PEDIATRICS Vol. 120 No. 3 September 2007, pp. e702-e712 (doi:10.1542/peds.2006-3317)
ARTICLE |
Attenuation of the September Epidemic of Asthma Exacerbations in Children: A Randomized, Controlled Trial of Montelukast Added to Usual Therapy
Firestone Institute for Respiratory Health, St Joseph's Healthcare and McMaster University Department of Medicine, Hamilton, Ontario, Canada
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX 1 GEE logit...APPENDIX 2 Forty-four Dummy...APPENDIX 3 Summary of...REFERENCES |
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BACKGROUND. A recurring epidemic of asthma exacerbations in children occurs annually in September in North America when school resumes after summer vacation.
OBJECTIVE. Our goal was to determine whether montelukast, added to usual asthma therapy, would reduce days with worse asthma symptoms and unscheduled physician visits of children during the September epidemic.
PATIENTS AND METHODS. A total of 194 asthmatic children aged 2 to 14 years, stratified according to age group (2–5, 6–9, and 10–14 years) and gender, participated in a double-blind, randomized, placebo-controlled trial of the addition of montelukast to usual asthma therapy between September 1 and October 15, 2005.
RESULTS. Children randomly assigned to receive montelukast experienced a 53% reduction in days with worse asthma symptoms compared with placebo (3.9% vs 8.3%) and a 78% reduction in unscheduled physician visits for asthma (4 [montelukast] vs 18 [placebo] visits). The benefit of montelukast was seen both in those using and not using regular inhaled corticosteroids and among those reporting and not reporting colds during the trial. There were differences in efficacy according to age and gender. Boys aged 2 to 5 years showed greater benefit from montelukast (0.4% vs 8.8% days with worse asthma symptoms) than did older boys, whereas among girls the treatment effect was most evident in 10- to 14-year-olds (4.6% [montelukast] vs 17.0% [placebo]), with nonsignificant effects in younger girls.
CONCLUSIONS. Montelukast added to usual treatment reduced the risk of worsened asthma symptoms and unscheduled physician visits during the predictable annual September asthma epidemic. Treatment-effect differences observed between age and gender groups require additional investigation.
Key Words: asthma exacerbations • children • school return • montelukast • asthma control • age • gender
Abbreviations: RVI—respiratory viral infection • ICS—inhaled corticosteroid • LTRA—leukotriene receptor antagonist • LABA—long-acting β2 agonist • OR—odds ratio • CI—confidence interval
Epidemics of asthma exacerbations requiring hospital treatment occur annually after school return after the summer vacation in both the Northern and Southern Hemispheres.1,2 In Canada, the peak of the epidemic in school-aged children occurs consistently 18 days after Labor Day, with slightly later and attenuated peaks seen in preschool-aged children and adults.3 Between 20% and 25% of children's hospital admissions for asthma in Canada occur in the month of September.4
Stress, possibly associated with school return, can worsen asthma symptoms in children,5 and high levels of environmental allergens occur in the late summer.6 Children returning to school after the summer vacation are reexposed to respiratory viral infections (RVIs),7 most commonly rhinovirus at that time,8,9 and sensitizing allergens in the school environment.10,11
Inhaled corticosteroids (ICSs) may be of lesser efficacy in the control of asthma symptom exacerbations associated with RVIs in children.12,13 In addition, compliance with ICS is generally poor,14 and filling of asthma control prescriptions decreases during the summer months.7 Increasing adherence to prescribed inhaled asthma control medication before and during the September school return period could be beneficial, but is unlikely to be easily and economically conducted in general practice.
Leukotriene receptor antagonists (LTRAs) have been shown to reduce the likelihood of exacerbations in children with persistent asthma.15,16 As a strategy to reduce the burden of asthma morbidity during the predictable September epidemic, the addition of oral LTRA to usual therapy may offer advantages over other possible interventions. The therapeutic effects of LTRA occur shortly after inception of treatment. LTRA could easily and safely be added to existing asthma therapy, and this strategy is readily generalizable to practice.
