corticosteroids (ICS) are a first-line ies that met inclusion criteria were appraised for quality.
treatment for mild persistent asthma, but montelukast Results: Of 214 identified studies, eight met inclusion criteria
(MON) monotherapy also has been beneficial. The aim of and seven were deemed high quality. Study sample sizes
this review is to evaluate current evidence comparing MON ranged from 62 to 994, 88% were multi-site, and the average
versus ICS monotherapy in pediatric patients. length of follow-up was 8.2 months. Asthma symptoms im-
Method: A systematic review was conducted of randomized proved with both therapies. Four studies reported superior-
controlled trials evaluating treatment of mild to moderate ity of ICS compared with MON; the remaining studies
persistent asthma in which MON was compared with ICS showed no differences between therapies.
monotherapy in children aged 2 to 18 years. PubMed, the Cu- Discussion: These results are consistent with the National
mulative Index to Nursing and Allied Health Literature, and Asthma Education and Prevention Program (2007) recom-
the Institute of Scientific Information’s Web of Knowledge 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.
Kristen Massingham, Pediatric Nurse Practitioner, Essex
Pediatrics, Doctor of Nursing Practice Program, Columbia
University School of Nursing, New York, NY. KEY WORDS
Shelley Fox, Family Nurse Practitioner, Khasak Dermatology, Asthma, inhaled corticosteroids, montelukast
Doctor of Nursing Practice Program, Columbia University School
of Nursing, New York, NY. Asthma affects approximately 7 million children
Arlene Smaldone, Associate Professor of Clinical Nursing, in the United States, accounting for 9.4% of the
Columbia University School of Nursing, New York, NY. pediatric population (Centers for Disease Control and
Conflicts of interest: None to report.
Prevention, 2010). Asthma prevalence in children has
increased considerably in recent years and currently is
Correspondence: Kristen Massingham, MS, CPNP, Columbia
at the highest level reported in the United States
University School of Nursing, 630 West 168th St, New York, NY
10032; e-mail: (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-
Copyright Q 2014 by the National Association of Pediatric comes, including hospitalization or emergency depart-
Nurse Practitioners. Published by Elsevier Inc. All rights
ment visits (Akinbami et al., 2011). Further, asthma
limits daily function. Approximately 60% of children
Published online January 10, 2013. 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 a spacer is recommended when using medication deliv-
17 years (Akinbami et al., 2011). ered by a meter dose inhaler to increase the efficiency of
A higher prevalence of asthma exists in children com- drug delivery. Proper delivery technique of aerosol
pared with adults. Although asthma generally is more medications is extremely important to ensure that the
common among women than among men in adult- patient receives the full dose of the prescribed medica-
hood, in children younger than 17 years, boys have tion. Spacer devices have been shown to increase the
a higher prevalence than do girls. Furthermore, racial amount of delivered medication and improve lung de-
and socioeconomic disparities persist, with Black chil- livery in children who may lack the ability to cooperate
dren and those with a family income below the federal with treatment because of limited developmental and
poverty level more likely to be affected by asthma cognitive abilities (Myers & Tomasio, 2011). Adminis-
(Akinbami et al., 2011). African American children tration via nebulization is beyond the scope of this re-
have a 16% prevalence rate for asthma compared with view because this method of delivery typically is used
8% in non-Hispanic White children (U.S. Department for acute exacerbations and is rarely indicated for
of Health & Human Services, 2011). chronic use. Many children with asthma have concur-
Effective management of persistent asthma in chil- rent rhinitis, a symptom that MON can address directly
dren can be extremely challenging. Asthma symptoms (Dahlen, 2006). In addition, MON has fewer safety
