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(Chest. 2007;131:180-186.)
© 2007 American College of Chest Physicians

The Effect of Montelukast on Bronchial Hyperreactivity in Preschool Children*

Fahed Hakim, MD; Daphna Vilozni, PhD; Adi Adler, MD; Galit Livnat, MD; Asher Tal, MD and Lea Bentur, MD

* From the Pediatric Pulmonology Unit (Drs. Hakim, Vilozni, Adler, Livnat, and Bentur), Meyer Children’s Hospital, Rambam Medical Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; and Soroka University Medical Center (Dr. Tal), Beer Sheva, Israel.

Correspondence to: Lea Bentur, MD, Director, Pediatric Pulmonology Unit, Meyer Children’s Hospital, Rambam Medical Center, PO Box 9602, Haifa, 31092 Israel; e-mail: l_bentur{at}rambam.health.gov.il

Abstract

Introduction: The effect of montelukast therapy on bronchial hyperreactivity (BHR) as measured by the methacholine challenge test in preschool children has not yet been reported.

Objective: To determine the effect of montelukast (4 mg/d) on BHR as evaluated by a provocative concentration of a substance causing a 20% fall in FEV1 (PC20) values in preschool asthmatic children.

Patients: A total of 26 preschool children (8 girls) aged 3.3 to 6.0 years (mean [± SD] age, 4.7 ± 0.8 years) with mild asthma.

Design: Double-blind randomized, placebo controlled, crossover study. Each child received 4 weeks of treatment with 4 mg of either montelukast or placebo separated by a 2-week washout period. Primary outcomes were PC20 values and the stage number (triple dose) at which FEV1 values dropped by 20%. Post-montelukast therapy PC20 was compared to those for the post-placebo period.

Results: Following 4 weeks of montelukast treatment, the mean PC20 was 4.79 ± 4.69 mg/mL, while after 4 weeks of placebo the mean PC20 was 2.07 ± 2.37 mg/mL (p = 0.001). The montelukast/placebo ratio for PC20 was 2.56 with a 95% confidence interval (CI) of 1.71 to 3.99. The median difference in stage was one triple dose with a 95% CI of 0.5 to 1.5.

Conclusions: Four weeks of treatment with montelukast resulted in a decreased BHR compared with placebo.

Key Words: bronchial reactivity • leukotrienes • pediatric asthma • preschool

The greatest prevalence of asthma in the general population is in preschool children. The clinical utility of asthma therapy for children in this age group is limited by a narrow therapeutic index, long-term tolerability, and the frequency and difficulty of administration.1 Assessing the response to treatment in children < 5 years old is additionally difficult because objective measurements are not generally available, and most studies rely on second-hand caregiver reports of symptom scores and exacerbation rates.

Montelukast is an orally bioavailable, cysteinyl leukotriene receptor antagonist (LTRA) that is effective, safe, well-tolerated, and has been approved by the US Food and Drug Administration as preventive therapy for the inflammatory component in asthma and allergic rhinitis in children ≥ 1 year old. The potential advantage of montelukast therapy is the ease of administering a once-daily tablet23. In children aged 6 to 14 years, montelukast treatment (5 mg/d) resulted in a statistically significant increase in FEV1 during an 8-week randomized, double-blind trial,4 with an improved provocative concentration of a substance causing a 20% fall in FEV1 (PC20) for adenosine monophosphate.5 Montelukast tablets in chewable form or granules of 4 mg/d are prescribed to young children < 5 years old. Therapy with montelukast showed significant improvements in multiple clinical parameters of asthma control in preschool children compared with placebo.6 Only two studies78 have used objective measures to evaluate the effect of montelukast in preschool children. Montelukast, 4 mg, also had a positive effect on lung function and airway inflammation as measured by nitric oxide levels,7 and improved bronchoprotection against the effects of hyperventilation due to breathing cold dry air.8

The most common and well-established test to measure bronchial hyperreactivity (BHR) is the methacholine challenge test (MCT), in which airway constriction is triggered by the inhalation of methacholine phosphate in adults and school children.910111213 The test requires multiple spirometry measurements and therefore is not commonly used for testing BHR of preschool children.