The prevalence of asthma symptoms and the risk of exacerbations are both significantly greater in boys than in girls before puberty.17,18 At puberty, a reversal in the relative risk of exacerbations between the genders occurs over a very short period.1 Previous studies of the September epidemic suggest that its intensity and timing in children varies with age.3
After a pilot study in September 2004,19 we undertook a larger study in September and October 2005 to test the hypothesis that the LTRA montelukast added to usual therapy of asthmatic children during this period of high risk of asthma exacerbations would decrease days with worse symptoms and unscheduled physician visits for asthma, and thus attenuate the epidemic. Because of the considerations noted earlier, we stratified subjects a priori according to gender and age group to facilitate testing of an exploratory hypothesis that there would be age and gender differences in the response to montelukast.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX 1 GEE logit...APPENDIX 2 Forty-four Dummy...APPENDIX 3 Summary of...REFERENCES |
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This randomized, double-blind, placebo-controlled, 45-day study compared the effect of adding montelukast (at the age-specific dose) or matching placebo to current therapy in children aged 2 to 14 years with diagnosed asthma. The study was approved by the research ethics board of St Joseph's Healthcare, Hamilton. Written informed consent was obtained from parents of all the subjects and assent from appropriately aged children.
The trial was designed and executed by the academic investigators. The study physicians did not intervene in the usual medical care of subjects, which was provided exclusively by their own physicians.
Setting and Participants
Study participants were recruited between May and August 2005 through advertising and from clinical practices in Hamilton and Brantford, Ontario, Canada. Entry criteria included 2 to 14 years old; physician-diagnosed asthma; needing a rescue inhaler in the last year; missing 
1 day from school because of asthma in the last year or having significant limitation of normal activity; having a history of asthma exacerbations associated with apparent RVIs; and ability to communicate in English. Children were excluded if they had significant cardiorespiratory comorbidity; were currently using a LTRA; were using regular oral corticosteroid; or had an asthma exacerbation in the month before study inception. Clinical history, demographic, and current-therapy information was obtained at recruitment by using an administered questionnaire.
Randomization
After recruitment, participants were contacted again in late August to confirm their continuing eligibility and were then randomly assigned to receive montelukast or placebo in blocks of 4, according to gender, within age groups 2 to 5, 6 to 9, and 10 to 14 years. The concealed, computer-generated randomization schedule was developed by an individual who was not otherwise involved with the study.
Intervention
Numbered vials containing 45 montelukast or placebo tablets and individual sealed randomization assignments were prepared by Merck Frosst Canada Ltd, with dosages (4 or 5 mg) appropriate for each age group. Participants were instructed to take 1 tablet daily in the evening, commencing on September 1, in addition to their usual asthma therapy.
Measurement of Study Outcomes
A magnet-backed "fridge" calendar (see Fig 1) for the period September 1 to October 15, 2005, had attached a supply of green, yellow, orange, red, and purple stickers, 1 of each color printed with the date of each study day. A green sticker was applied on days when a child had no asthma symptoms, a yellow sticker indicated usual asthma symptoms, an orange sticker indicated symptoms that were worse than usual or needed extra asthma medication, and a red sticker was applied if a child's breathing symptoms required an unscheduled visit to a physician or treatment with oral corticosteroids. In addition, a purple sticker was applied on days that a child had symptoms of a cold.
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Within a week of study completion, a follow-up telephone questionnaire, including verbal reporting of the calendar stickers for all subjects, was completed. Frequency of use of nonstudy asthma medications, primarily ICSs, short-acting and long-acting β2 agonists (LABA) during the study was obtained by the poststudy telephone questionnaire. Calendars and any remaining trial medication were returned by participants and reported sticker assignment verified. Reported unscheduled physician visits for asthma were verified with the physicians concerned. Questionnaire data were double-entered by different operators, and any inconsistencies were reconciled by a study coordinator.
