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 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. (2013) -, ---. 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 because of asthma exacerbations in children aged 5 to 17 years (Akinbami et al., 2011). 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: [email protected]. 0891-5245/$36.00 Copyright Q 2013 by the National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pedhc.2012.11.005 www.jpedhc.org -/- 2013 1
Transcript
ARTICLE
Asthma Therapy in PediatricPatients: A SystematicReview of Treatment WithMontelukast Versus InhaledCorticosteroids
ABSTRACTIntroduction: Inhaled corticosteroids (ICS) are a first-linetreatment for mild persistent asthma, but montelukast(MON) monotherapy also has been beneficial. The aim ofthis review is to evaluate current evidence comparing MONversus ICS monotherapy in pediatric patients.Method: A systematic review was conducted of randomizedcontrolled trials evaluating treatment of mild to moderatepersistent asthma in which MON was compared with ICSmonotherapy in children aged 2 to 18 years. PubMed, the Cu-mulative Index to Nursing and Allied Health Literature, andthe Institute of Scientific Information’s Web of Knowledgewere searched using key words asthma, MON, and ICS. Stud-ies that met inclusion criteria were appraised for quality.
Kristen Massingham, Pediatric Nurse Practitioner, EssexPediatrics, 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, ColumbiaUniversity School of Nursing, 630 West 168th St, New York, NY
Copyright Q 2013 by the National Association of Pediatric
Nurse Practitioners. Published by Elsevier Inc. All rights
reserved.
http://dx.doi.org/10.1016/j.pedhc.2012.11.005
www.jpedhc.org
Results: Of 214 identified studies, eight met inclusion criteriaand seven were deemed high quality. Study sample sizesranged from 62 to 994, 88% were multi-site, and the averagelength 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 studiesshowed no differences between therapies.Discussion: These results are consistent with the NationalAsthma Education and Prevention Program (2007) recom-mendation that ICS therapy should be first-line treatment inchildren with mild to moderate persistent asthma. J PediatrHealth Care. (2013) -, ---.
Asthma affects approximately 7 million childrenin the United States, accounting for 9.4% of thepediatric population (Centers for Disease Control andPrevention, 2010). Asthma prevalence in children hasincreased considerably in recent years and currently isat the highest level reported in the United States(Akinbami, Moorman, & Liu, 2011). Asthma is associ-ated with a high risk of morbidity. In children withmild persistent asthma, 52% are at risk for adverse out-comes, including hospitalization or emergency depart-ment visits (Akinbami et al., 2011). Further, asthmalimits daily function. Approximately 60% of childrenwith asthma miss at least one day of school each year.In 2008, more than 10 million school days were missedbecause of asthma exacerbations in children aged 5 to17 years (Akinbami et al., 2011).
Ahigher prevalence of asthmaexists in children com-pared with adults. Although asthma generally is morecommon among women than among men in adult-hood, in children younger than 17 years, boys havea higher prevalence than do girls. Furthermore, racialand socioeconomic disparities persist, with Black chil-dren and those with a family income below the federalpoverty level more likely to be affected by asthma(Akinbami et al., 2011). African American childrenhave a 16% prevalence rate for asthma compared with8% in non-Hispanic White children (U.S. Departmentof Health & Human Services, 2011).
Effective management of persistent asthma in chil-dren can be extremely challenging. Asthma symptomscan be managed by avoiding environmental stimuli,monitoring disease progression, using controller med-ications, and/or using quick-relief medications (Fanta,2009). Current recommendations by the AmericanAcademy of Pediatrics and the National AsthmaEducation and Prevention Program guidelines (2007)include using inhaled corticosteroids (ICS) as a first-line controller medication (Rachelefsky, 2009). ICSwork by decreasing inflammation and hyperrespon-siveness of the bronchioles (Wolthers, 2009). A keycomponent to management of persistent asthma isprevention of asthma exacerbations. Use of anti-inflammatory medication, including ICS, is an impor-tant tool in asthma management. Because asthmavaries in severity, treatment must be tailored to indi-vidual patients to best manage symptoms. Montelu-kast (MON), a leukotriene antagonist, is analternative treatment option to ICS. MON works byblocking cysteinyl leukotrienes, a class of proinflam-matory mediators, which decrease eosinophilmigration, bronchoconstriction, and mucous hyperse-cretion (Harmanci, 2007). MON typically is used as ei-ther second-line monotherapy or as combinedtherapy with ICS but can possibly be used as a first-line treatment option (Dahl�en, Dahl�en, & Drazen,2011). One published systematic review compared ef-fectiveness of monotherapy with MON versus ICS inchildren and adults with mild to moderate persistentasthma (Ducharme & di Salvio, 2004). However,only one trial included in the systematic review waslimited to children with persistent asthma youngerthan 18 years, and the results were inconclusive(Maspero et al., 2001), thus indicating a need forfurther investigation of this topic in the pediatricpopulation.