can be managed by avoiding environmental stimuli, concerns and is well tolerated (Knorr et al., 2001).
monitoring disease progression, using controller medi- The most frequently reported adverse events include
cations, and/or using quick-relief medications (Fanta, headache, pharyngitis, gastrointestinal disorders, and
2009). Current recommendations by the American rash, although rates of these events are similar between
Academy of Pediatrics and the National Asthma those receiving active medication and placebo
Education and Prevention Program guidelines (2007) in- (Montella et al., 2012). Although ICS also have few ad-
clude using inhaled corticosteroids (ICS) as a first-line verse effects, particular concern exists about delayed
controller medication (Rachelefsky, 2009). ICS work bone growth in children who take ICS on a long-term
by decreasing inflammation and hyperresponsiveness basis (Pedersen et al., 2007). Until more is known about
of the bronchioles (Wolthers, 2009). A key component the long-term effects of ICS, MON is considered a safe
to management of persistent asthma is prevention of alternative pharmacotherapy (Kazani, Ware, Drazen,
asthma exacerbations. Use of anti-inflammatory medi- Taylor, & Sears, 2010).
cation, including ICS, is an important tool in asthma This article seeks to systematically review the litera-
management. Because asthma varies in severity, treat- ture, following the Preferred Reporting Items for
ment must be tailored to individual patients to best Systematic Reviews and Meta-Analysis (PRISMA) guide-
manage symptoms. Montelukast (MON), a leukotriene lines (Moher, Liberati, Tetzlaff, Altman, & the PRISMA
antagonist, is an alternative treatment option to ICS. Group, 2009), to evaluate the effectiveness of asthma
MON works by blocking cysteinyl leukotrienes, a class management using MON monotherapy compared
of proinflammatory mediators, which decrease eosino- with ICS monotherapy in children between 2 to 18 years
phil migration, bronchoconstriction, and mucous hy- of age with mild to moderate persistent asthma.
persecretion (Harmanci, 2007). MON typically is used
as either second-line monotherapy or as combined ther- METHODS
apy with ICS but can possibly be used as a first-line treat- Search
ment option (Dahl en, Dahl
en, & Drazen, 2011). One Before beginning this review, searches of PubMed, the
published systematic review compared effectiveness Cochrane Library, and the Turning Research into Prac-
of monotherapy with MON versus ICS in children and tice (TRIP) database (
adults with mild to moderate persistent asthma were conducted to ensure that a comparable systematic
(Ducharme & di Salvio, 2004). However, only one trial review had not been published. The search for random-
included in the systematic review was limited to children ized controlled trials (RCTs) on this topic was per-
with persistent asthma younger than 18 years, and the formed using PubMed, the Cumulative Index to
results were inconclusive (Maspero et al., 2001), thus in- Nursing and Allied Health (CINAHL), and the Institute
dicating a need for further investigation of this topic in of Scientific Information’s Web of Knowledge. Searches
the pediatric population. were conducted independently by two reviewers, us-
Although ICS are the recommended first-line ing the following key words: asthma, MON, and ICS.
controller medication for mild to moderate persistent To reflect current treatment strategies, we restricted
asthma, equally effective alternative options may exist studies to those published in the past 10 years (January
(Dahl en et al., 2011). One potential advantage of 2002 to November 2011). The reference lists of studies
MON is the ease of administration because it is identified in the search were assessed for additional
a once-daily oral medication compared with ICS, which studies that met the specified inclusion criteria. Only
is a twice-daily inhaled medication and requires greater RCTs that compared MON monotherapy with ICS
cooperation from the child. In the pediatric population, monotherapy were included; all other study designs