Definitions
Days with worse asthma symptoms were defined as those with either an orange or red sticker. A "cold" was defined by the presence of 2 consecutive purple stickers indicating days with cold symptoms. At least 5 days with no cold symptoms were required before a subsequent new cold was identified.
Statistical Analysis
Sample-Size Considerations
We expected a 40% reduction in days with worse asthma symptoms in the montelukast group. This difference was estimated from the results of our pilot study,19 in which we observed a 30% reduction in days with any asthma symptoms. We set 1-β at .2 and 
(2-sided) at .05. These criteria produced a sample-size requirement of 88 per group. We allowed for a 10% dropout rate, which produced a final sample requirement of 97 per group.
Univariate Analysis
Univariate analyses of baseline characteristics and primary and secondary outcomes were conducted before unblinding. The primary outcome was the percentage of days in which a child experienced a worsening of asthma symptoms. The combined numbers of red and orange calendar stickers for each child, irrespective of whether cold symptoms (purple sticker) were present, was expressed as a percentage of the total green, yellow, orange, or red stickers applied for each child. Wilcoxon rank-sum test (Mann-Whitney test) was used to compare overall rankings between montelukast and placebo, with stratification according to age group and gender. The secondary outcome was the number of unscheduled physician visits for treatment of asthma.
Comparisons of the baseline characteristics of the study groups, the secondary outcome of unscheduled physician visits, and cold frequencies were conducted by using 
2 and Fisher's exact tests.
Multivariable Analysis
For each subject for each day, a dichotomous variable identified days where the child experienced a worsening of their asthma symptoms (red or orange sticker) or usual or no asthma symptoms (yellow or green sticker), irrespective of whether cold symptoms (purple sticker) were present. Logistic general estimating equations, correcting for the repeated and serially correlated nature of these data with robust errors (Stata 9.1; Stata Corp, College Station, TX), were used to estimate the adjusted odds ratios (ORs) for worsening symptoms (Appendix 1), comparing montelukast versus placebo controlling for age group, gender, baseline characteristics, days with cold symptoms, use of ICS, and of ICS combined with a LABA (Appendix 2). Comparisons of treatment groups for nonstudy asthma medication use were conducted by using t tests for samples of unequal variance. Use of both ICS and ICS-LABA was classified as none, intermittent (<40 days with 1 dose), and regular (40 days with 1 dose) during the 45-day trial period.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX 1 GEE logit...APPENDIX 2 Forty-four Dummy...APPENDIX 3 Summary of...REFERENCES |
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Study Subjects
Of 363 children screened for the study, 82 were already taking montelukast and 85 did not meet other study criteria. We recruited 196 eligible subjects of whom 2 became ineligible after recruitment and before randomization (Fig 2). All 194 children who began treatment (98 montelukast, 96 placebo) completed the study and were included in the analyses.
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There were no clinically important baseline differences between treatment groups in medical history or prescribed asthma treatments (Tables 1 and 2). More than 90% of children had been prescribed an ICS, with 30% of each group prescribed a combination product (ICS with LABA). There were no children prescribed a LABA without ICS. Slightly more emergency department visits and inpatient hospitalizations for asthma in the previous year were reported by the group that was randomly assigned to receive montelukast, whereas more lifetime hospitalizations for asthma had occurred in the placebo group.
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Compliance
Almost all (188 of 194) children commenced treatment on September 1. Four children started the study on September 2, and 1 each on September 4 and 5. A total of 8689 (99.7%) of a possible 8719 daily stickers were applied during the study. Twenty days were left blank by children on montelukast and 10 by children on placebo. Compliance with therapy was 91.7% for montelukast and 93.2% for placebo (P = .27), with no differences observed within age groups. Ten children randomly assigned to receive montelukast and 7 to receive placebo reported taking <80% of study medication.
Adverse Events
Two children discontinued study medication because of adverse events, 1 with personality change and 1 with changes in appetite and increased tiredness, but the trial code was not broken and symptom recording was continued. Both were taking placebo. One more significant event was identified only at the follow-up interview; a child randomly assigned to receive montelukast required emergency treatment for an acute behavior disorder after a family dispute. Minor adverse events, whether medical attention was sought, occurred in 25 children taking montelukast and in 35 taking placebo. A list of adverse events is provided in Appendix 3.