Although ICS are the recommended first-linecontroller medication for mild to moderate persistentasthma, equally effective alternative options may exist(Dahl�en et al., 2011). One potential advantage ofMON is the ease of administration because it isa once-daily oral medication comparedwith ICS, whichis a twice-daily inhaledmedication and requires greatercooperation from the child. In the pediatric population,
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a spacer is recommendedwhenusingmedication deliv-eredby ameter dose inhaler to increase the efficiency ofdrug delivery. Proper delivery technique of aerosolmedications is extremely important to ensure that thepatient receives the full dose of the prescribed medica-tion. Spacer devices have been shown to increase theamount of delivered medication and improve lung de-livery in children who may lack the ability to cooperatewith treatment because of limited developmental andcognitive abilities (Myers & Tomasio, 2011). Adminis-tration via nebulization is beyond the scope of this re-view because this method of delivery typically is usedfor acute exacerbations and is rarely indicated forchronic use. Many children with asthma have concur-rent rhinitis, a symptom that MON can address directly(Dahl�en, 2006). In addition, MON has fewer safetyconcerns and is well tolerated (Knorr et al., 2001).The most frequently reported adverse events includeheadache, pharyngitis, gastrointestinal disorders, andrash, although rates of these events are similar betweenthose receiving active medication and placebo(Montella et al., 2012). Although ICS also have few ad-verse effects, particular concern exists about delayedbone growth in children who take ICS on a long-termbasis (Pedersen et al., 2007). Until more is known aboutthe long-term effects of ICS, MON is considered a safealternative pharmacotherapy (Kazani, Ware, Drazen,Taylor, & Sears, 2010).This article seeks to systematically review the litera-
ture, following the Preferred Reporting Items forSystematic Reviews andMeta-Analysis (PRISMA) guide-lines (Moher, Liberati, Tetzlaff, Altman, & the PRISMAGroup, 2009), to evaluate the effectiveness of asthmamanagement using MON monotherapy comparedwith ICSmonotherapy in children between 2 to 18 yearsof age with mild to moderate persistent asthma.
METHODSSearchBefore beginning this review, searches of PubMed, theCochrane Library, and the Turning Research into Prac-tice (TRIP) database (http://www.tripdatabase.com/)were conducted to ensure that a comparable systematicreviewhadnot beenpublished. The search for random-ized controlled trials (RCTs) on this topic was per-formed using PubMed, the Cumulative Index toNursing and Allied Health (CINAHL), and the Instituteof Scientific Information’sWeb of Knowledge. Searcheswere conducted independently by two reviewers, us-ing the following key words: asthma, MON, and ICS.To reflect current treatment strategies, we restrictedstudies to those published in the past 10 years (January2002 to November 2011). The reference lists of studiesidentified in the search were assessed for additionalstudies that met the specified inclusion criteria. OnlyRCTs that compared MON monotherapy with ICSmonotherapy were included; all other study designs
were excluded. Studies that assessed effectiveness ofasthma treatmentwith the aforementionedmedicationswere 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 forchildren with severe persistent asthma were excludedbecause these patients require more intensive treat-ment and are not eligible for monotherapy. Finally,studieswere restricted to those published in the Englishlanguage.
Two reviewers independently evaluated each studyidentified by the literature search to determine eligibil-ity for inclusion. Search engine results were screenedfor full text availability. Each study identified by thesearchwas assessed basedon the title and abstract in ac-cordance with the inclusion/exclusion criteria. Studiesthatmet inclusion/exclusion criteria based on the initialscreening were further reviewed to verify that studycharacteristics and proceduresmet the criteria for inclu-sion in the systematic review.