52 Volume 28  Number 1 Journal of Pediatric Health Care

were excluded. Studies that assessed effectiveness of RESULTS
asthma treatment with the aforementioned medications Study Selection
were included regardless of the outcomes measured. After the initial search of three databases, 214 records
Studies were restricted to pediatric trials of children be- were identified and duplicates were eliminated, leaving
tween 2 and 18 years of age with mild to moderate per- 157 studies. After the initial screening of the title and ab-
sistent asthma; studies comparing treatment options for stract, 108 studies were eliminated. The primary reason
children with severe persistent asthma were excluded for exclusion was study design, including combination
because these patients require more intensive treat- therapy. The full text of 49 studies was further evalu-
ment and are not eligible for monotherapy. Finally, ated, and 41 studies were eliminated, primarily because
studies were restricted to those published in the English the study design was not an RCT. In total, 8 studies
language. met all inclusion/exclusion criteria and were included
Two reviewers independently evaluated each study in the review. The Figure provides detailed results of
identified by the literature search to determine eligibil- the literature search.
ity for inclusion. Search engine results were screened
for full text availability. Each study identified by the Quality Assessment
search was assessed based on the title and abstract in ac- Seven of the eight studies were deemed to be of high
cordance with the inclusion/exclusion criteria. Studies quality with a score of 8 or higher on the PEDro scale.
that met inclusion/exclusion criteria based on the initial Table 1 provides a detailed assessment of each study us-
screening were further reviewed to verify that study ing the PEDro criteria. Risk of bias primarily was related
characteristics and procedures met the criteria for inclu- to dropout rates greater than 15% in three studies (Kooi
sion in the systematic review. et al., 2008; Ostrom et al., 2005; Szefler, Baker, Uryniak,
Goldman, & Silkoff, 2007) and lack of intention-to-treat
Quality Assessment analysis in two studies (Kumar, Ramesh, Lodha,
The PEDro scale was used to assess risk of bias and Pandey, & Kabra, 2007; Szefler et al., 2005). One study
validity of individual studies. A number of scales cur- did not use subject and investigator blinding by having
rently are available to assess the methodological each participant take either a placebo oral tablet or in-
quality of RCTs. Using a Delphi technique, items of haler in addition to the active medication (Szefler
the PEDro scale (Verhagen et al., 1998) were based on et al., 2007). Four studies specified the method used
a consensus of experts. The scale has face validity to blind patients to active versus placebo MON through
(Verhagen et al., 1998) and good interrater reliability overencapsulated tablets (Sorkness et al., 2007), sugar-
(Maher, Sherrington, Herbert, Moseley, & Elkins, coated tablets (Maspero et al., 2008; Ostrom et al.,
2003). The PEDro scale evaluates 11 quality elements: 2005), and similar appearance of tablets (Kooi et al.,
eligibility criteria specified; random allocation; alloca- 2008; Kumar et al., 2007), and three studies specified
tion concealment; similarity of groups at baseline; use of identical diskus devices to blind patients to active
blinding of participants; blinding of therapists; blinding versus placebo ICS (Kooi et al., 2008; Kumar et al., 2007;
of assessors; dropout rate; intention-to-treat analysis; Sorkness et al., 2007). Patients lost to follow-up ranged
statistical analysis of outcomes measured; and differ- between 6.9% to 29% across studies. In three studies, at-
ences in the treatment effects between outcome mea- trition rates greater than 15% were reported (Kooi et al.,
sures of each group. A point is awarded when a study 2008; Ostrom et al., 2005; Szefler et al., 2007). The study
clearly satisfies a criterion, and if the criterion is not sat- by Szefler and colleagues (2007) had the greatest drop-
isfied, no point is awarded. Two reviewers indepen- out rate at 29%.
dently assessed the quality of each study. If the
category was satisfied, a score of 1 was assigned. If Study Findings
the category was not satisfied, a score of 0 was assigned. Table 2 summarizes each of the eight randomized tri-
The maximum score was 11. If disagreement occurred als included in the review. A total of 2,833 children
between reviewers on the assigned score, consensus (62% male) participated in the studies. Four trials
was achieved through discussion. Each study with a to- were conducted in the United States (Ostrom et al.,
tal score of 8 or higher was considered to be of high 2005; Sorkness et al., 2007; Szefler et al., 2005;
methodological quality. After appraisal of individual Szefler et al., 2007). Of these, participant race and eth-
studies, risk of bias across studies was assessed by nicity characteristics were reported in three studies,
examining sample size, length of follow-up, blinding, with a total of 70.1% of participants reported as White.
assessment of asthma severity, and consistency of study Study participants ranged in age from 2 to 17 years,
findings. The frequency of reported adverse events with a mean age of 8.6  1.9 years. Only two studies
were quantitatively synthesized across studies where included children younger than 5 years (Kooi et al.,
data were available; comparisons between groups 2008; Szefler et al., 2007). The sample sizes varied
are reported as relative risks with a 95% confidence greatly across studies, as did the study locations and
interval. 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

database searching (n=214)
Additional studies identified
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)