Univariate Analysis
Primary Outcome
Overall, children taking montelukast experienced 53% fewer days with worse asthma symptoms (red and orange stickers combined) compared with those taking placebo (3.9% vs 8.3%; P < .02). Children taking montelukast classified only 167 days in total as days with worse asthma symptoms (orange stickers) compared with 340 on placebo (Table 3).
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Secondary Outcome
There was a marked reduction in unscheduled visits to physicians for asthma, 4 visits occurring in 4 subjects in the montelukast treated group compared with 18 visits by 14 subjects in the placebo group (78% decrease; P = .011). All oral steroid use occurred as a consequence of a physician visit. There was no significant difference in the number of physician visits for nonrespiratory problems between the 2 groups (montelukast: 28; placebo: 32).
Children taking montelukast were less likely to report using short-acting β2 agonists during the study (average: 6.8 days [SD: 1.0] vs 9.4 [SD: 1.2] days with placebo [P = .05]). The mean number of days of reported use of any ICS preparation during the study was similar between treatments, 18.4 (SD: 2.0) days with montelukast and 19.4 (SD: 2.0) with placebo (not significant).
Exploratory Hypothesis: Outcomes According to Age Group and Gender
There were significant differences in the effect of montelukast on asthma morbidity between the genders and age groups (Fig 3). Among 2- to 5-year-olds, boys taking montelukast had an average of only 0.4% of days with worse asthma symptoms compared with 8.8% on placebo (P < .001) whereas in girls, the difference was not significant (5.7% [montelukast] and 6.9% [placebo]). Among 6- to 9-year-olds, boys taking montelukast experienced an average of 2.0% worse symptom days compared with 7.0% on placebo (P = .12), whereas girls showed no effect (4.5% [montelukast] and 4.6% [placebo]). Among 10- to 14-year-olds, the direction of the difference between the genders observed in younger children was reversed; boys reported little difference in worse symptom days (6.3% [montelukast] vs 8.2% [placebo]; P = .44), whereas girls reported only 4.6% worse symptom days with montelukast compared with 17.0% with placebo (P = .03).
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Multivariable Analysis
Use of Other Asthma Medications
We did not examine differences in outcomes between those with and without baseline ICS prescriptions because >90% of children had prescriptions for ICS, but rather analyzed differences in outcomes between montelukast and placebo treatment within groups reporting taking no, intermittent, and regular ICS or ICS/LABA during the study (Table 4). Montelukast significantly reduced the risk of asthma worsening among those reporting regular ICS use (OR: 0.13; 95% confidence interval [CI]: 0.03–0.51), and no ICS use (OR: 0.14; 95% CI: 0.04–0.53). Among a smaller number of children reporting intermittent ICS use, the effect of montelukast was similar but not statistically significant (OR: 0.37; 95% CI: 0.10–1.31). In those prescribed ICS/LABA in combination, the benefit of montelukast over placebo was not significant in either those reporting regular use (OR: 0.44; 95% CI: 0.11–1.75) or those using ICS/LABA intermittently (OR: 1.24; 95% CI: 0.31–4.89).
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Colds and Cold Symptoms
Equal numbers of colds, as defined earlier, were reported by the 2 groups (84 in each). Across all subjects, a day with reported cold symptoms (purple sticker) increased the risk of having worse asthma symptoms over fivefold (OR: 5.29; 95% CI: 3.70–7.56; P < .001). The effect of montelukast on the primary outcome, days with worse asthma symptoms, was seen equally on days with reported colds compared with other times during the study.