Quality AssessmentThe PEDro scale was used to assess risk of bias andvalidity of individual studies. A number of scales cur-rently are available to assess the methodologicalquality of RCTs. Using a Delphi technique, items ofthe PEDro scale (Verhagen et al., 1998) were based ona 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; blindingof 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 studyclearly 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 thecategory was satisfied, a score of 1 was assigned. Ifthe categorywas not satisfied, a score of 0was assigned.The maximum score was 11. If disagreement occurredbetween reviewers on the assigned score, consensuswas achieved through discussion. Each study with a to-tal score of 8 or higher was considered to be of highmethodological quality. After appraisal of individualstudies, risk of bias across studies was assessed byexamining sample size, length of follow-up, blinding,assessment of asthma severity, and consistency of studyfindings. The frequency of reported adverse eventswere quantitatively synthesized across studies wheredata were available; comparisons between groupsare reported as relative risks with a 95% confidenceinterval.
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RESULTSStudy SelectionAfter the initial search of three databases, 214 recordswere identified and duplicateswere eliminated, leaving157 studies. After the initial screening of the title and ab-stract, 108 studies were eliminated. The primary reasonfor exclusion was study design, including combinationtherapy. The full text of 49 studies was further evalu-ated, and 41 studieswere eliminated, primarily becausethe study design was not an RCT. In total, 8 studiesmet all inclusion/exclusion criteria and were includedin the review. The Figure provides detailed results ofthe literature search.
Quality AssessmentSeven of the eight studies were deemed to be of highquality with a score of 8 or higher on the PEDro scale.Table 1 provides a detailed assessment of each studyus-ing the PEDro criteria. Risk of bias primarily was relatedto dropout rates greater than 15% in three studies (Kooiet al., 2008; Ostrom et al., 2005; Szefler, Baker, Uryniak,Goldman, & Silkoff, 2007) and lack of intention-to-treatanalysis in two studies (Kumar, Ramesh, Lodha,Pandey, & Kabra, 2007; Szefler et al., 2005). One studydid not use subject and investigator blinding by havingeach participant take either a placebo oral tablet or in-haler in addition to the active medication (Szefleret al., 2007). Four studies specified the method usedto blind patients to active versus placeboMON throughoverencapsulated 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 specifieduse of identical diskus devices to blind patients to activeversus placebo ICS (Kooi et al., 2008; Kumar et al., 2007;Sorkness et al., 2007). Patients lost to follow-up rangedbetween 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 studyby Szefler and colleagues (2007) had the greatest drop-out rate at 29%.
Study FindingsTable 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 trialswere 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 studiesincluded children younger than 5 years (Kooi et al.,2008; Szefler et al., 2007). The sample sizes variedgreatly across studies, as did the study locations andthe length of follow-up. Sample size ranged from 62
FIGURE. Flow diagram of study inclusion process. CINAHL, Cumulative Index to Nursing and AlliedHealth Literature; ICS, inhaled corticosteroids; RCT, randomized controlled trial.
Studies identified through database searching (n=214)
fromPubMed (n=105)CINAHL(n= 0)
ISI Web of Knowledge (n=109)
Additional studies identified through review of reference list
of included articles (n=22)
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)
Full-text studies assessed for eligibility (n=49)
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)
Studies included in qualitative synthesis (n=8)
Studies screened (n=157)
Incl
uded
Elig
ibili
tySc
reen
ing
Iden
tific
atio
n
to 994 participants, with most studies (n = 6) havinga sample greater than 100 participants. Most studies(n = 7) were multi-site trials, with the number of studysites ranging from 3 to 104. Length of follow-upranged from 2 months to 2 years with an average of8.2 months; five trials were conducted over a periodof 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 alsovaried across studies.
Outcome measures varied across studies. It is of in-terest that in all studies, subjects showed an improve-
TABLE 1. Assessment of potential bias in includedscoring system
Author I II III IV V
Garcia et al. (2005) 1 1 1 1 1Kooi et al. (2008) 1 1 1 1 1Kumar et al. (2007) 1 1 1 1 1Maspero et al. (2008) 1 1 1 1 1Ostrom et al. (2005) 1 1 1 1 1Sorkness et al. (2007) 1 1 1 1 1Szefler et al. (2005) 1 1 1 1 1Szefler et al. (2007) 1 1 1 1 0
1, criteria fulfilled, low possibility of bias; 0, criteria not fulfilled, high pos
Assessment criteria: I, Eligibility criteria specified; II, random allocation;
blinding; VI, therapist blinding; VII, assessor blinding; VIII, less than 15%
ference between groups in outcomes; XI, size of treatment effect andme
dard deviations, interquartile ranges, and minimum-maximum range).