•Intermittent or severe persistent

•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)

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
•Not RCT (n=11)
•Outcome measure not control of

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 ment in asthma symptoms from baseline regardless of
a sample greater than 100 participants. Most studies treatment assignment. Pulmonary function was an out-
(n = 7) were multi-site trials, with the number of study come of interest in seven studies, with results favoring
sites ranging from 3 to 104. Length of follow-up ICS over MON. These studies reported significant
ranged from 2 months to 2 years with an average of changes in peak expiratory flow rate (Maspero et al.,
8.2 months; five trials were conducted over a period 2008), forced expiratory volume in 1 second (FEV1;
of 3 months or less (Kooi et al., 2008; Kumar et al., Garcia et al., 2005; Maspero et al., 2008; Ostrom et al.,
2007; Maspero et al., 2008; Ostrom et al., 2005; 2005; Sorkness et al., 2007; Szefler et al., 2005), and
Szefler et al., 2005). The dose of ICS and MON also asthma control days (Sorkness et al., 2007). Only one
varied across studies. study that measured an objective pulmonary function
Outcome measures varied across studies. It is of in- parameter (change in FEV1) as its primary outcome de-
terest that in all studies, subjects showed an improve- tected no differences between groups (Kumar et al.,

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

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
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
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%
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%
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%