Age- and Gender-Group Differences
Boys aged 2 to 5 years taking montelukast had a 97% reduced risk of having days with worse asthma symptoms compared with placebo by multi-variable analysis (OR: 0.03; 95% CI: 0.01–0.21; P < .001) (Table 5). Boys 6 to 9 years old had a 73% reduction (OR: 0.27; 95% CI: 0.09–0.87; P = .03), whereas there was no significant reduction in risk for boys aged 10 to 14 (OR: 0.81; 95% CI: 0.24–2.77). For girls, this age-related trend was reversed, with an 83% risk reduction in 10 to 14-year-olds (OR: 0.17; 95% CI: 0.05–0.52; P = .03) and no significant effect in either the 2- to 5-year-olds (OR: 1.29; 95% CI: 0.18–9.1) or 6- to 9-year-olds (OR: 0.68; 95% CI: 0.13–3.45).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX 1 GEE logit...APPENDIX 2 Forty-four Dummy...APPENDIX 3 Summary of...REFERENCES |
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In this study, asthmatic children given montelukast in addition to regular therapy experienced half the number of days with worsened asthma symptoms of those taking placebo during an annual September asthma epidemic period. Children taking montelukast were also 4 times less likely than those receiving placebo to require unscheduled medical intervention for asthma symptoms.
More than 90% of the children in this study had prescriptions for ICs, either alone or in combination with a LABA, but <50% of these children reported regular use of these medications through the study period. The addition of montelukast in this situation of relatively low compliance with usual therapy reduced days of worsening asthma and greatly reduced the need for unscheduled medical attention.
We conducted this study to determine whether asthma morbidity and health service use during the postsummer vacation asthma epidemic could be reduced, irrespective of its causes. We wished to intrude as little as possible into subjects' routines and not artificially influence their compliance with usual asthma treatments, knowing that ICS prescription filling is at its lowest level just before school return.7 Accordingly, we asked for an estimate of ICS use at the end of the study, which may have provided a less accurate measure of usage than data collected prospectively through the 6 weeks, but which more likely reflected real world use. We did not confirm the presence of colds with virological testing, because we believed that the information gained would be at the expense of possible changes in subject's normal behavior during the study.
Our poststudy questionnaire revealed substantial lack of compliance with prescribed ICS therapy during the 6-week study period, and prescribing data similarly indicate that use of ICS is low over the summer months.7 When children with asthma are reexposed to risk factors on return to school, whether viral, allergic, stress-related, or other, the lack of adequate controller medication increases their risk of worsening asthma. The addition during this high-risk period of an easily taken oral therapy, added to whatever usual therapy the child did take, was effective in reducing morbidity. Compliance with the oral therapy in our study was very high. This may well translate into the real world, because giving a controller therapy for a defined short period and in oral form would likely result in much better adherence than generally achieved with ICS. The intervention was effective in reducing morbidity irrespective of usual therapy and of the presence of colds.
Although our study was not powered to investigate this, montelukast seemed to benefit those subjects prescribed ICS alone more than those taking ICS/LABA combination therapy. This may reflect an additional benefit of LABA, or could indicate that those using combination therapy were more compliant with usual therapy than those on ICS alone. A larger sample using regular ICS/LABA is required to determine whether adding montelukast to regular ICS/LABA use does reduce morbidity.
The magnitude of effect in the population can be estimated from the study results. Among 96 children taking placebo in addition to usual therapy, there were 18 physician encounters by 14 children, and only 4 among a near equal number taking montelukast. Hence, the number needed to treat to prevent 1 exacerbation requiring a physician visit in this epidemic period is <10. Such an effect may also be achievable by enhancing compliance with ICS therapy but this remains to be shown.
We found that adding montelukast to usual therapy was most clearly beneficial in younger boys and older girls. To our knowledge, this is the first study to report large gender differences in the effectiveness of an asthma therapy. Moreover, the direction of the gender difference was reversed during the years of puberty. Other randomized, controlled trials that have established the efficacy of montelukast in children, did not examine differences between the genders.15,16,20 A report of additional analyses21 from 2 of these studies15,16 stated that in 6- to 14-year-old patients, differences in efficacy were observed between the genders, but data were not provided to substantiate this. Szefler et al,22 in a study comparing the effects of fluticasone propionate and montelukast, reported a greater increase in forced expiratory volume in 1 second in girls compared with boy subjects aged 6 to 17 taking montelukast (difference: 3.9%; P = .026).