The feasibility of performing forced expiratory flow volume (FEFV) measurements in young children was shown in several studies from the past few years.1415161718 Recently, our group has shown19 that the determination of PC20 by spirometry is feasible in preschool children. The effect of montelukast on methacholine-inducing BHR as evaluated by PC20 has not been determined. We hypothesized that treatment with montelukast (chewable tablets, 4 mg/d) will result in a reduction in PC20 in asthmatic preschool children.

Materials and Methods

Subjects
The study was conducted between February and May 2005. Outpatient preschool children were referred to the Pediatric Pulmonary Clinic, Meyer Children’s Hospital, Rambam Medical Center (Haifa, Israel). Inclusion criteria were age 3 to 6 years, diagnosis of asthma by American Thoracic Society criteria, the ability to perform spirometry consistently, asthma severity classified as "mild intermittent or mild persistent" according to the Global Initiative for Asthma workshop report,20 and no antiinflammatory medication or antihistamine agents received for at least 2 weeks prior to study enrollment. Exclusion criteria were the presence of other chronic conditions, emergency department visit in the past 3 months, respiratory infection in the past month, steroids or other antiinflammatory medication received in the last 2 weeks, and bronchodilator or theophylline preparations received in the 24 h prior to undergoing spirometry. Only children with a positive baseline methacholine test result who completed the full study period were included. The Rambam Medical Center Ethics Board approved the study. Parental consent was obtained for each child. Demographics, the child’s asthma history, atopy, and the family history of asthma and smoking were recorded.

Study Design
The study was a double-blind, randomized, placebo-controlled crossover design. Each child received 4 weeks of treatment with either montelukast tablets, 4-mg, or placebo tablets with a 2-week washout period in between (Fig 1 ). The placebo tablets were prepared by the hospital pharmacy (Soroka University Medical Center; Beer Sheva, Israel); montelukast and placebo tablets were provided in identical, similarly colored, opaque capsule containers. The order of receiving medication for each child was randomized by the hospital pharmacy, independently of trial staff, prior to commencement of the study. Randomization occurred in blocks of 10 children (5 children initially received montelukast followed by placebo, and five children initially received placebo followed by montelukast). For the period of the study, each child was given a pediatric asthma caregiver diary to assess daytime asthma symptoms, overnight asthma symptoms, the use of ß2-agonists, and the use of resources for worsening asthma. Daily asthma symptom scores ranged from 0 to 5 (0, no symptoms; 5, very severe symptoms). Nighttime scores ranged from 0 to 2. Daytime and nighttime use of ß2-agonist was recorded. Compliance was assessed by counting the empty capsules at each visit.


Figure 1
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  		Figure 1. Study plan. Daytime and overnight asthma symptoms and ß2-agonist treatment were recorded during the 10 weeks of the study. MCTs and spirometry were performed at the following three points: at baseline; after phase I; and at the end of phase II. Short-acting ß2-agonist treatment was withheld for > 24 h.

 
Spirometry
Spirometry was performed using a pulmonary function testing system (KoKo system; PDS Inc, Ferraris Cardiopulmonary Systems Group; Louisville, CO). FEFV curves were measured using the program incentive targets provided by the pulmonary function testing system. and tests were performed with the patient standing up without a noseclip. An experienced pulmonary technician instructed each child on how to operate the computerized, animated spirometry games. Baseline maneuvers were repeated to obtain the best possible visual efforts on at least three technically acceptable FEFV curves. Calibration of the system was performed before the testing sessions. The atmospheric pressure, ambient temperature, and humidity were measured daily, and the results were automatically corrected by the program to body temperature and pressure-saturated conditions. The spirometry curves were reviewed visually, but were coded for name, sex, age, and height of the children for anonymity. Spirometry curves had to meet the modified criteria for quality control in preschool children21 including visual inspection for "noncooperation" errors, which included poor effort, incomplete expiration, and cough and glottis closure. Acceptable curves had to show a rapid rise to peak flow, and a gradual, smooth decline of flow down to residual volume. Baseline maneuvers were repeated to obtain the best possible visual efforts on at least three technically acceptable FEFV curves.