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
MON, 0.05 L
ICS, 0.09 L
p = NS
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
2007). Six studies measured rescue-free days, with the trials, only one study (Garcia et al., 2005) reported the
majority reporting superiority of ICS over MON change in eosinophil level in the MON and ICS groups
(Garcia et al., 2005; Maspero et al., 2008; Ostrom before and after intervention ( 0.08  103 vs. 0.06 
et al., 2005; Sorkness et al., 2007). In general, studies 103, p = .411). Three studies measured the child’s linear
that found no differences between treatment groups growth over the duration of the study. One study found
measured more subjective patient outcomes: change that children in the MON group demonstrated greater
in daily symptom score (Kooi et al., 2008) and change annual height increase compared with the ICS group
in the probability of asthma exacerbation (Szefler (6.18 vs. 5.81 cm, p = .018; Garcia et al., 2005). The re-
et al., 2007). maining two studies found no differences between
Clinical adverse events were reported in all studies groups (Sorkness et al., 2007; Szefler et al., 2007).
and favored ICS versus MON. Asthma exacerbation Several areas of bias were noted across studies. Two
was the most frequently reported event and was re- studies had sample sizes of less than 100 subjects and
ported in all eight studies. Across studies, 182 of 1,345 may have lacked statistical power to detect treatment
children (13.5%) assigned to MON and 128 of 1,468 chil- differences; thus the results may be subject to type II er-
dren (8.7%) assigned to ICS experienced an asthma ex- ror (Kooi et al., 2008; Kumar et al., 2007). Furthermore,
acerbation; the risk of asthma exacerbation was 1.6 five of the studies were conducted for a 3-month dura-
times higher (relative risk [RR] 1.56, 95% confidence in- tion or less (Kooi et al., 2008; Maspero et al., 2008;
terval [CI] 1.3-1.9) for children assigned to MON com- Ostrom et al., 2005; Szefler et al., 2005), a period that
pared with ICS. Five studies reported the need for oral may have been too short to fully evaluate treatment re-
corticosteroid use (Kooi et al., 2008; Kumar et al., sponse and maintenance of asthma control.
2007; Ostrom et al., 2005; Szefler et al., 2005; Szefler
et al., 2007). Across studies, 81 of 488 children (16.6%) DISCUSSION
assigned to MON and 58 of 498 children assigned to Summary of Evidence
ICS (11.6%) required oral corticosteroids, with the risk Eight RCTs comparing the effects of ICS and MON in the
of oral corticosteroid use 1.4 times higher (RR 1.43, treatment of pediatric patients with mild to moderate
95% CI 1.04-1.9) for children assigned to MON versus persistent asthma were included in this systematic re-
ICS. Other less frequently reported events were head- view. All studies demonstrated that, regardless of treat-
ache (Maspero et al., 2008; Ostrom et al., 2005), upper ment assignment, asthma symptoms improved from
respiratory infection (Kooi et al., 2008; Ostrom et al., baseline. This im-
2008), and skin rash (Kooi et al., 2008; Kumar et al., provement may be .although four
2007). related to several fac-
Six studies measured treatment adherence using self- tors, including re- studies favored ICS
report (n = 3), pill counts (n = 4), diskus counts (n = 4), sponse to the assigned and four studies
and Electronic Drug Exposure Monitor (n = 2) methods. treatment medication found no
Three studies used more than one method to measure or the Hawthorne ef-
treatment adherence, such as measuring capsule counts fect, where subjects differences
and diskus dose indicator in addition to either diary may change their be- between groups,
cards or an electronic measure (Ostrom et al., 2005; havior because they no study found
Sorkness et al., 2007; Szefler et al., 2005). On average, are aware that they are
self-reported adherence was high ($ 80%) across stud- in a clinical trial. Im- MON monotherapy
ies. Study findings were inconsistent across studies. portantly, although superior to
Two studies reported higher adherence in the MON four studies favored monotherapy with
group (Ostrom et al., 2005; Szefler et al., 2005), two re- ICS and four studies
ported higher adherence in the ICS group (Maspero found no differences ICS.
et al., 2008; Sorkness et al., 2007), and two found no dif- between groups, no
ferences in adherence between the MON and ICS study found MON monotherapy superior to monother-
groups (Garcia et al., 2005; Szefler et al., 2007). apy with ICS. In addition, the two studies that reported
Less frequently measured outcomes of interest were no differences between groups had small samples and
school and parental work attendance, eosinophil may have lacked statistical power to detect differences
count, and linear growth. One study examined missed between treatments, leading to type II error.
school days (children) and missed work days (parents) Most studies restricted their inclusion criteria to chil-
and found no differences between children in the ICS dren with mild persistent asthma. Only three studies in-
group compared with the MON group (2.1% vs. 1.9%) cluded children with moderate persistent asthma
during the 12-month trial (Garcia et al., 2005). Three (Ostrom et al., 2005; Sorkness et al., 2007; Szefler
studies measured serum eosinophil levels, and none et al., 2005). Therefore the ability to generalize the study
found differences between groups (Garcia et al., findings must be considered cautiously in treatment of
2005; Kooi et al., 2008; Szefler et al., 2005). Of these patients with moderate asthma. In addition, the ability