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ment in asthma symptoms from baseline regardless oftreatment assignment. Pulmonary function was an out-come of interest in seven studies, with results favoringICS over MON. These studies reported significantchanges 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), andasthma control days (Sorkness et al., 2007). Only onestudy that measured an objective pulmonary functionparameter (change in FEV1) as its primary outcome de-tected no differences between groups (Kumar et al.,
.although fourstudies favored ICSand four studiesfound nodifferencesbetween groups,no study foundMON monotherapysuperior tomonotherapy withICS.
2007). Six studies measured rescue-free days, with themajority reporting superiority of ICS over MON(Garcia et al., 2005; Maspero et al., 2008; Ostromet al., 2005; Sorkness et al., 2007). In general, studiesthat found no differences between treatment groupsmeasured more subjective patient outcomes: changein daily symptom score (Kooi et al., 2008) and changein the probability of asthma exacerbation (Szefleret al., 2007).
Clinical adverse events were reported in all studiesand favored ICS versus MON. Asthma exacerbationwas the most frequently reported event and was re-ported in all eight studies. Across studies, 182 of 1,345children (13.5%) assigned toMONand 128of 1,468 chil-dren (8.7%) assigned to ICS experienced an asthma ex-acerbation; the risk of asthma exacerbation was 1.6times 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 oralcorticosteroid use (Kooi et al., 2008; Kumar et al.,2007; Ostrom et al., 2005; Szefler et al., 2005; Szefleret al., 2007). Across studies, 81 of 488 children (16.6%)assigned to MON and 58 of 498 children assigned toICS (11.6%) required oral corticosteroids, with the riskof oral corticosteroid use 1.4 times higher (RR 1.43,95% CI 1.04-1.9) for children assigned to MON versusICS. Other less frequently reported events were head-ache (Maspero et al., 2008; Ostrom et al., 2005), upperrespiratory infection (Kooi et al., 2008; Ostrom et al.,2008), and skin rash (Kooi et al., 2008; Kumar et al.,2007).
Six studiesmeasured treatment adherence using self-report (n = 3), pill counts (n = 4), diskus counts (n = 4),and ElectronicDrug ExposureMonitor (n= 2)methods.Three studies used more than one method to measuretreatment adherence, such asmeasuring capsule countsand diskus dose indicator in addition to either diarycards 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 MONgroup (Ostrom et al., 2005; Szefler et al., 2005), two re-ported higher adherence in the ICS group (Masperoet al., 2008; Sorkness et al., 2007), and two found no dif-ferences in adherence between the MON and ICSgroups (Garcia et al., 2005; Szefler et al., 2007).
Less frequently measured outcomes of interest wereschool and parental work attendance, eosinophilcount, and linear growth. One study examined missedschool days (children) and missed work days (parents)and found no differences between children in the ICSgroup compared with the MON group (2.1% vs. 1.9%)during the 12-month trial (Garcia et al., 2005). Threestudies measured serum eosinophil levels, and nonefound 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 thechange in eosinophil level in the MON and ICS groupsbefore and after intervention (�0.08 � 103 vs. �0.06 �103, p = .411). Three studies measured the child’s lineargrowth over the duration of the study. One study foundthat children in the MON group demonstrated greaterannual 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 betweengroups (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 andmay have lacked statistical power to detect treatmentdifferences; 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 thatmay have been too short to fully evaluate treatment re-sponse and maintenance of asthma control.