Days of worse asthma symptoms may be perceived differently by boys and girls, although the crossover of benefit observed in older children makes this unlikely. Among boys given montelukast, we observed a decreasing gradient of the percentage of days with worse asthma symptoms with age group, but this remained quite constant in the placebo group (Fig 3). Among girls given montelukast, the percentage of days with worse asthma symptoms was similar in all 3 age groups and in the 2 younger age groups taking placebo, but 10- to 14-year-old girls receiving placebo had much higher rates of asthma worsening.
Asthma is generally more severe in boys than in girls before puberty and more severe in women than men after puberty.17,18,23 In this study, the direction of the gender difference was reversed during the years of puberty raising the possibility that the effects of montelukast may be influenced by gender and hormonal changes. It could be speculated that the efficacy of montelukast in boys diminishes as they move toward sexual maturity, but that in girls there is an increase in the severity or instability of asthma during and after puberty when montelukast seems to be more efficacious. If the cysteinyl leukotriene receptor gene Cys-LT1 situated on the X chromosome24 is downregulated at puberty in males and/or upregulated in females, this could modulate effects of montelukast.
The numbers of subjects in some of our subgroups were small, and our findings of potentially clinically important age and gender differences are, therefore, tentative. However, multivariate analysis, which took into account the influence of many other factors, showed even stronger effects of montelukast than our primary analysis and more profound differences between age and gender groups. These findings require substantiation in additional studies.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX 1 GEE logit...APPENDIX 2 Forty-four Dummy...APPENDIX 3 Summary of...REFERENCES |
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There was a substantial benefit of adding montelukast once daily to usual therapy in asthmatic children during the September epidemic of exacerbations. Although numerous studies have shown that montelukast is effective in reducing asthma symptoms compared with placebo, our study demonstrated that the short-term addition of montelukast to usual asthma therapy for a limited time of 6 weeks after school return could substantially reduce asthma morbidity and health service consumption during this predictably high-risk period when use of other controller medication is known to be at its lowest level.
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APPENDIX 1 GEE logit AR(1) Models for Factors Associated With Having a Red/Orange Sticker |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX 1 GEE logit...APPENDIX 2 Forty-four Dummy...APPENDIX 3 Summary of...REFERENCES |
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APPENDIX 2 Forty-four Dummy Codes to Control for Each Day of the Study |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX 1 GEE logit...APPENDIX 2 Forty-four Dummy...APPENDIX 3 Summary of...REFERENCES |
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APPENDIX 3 Summary of Incidence of All Reported Adverse Events by Chart Review |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX 1 GEE logit...APPENDIX 2 Forty-four Dummy...APPENDIX 3 Summary of...REFERENCES |
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ACKNOWLEDGMENTS |
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This work was funded by a Medical School Grant from Merck Frosst Canada Limited.
We thank Dr Lori Whitehead and Anne Merklinger for recruitment of patients for this study, and Professors Sebastian L. Johnston and Paul M. O'Byrne for careful review of the manuscript.
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FOOTNOTES |
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Accepted Mar 14, 2007.
Address correspondence to Neil W. Johnston, MSc, Firestone Institute for Respiratory Health, St Joseph's Healthcare, 50 Charlton Ave E, Hamilton, Ontario, Canada L8N 4A6. E-mail: njohnsto{at}mcmaster.ca
Merck Frosst Canada Ltd funded the study and provided the drug and placebo but did not participate in the design and conduct of the study, data collection, analysis, interpretation of the data, or writing of the article.
This trial has been registered at www.clinicaltrials.gov (identifier NCT00196547).
Mr Sears and Mr Johnston have received honoraria and/or research funding from Merck Frosst Canada Limited. The other authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX 1 GEE logit...APPENDIX 2 Forty-four Dummy...APPENDIX 3 Summary of...REFERENCES |
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