58 Volume 28  Number 1 Journal of Pediatric Health Care

to generalize findings is limited in patients younger growth, several studies assessing linear growth over
than 5 years because only two studies examined this time in children treated with ICS have shown a tempo-
population (Kooi et al., 2008; Szefler et al., 2007). Inter- rary decrease in growth velocity but no effect on final
estingly, the two studies that included children younger adult height (Agertoft & Pedersen, 2000; Stefanovic,
than 5 years found no differences between treatment Verona, Cicak, & Vrsalovic, 2011; The Childhood
groups (Kooi et al., 2008; Szefler et al., 2007), suggest- Asthma Management Program Research group, 2000).
ing that MON may be of equal benefit in young chil- However, one recent study found that decreased skele-
dren. One possible explanation for this finding may tal growth in prepubertal children treated with ICS per-
be that asthma in young children is frequently virally in- sisted as decreased adult height (Kelly et al., 2012).
duced and therefore may not require maintenance ther- Blinding of study medication may have been prob-
apy with inhaled corticosteroids (Bisgaard et al., 2005; lematic in some of the included RCTs. Most studies im-
Knorr et al., 2001). On the other hand, an alternative ex- plemented use of either a placebo oral tablet or inhaler
planation for this finding could be that asthma exacer- in addition to active medication. However, only three of
bations in this population were mild and ICS did not the studies specified the techniques used to make the
provide increased benefit at reducing inflammation active medication and placebo similar in taste or odor
compared with MON. Further research is needed in (Ostrom et al., 2005; Sorkness et al., 2007; Szefler
management and best treatment options for young chil- et al., 2005). Without this detail, it is difficult to assess
dren with mild to moderate persistent asthma. the adequacy of blinding in the remaining studies. Fur-
FEV1 was a physiologic outcome of several of the in- ther, the lack of attempting to blind the study medica-
cluded studies, with most studies favoring ICS. This tion in the additional studies may have led to bias that
finding reinforces the current recommendation that affected the results.
ICS be used as first-line pharmacotherapy for persistent Enrollment of minority children at higher risk for
asthma (Rachelefsky, 2009). Previous research has asthma was limited. Only four studies reported race
demonstrated that a clinically relevant change in FEV1 and ethnicity characteristics of their samples. Of these,
is a 10% improvement from baseline (Santanello, most subjects reported their race as white (Garcia et al.,
Zhang, Seidenberg, Reiss, & Barber, 1999). In the study 2005; Maspero et al., 2008; Szefler et al., 2005; Szefler
by Garcia and colleagues (2005), the absolute FEV1 dif- et al., 2007). In the remaining studies, one in the Nether-
ference between groups was only 2.2% and, although lands, one in India, and two in the United States, race
statistically significant, may not be clinically important. and ethnicity were not reported. This lack of informa-
The large sample size in this study (N = 994) may have tion is particularly important in studies conducted in
provided statistical power to detect very small differ- the United States because of the diversity of the popula-
ences between groups. tion. There is a higher prevalence of asthma in Black
Asthma exacerbations occurred more frequently in children compared with White children and a lower
the MON group. This finding is a significant consider- prevalence among Asian children (Akinbami et al.,
ation; however, it is important to note that the criterion 2011). Failure to include minority children in the trials
for exacerbation was subjective assessment of symp- may limit the ability to generalize findings to these pop-
toms, which may have had an impact on the differences ulations.
identified between groups. Interestingly, only one study Of note, all studies included a higher percentage of
evaluated missed days of school and work and found no male participants and reflect the higher prevalence of
differences between those assigned to ICS versus MON asthma in male youth. However, it is unclear if children
(Garcia et al., 2005). We include these findings in this of families with income below the federal poverty level,
systematic review because both school and work atten- known to be at higher risk of asthma (Akinbami et al.,
dance is important to the quality of life of both children 2011), were included in the research because socioeco-
with asthma and their parents. However, when inter- nomic status was not reported in any of the included
preting this finding, it is important to consider this result studies.
as the outcome of one study only. More studies are All studies included in this review used medication
needed to determine the relationship between ICS dosages within the recommended range by specific
and MON monotherapy treatment and missed school age categories of the children enrolled (Taketomo,
or work days. Other adverse effects were comparable Hodding, & Kraus, 2010). Interestingly, although differ-
between groups across all studies. Although one trial ences in dosing occurred across studies, the variability
found a clinically significant difference in linear growth in dosing did not seem to have affected the results.
in the MON group compared with the ICS group (Garcia For example, ICS was not superior to MON when
et al., 2005), the mean difference in annual growth a high dose (200 mcg) of ICS was used (Kumar et al.,
velocity between groups was very small and most likely 2007). Furthermore, no decrease in efficacy was re-
not clinically important. Although concern has been ex- ported when a lower dose of either MON or ICS was
pressed about using ICS in prepubertal children with used (Kooi et al., 2008; Ostrom et al., 2005; Szefler
asthma because of the potential for decreased skeletal et al., 2007). January/February 2014 59