DISCUSSIONSummary of EvidenceEight RCTs comparing the effects of ICS andMON in thetreatment of pediatric patients with mild to moderatepersistent 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 berelated to several fac-tors, including re-sponse to the assignedtreatment medicationor the Hawthorne ef-fect, where subjectsmay change their be-havior because theyare aware that they arein a clinical trial. Im-portantly, althoughfour studies favoredICS and four studiesfound no differencesbetween groups, no study found MONmonotherapy superior to monother-apy with ICS. In addition, the two studies that reportedno differences between groups had small samples andmay have lacked statistical power to detect differencesbetween 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; Szefleret al., 2005). Therefore the ability to generalize the studyfindings must be considered cautiously in treatment ofpatients with moderate asthma. In addition, the ability
Journal of Pediatric Health Care
to generalize findings is limited in patients youngerthan 5 years because only two studies examined thispopulation (Kooi et al., 2008; Szefler et al., 2007). Inter-estingly, the two studies that included children youngerthan 5 years found no differences between treatmentgroups (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 maybe that asthma in young children is frequently virally in-duced and thereforemaynot requiremaintenance 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 notprovide increased benefit at reducing inflammationcompared with MON. Further research is needed inmanagement 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. Thisfinding reinforces the current recommendation thatICS be used as first-line pharmacotherapy for persistentasthma (Rachelefsky, 2009). Previous research hasdemonstrated that a clinically relevant change in FEV1is a 10% improvement from baseline (Santanello,Zhang, Seidenberg, Reiss, & Barber, 1999). In the studyby Garcia and colleagues (2005), the absolute FEV1 dif-ference between groups was only 2.2% and, althoughstatistically significant, may not be clinically important.The large sample size in this study (N = 994) may haveprovided statistical power to detect very small differ-ences between groups.
Asthma exacerbations occurred more frequently inthe MON group. This finding is a significant consider-ation; however, it is important to note that the criterionfor exacerbation was subjective assessment of symp-toms, whichmay have had an impact on the differencesidentifiedbetweengroups. Interestingly, onlyone studyevaluatedmisseddaysof school andwork and foundnodifferences between those assigned to ICS versus MON(Garcia et al., 2005). We include these findings in thissystematic review because both school and work atten-dance is important to the quality of life of both childrenwith asthma and their parents. However, when inter-preting this finding, it is important to consider this resultas the outcome of one study only. More studies areneeded to determine the relationship between ICSand MON monotherapy treatment and missed schoolor work days. Other adverse effects were comparablebetween groups across all studies. Although one trialfound a clinically significant difference in linear growthin theMONgroup comparedwith the ICS group (Garciaet al., 2005), the mean difference in annual growthvelocity between groups was very small andmost likelynot clinically important. Although concern has been ex-pressed about using ICS in prepubertal children withasthma because of the potential for decreased skeletal
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growth, several studies assessing linear growth overtime in children treated with ICS have shown a tempo-rary decrease in growth velocity but no effect on finaladult height (Agertoft & Pedersen, 2000; Stefanovic,Verona, Cicak, & Vrsalovic, 2011; The ChildhoodAsthma 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 inhalerin addition to activemedication. However, only three ofthe studies specified the techniques used to make theactive medication and placebo similar in taste or odor(Ostrom et al., 2005; Sorkness et al., 2007; Szefleret al., 2005). Without this detail, it is difficult to assessthe 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 thataffected the results.Enrollment of minority children at higher risk for
asthma was limited. Only four studies reported raceand 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; Szefleret al., 2007). In the remaining studies, one in theNether-lands, one in India, and two in the United States, raceand ethnicity were not reported. This lack of informa-tion is particularly important in studies conducted inthe United States because of the diversity of the popula-tion. There is a higher prevalence of asthma in Blackchildren compared with White children and a lowerprevalence among Asian children (Akinbami et al.,2011). Failure to include minority children in the trialsmay 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 ofasthma in male youth. However, it is unclear if childrenof familieswith 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 includedstudies.All studies included in this review used medication
dosages within the recommended range by specificage categories of the children enrolled (Taketomo,Hodding, &Kraus, 2010). Interestingly, although differ-ences in dosing occurred across studies, the variabilityin dosing did not seem to have affected the results.For example, ICS was not superior to MON whena 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 wasused (Kooi et al., 2008; Ostrom et al., 2005; Szefleret al., 2007).
MON may beparticularlybeneficial fortreatment ofasthma in certainpopulations suchas children youngerthan 5 years.