Adherence to the assigned medication was generally exacerbations that require more intensive manage-
high across studies, with comparable compliance rates ment. One of the primary reasons for patient with-
between MON and ICS groups. This finding is surpris- drawal in the studies included in this review was
ing because a large body of research documents the asthma exacerbation. High dropout rates can affect val-
problem of poor adherence with controller medication idity; however, it is important to note that each study
in children with asthma (McQuaid, Kopel, Klein, & reporting a high rate of attrition conducted an
Fritz, 2003). Parental report, used to measure adher- intention-to-treat anal-
ence, has been shown to overestimate medication ad- ysis that minimized
herence compared with other measurement methods bias by including data
MON may be
such as canister weight or pharmacy refill (Burgess, of all enrolled partici- particularly
Sly, & Devadason, 2010). Bukstein, Luskin, and pants in the analysis. beneficial for
Bernstein (2003) reported higher medication refill rates The evidence sum-
over a 12-month period for MON (7.7  3) compared marized in this review
treatment of
with ICS (5.5  3). Adherence with ICS may be poorer supports the current asthma in certain
because of twice-per-day dosing and the need to rinse guidelines that ICS populations such
the mouth after inhalation to prevent oropharyngeal should be prescribed
candidiasis and systemic absorption of the medication as first-line for treat-
as children younger
(Makino, Ohta, Nishima, & Morikawa, 2005). The ment of persistent than 5 years.
high adherence rates identified in this review may asthma (Rachelefsky,
have been influenced by the method of measurement, 2009). However, MON may be particularly beneficial
because several studies used parental report, which for treatment of asthma in certain populations such as
may have overestimated medication adherence. How- children younger than 5 years. Because most studies in-
ever, it is important to note that all studies that measured cluded in this review did not include young children in
adherence via self-report used validated measures such their samples, this question remains unanswered and
as The Pediatric Asthma Diary (Santanello et al., 1999). requires further research. In addition, the ability to gen-
Further, only one study used self-report as the only eralize these findings to African American and Hispanic
method of measuring adherence, with most using children is limited because these children were not well
a combined approach such as diskus and pill counts represented in the included clinical trials.
in addition to parental self-report. Using combinations
of indirect measures of adherence such as these have Limitations
been shown to improve measurement (Osterberg & Our systematic review has several limitations. The liter-
Blaschke, 2005). ature search only included studies published in the En-
Study duration varied across studies and warrants glish language. Only three large databases were
special mention because greater duration allows exam- searched, and thus additional studies not identified
ination of response to asthma therapy over time. Five of via use of these particular databases potentially were
the eight studies were conducted over 3 months or less. not included. Although in four of the studies included
Because asthma is associated with exacerbations that in this review no differences were found between treat-
fluctuate across seasons, the short follow-up period ment groups, it is possible that publication bias may
may have limited the ability to identify true differences have led to a failure to publish other studies finding
in response to asthma management (Kooi et al., 2008; no significant differences between ICS and MON.
Kumar et al., 2007; Maspero et al., 2008; Ostrom et al.,
2005; Szefler et al., 2005). Larger sample sizes and CONCLUSION
more sufficient follow-up times are needed to better In children ages 2 to 18 years with mild to moderate per-
understand the long-term effects of ICS compared sistent asthma, both MON and ICS monotherapies are
with MON. effective options in improving asthma symptoms,
Motivation of participants to continue in clinical trials with a somewhat more favorable response to ICS
often is challenging and tends to decline over time. At- monotherapy. The findings of this systematic review
trition rates varied across studies, and three studies had are consistent with the recommendation of the
attrition rates greater than 15%. The study with the high- National Asthma Education and Prevention Program
est attrition rate included in this review (Szefler et al., (2007) that ICS therapy should be first-line for all pedi-
2007) had a follow-up length of 11 months, which atric patients with mild to moderate persistent asthma.
may have added to the attrition because of the length Further studies are needed that include minority chil-
of follow-up. Participants with chronic illnesses such dren at higher risk for asthma. Examination of the use of
as asthma have been identified as having associated MON and ICS also is needed in preschool children
psychosocial factors, such as depression, which may younger than 5 years, because this population may par-
add to dropout rates (Bender et al., 2003). Furthermore, ticularly benefit from MON treatment. Additionally, fur-
asthma is a chronic illness in which patients experience ther research is needed to compare the effectiveness of

60 Volume 28  Number 1 Journal of Pediatric Health Care

MON to ICS in moderate persistent asthma, because this and/or chronic asthma in adults and children. Cochrane Data-
review included only three studies examining patients base of Systematic Reviews, 1, CD002314.
Fanta, C. (2009). Asthma. New England Journal of Medicine,
with asthma categorized as moderate severity. 360(10), 1002-1014.
Garcia, G. M. L., Wahn, U., Gilles, L., Swern, A., Tozzi, C. A., & Polos,
RELEVANCE TO CLINICAL PRACTICE P. (2005). Montelukast, compared with fluticasone, for control
This systematic review examined monotherapy with of asthma among 6- to 14-year-old patients with mild asthma:
MON compared with ICS in children with mild to mod- The MOSAIC study. Pediatrics, 116(2), 360-369.
Harmanci, K. (2007). Montelukast: Its role in the treatment of children
erate persistent asthma. The results reinforce the cur- with asthma. Journal of Therapeutics and Clinical Risk Manage-
rent National Asthma Education and Prevention ment, 3(5), 885-892.
Program (2007) guidelines that ICS should be used as Kazani, S., Ware, J. H., Drazen, J. H., Taylor, D. R., & Sears, M. R.
first-line therapy in patients with mild to moderate per- (2010). The safety of long-acting beta-agonists: More evidence
sistent asthma. MON may be considered as a therapeutic is needed. Respirology, 15(6), 881-886.
Kelly, H. W., Sternberg, A. L., Lescher, R., Fuhlbrigge, A. L., Williams,
agent for patients when ICS therapy does not provide P., Zeiger, R. S., . Strunk, R. C. (2012). Effect of inhaled glu-
adequate symptom management or for persons who cocorticoids in childhood on adult height. New England Journal
have difficulty using inhalers or adhering to the twice- of Medicine, 367(10), 904-912.
daily dosing regimen. An appropriate therapeutic regi- Knorr, B., Franchi, L. M., Bisgaard, H., Vermeulen, J. H., LeSouef, P.,
men must be developed for each individual patient. Santanello, N., . Bratton, D. L. (2001). Montelukast, a leukotri-
ene receptor antagonist, for the treatment of persistent asthma
Because this review focuses on treatment for mild to in children aged 2 to 5 years. Pediatrics, 108(3), e48-e58.
moderate asthma, it is important to consider the severity Kooi, E. M. W., Schokker, S., Boezen, M., de Vries, T. W., Vaessen-
of symptoms. Because only three studies in this review Verbern, A. A. P. H., van der Molen, T., & Duiverman, E. J.
included subjects with asthma of moderate severity, (2008). Fluticasone or montelukast for preschool children with
findings of this systematic review should be used with asthma-like symptoms: Randomized controlled trial. Pulmonary
Pharmacology & Therapeutics, 21(5), 798-804.
caution in patients with moderate severity symptoms. Kumar, V., Ramesh, P., Lodha, R., Pandey, R. M., & Kabra, S. K.
Furthermore, because only two studies included chil- (2007). Montelukast vs. inhaled low-dose budesonide as mono-
dren younger than 5 years, the results of this review therapy in the treatment of mild persistent asthma: A random-
must be used carefully with this population. ized double blind controlled trial. Journal of Tropical
Pediatrics, 53(5), 325-330.
Maher, C. G., Sherrington, C., Herbert, R. D., Moseley, A. M., &
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62 Volume 28  Number 1 Journal of Pediatric Health Care