Adherence to the assigned medication was generallyhigh across studies, with comparable compliance ratesbetween MON and ICS groups. This finding is surpris-ing because a large body of research documents theproblem of poor adherence with controller medicationin 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 methodssuch as canister weight or pharmacy refill (Burgess,Sly, & Devadason, 2010). Bukstein, Luskin, andBernstein (2003) reported higher medication refill ratesover a 12-month period for MON (7.7 � 3) comparedwith ICS (5.5 � 3). Adherence with ICS may be poorerbecause of twice-per-day dosing and the need to rinsethe mouth after inhalation to prevent oropharyngealcandidiasis and systemic absorption of the medication(Makino, Ohta, Nishima, & Morikawa, 2005). Thehigh adherence rates identified in this review mayhave been influenced by the method of measurement,because several studies used parental report, whichmay have overestimated medication adherence. How-ever, it is important to note that all studies thatmeasuredadherence via self-report used validatedmeasures suchas The Pediatric Asthma Diary (Santanello et al., 1999).Further, only one study used self-report as the onlymethod of measuring adherence, with most usinga combined approach such as diskus and pill countsin addition to parental self-report. Using combinationsof indirect measures of adherence such as these havebeen shown to improve measurement (Osterberg &Blaschke, 2005).
Study duration varied across studies and warrantsspecial mention because greater duration allows exam-ination of response to asthma therapy over time. Five ofthe eight studies were conducted over 3months or less.Because asthma is associated with exacerbations thatfluctuate across seasons, the short follow-up periodmay have limited the ability to identify true differencesin 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 andmore sufficient follow-up times are needed to betterunderstand the long-term effects of ICS comparedwith MON.
Motivation of participants to continue in clinical trialsoften is challenging and tends to decline over time. At-trition rates varied across studies, and three studies hadattrition rates greater than 15%. The studywith the high-est attrition rate included in this review (Szefler et al.,2007) had a follow-up length of 11 months, whichmay have added to the attrition because of the lengthof follow-up. Participants with chronic illnesses suchas asthma have been identified as having associatedpsychosocial factors, such as depression, which mayadd to dropout rates (Bender et al., 2003). Furthermore,asthma is a chronic illness in which patients experience
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exacerbations that require more intensive manage-ment. One of the primary reasons for patient with-drawal in the studies included in this review wasasthma exacerbation. High dropout rates can affect val-idity; however, it is important to note that each studyreporting a high rate of attrition conducted an
intention-to-treat anal-ysis that minimizedbias by including dataof all enrolled partici-pants in the analysis.The evidence sum-
marized in this reviewsupports the currentguidelines that ICSshould be prescribedas first-line for treat-ment of persistentasthma (Rachelefsky,
2009). However, MON may be particularly beneficialfor treatment of asthma in certain populations such aschildren younger than 5 years. Becausemost studies in-cluded in this review did not include young children intheir samples, this question remains unanswered andrequires further research. In addition, the ability to gen-eralize these findings to African American andHispanicchildren is limited because these childrenwere not wellrepresented in the included clinical trials.
LimitationsOur systematic review has several limitations. The liter-ature search only included studies published in the En-glish language. Only three large databases weresearched, and thus additional studies not identifiedvia use of these particular databases potentially werenot included. Although in four of the studies includedin this review no differences were found between treat-ment groups, it is possible that publication bias mayhave led to a failure to publish other studies findingno significant differences between ICS and MON.
CONCLUSIONIn children ages 2 to 18 yearswithmild tomoderate per-sistent asthma, both MON and ICS monotherapies areeffective options in improving asthma symptoms,with a somewhat more favorable response to ICSmonotherapy. The findings of this systematic revieware consistent with the recommendation of theNational 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 includeminority chil-
dren at higher risk for asthma. Examination of the use ofMON and ICS also is needed in preschool childrenyounger than 5 years, because this populationmay par-ticularly benefit fromMON treatment. Additionally, fur-ther research is needed to compare the effectiveness of
Journal of Pediatric Health Care
MON to ICS inmoderate persistent asthma, because thisreview included only three studies examining patientswith asthma categorized as moderate severity.
RELEVANCE TO CLINICAL PRACTICEThis systematic review examined monotherapy withMON compared with ICS in children with mild to mod-erate persistent asthma. The results reinforce the cur-rent National Asthma Education and PreventionProgram (2007) guidelines that ICS should be used asfirst-line therapy in patients with mild to moderate per-sistent asthma.MONmaybeconsideredasa therapeuticagent for patients when ICS therapy does not provideadequate symptom management or for persons whohave 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 tomoderate asthma, it is important to consider the severityof symptoms. Because only three studies in this reviewincluded subjects with asthma of moderate severity,findings of this systematic review should be used withcaution in patients with moderate severity symptoms.Furthermore, because only two studies included chil-dren younger than 5 years, the results of this reviewmust be used carefully with this population.
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