MCT
After obtaining baseline spirometry results, the MCT was performed. MCTs were performed in a designated room at the Pediatric Pulmonary Unit, Meyer Children’s Hospital (Haifa, Israel). A parent and the investigating team (consisting of a pediatric pulmonary physician, a respiratory physiologist, and a technician) were present throughout the test. The MCT was performed according to published guidelines,2223 with triple doses of fresh methacholine solution (0.057 to 13.925 mg/mL) dissolved in saline solution. The solutions were prepared using a pulmonary dosimeter (KoKo; PDS Inc) according to the manufacturer’s instructions, using a mouthpiece with a nose clip and breathing deep breaths while the child was sitting up straight. A 5-min interval was phased in between doses, and a duplicate spirometry set was performed. The MCT ended when FEV1 dropped to ≥ 20% from baseline FEV1 values. The exact PC20 value was then calculated by the program according to the log-transformed formula, as described in the guidelines for methacholine and exercise challenge testing.23 In order to ensure safety, the methacholine increment was only half the usual amount when transient wheeze or cough was noted or when FEV1 decreased by > 15% of baseline values, keeping in mind that the cumulative dose is affected by this manipulation. Oxygen saturation and heart rate were monitored continuously by pulse oximetry (Biox 3700e; Ohmeda; Louisville, CO). A single observer (L.B.) performed auscultation for 20 s over the trachea and two zones of both lungs (upper front and lower back) according to the procedure of Springer et al24 as a safety measure. A fall of 20% in FEV1 from baseline values was considered to be the end of test. At that point, nebulized albuterol (2.5 mg) was administered.

Statistical Analysis
The primary efficacy end points were defined as the PC20 and. the stage number (triple dose) at which FEV1 dropped by 20%. A sample size of 26 patients was calculated as needed to detect a decrease of 0.5 SD in BHR with a power of 80%. For the determination of PC20, we used an analysis of variance model with log (PC20) as explained (dependent) variable by the following explanatory (independent) factors: treatment (montelukast or placebo); period (first or second); sequence (placebo followed by montelukast or montelukast followed by placebo); and patients included (1 through 26) nested within the sequence. The sequence effect was tested against subjects who were nested within sequence; this test validated the model in ruling out a significant carryover effect.

A formal residual analysis for the distribution of residuals was performed; homogeneity, normality, and outlying observations were examined. The treatment effect was estimated by the ratio of the PC20 for montelukast) to the PC20 for placebo with corresponding 95% confidence interval (CI). Least squares means were adjusted by the model and were used for estimation.

For the primary parameter, PC20, and stage, we built a nonparametric model using the method of Hauschke et al,25 which is distribution-independent, and includes as explanatory factors all the factors included into the parametric models and computes a nonparametric 95% CI for the median difference or ratio (ie, montelukast/placebo or montelukast/placebo).

The analysis was done in accordance with the Center for Drug Evaluation and Research guidance for comparisons of drug effect and bioequivalence.25 Statistical analysis was performed with the aid of a statistical software package (SAS, version 9.1.3 [procedures UNIVARIATE, GLM, and MIXED]; SAS Institute; Cary, NC).2627

Results

Forty-four preschool children were invited to our clinic. Of the 30 children who performed baseline MCTs, 6 children did not perform an MCT with spirometry, 8 children had a negative baseline MCT result, and 4 children did not complete the full study period. The remaining 26 children (8 girls; age range, 3.3 to 6.0 years; mean [± SD] age, 4.7 ± 0.76 years) completed three full MCTs with spirometry in the 10-week period of the study. After opening the codes of treatments, we found that 12 children started with 4 weeks of montelukast therapy followed by a 2-week washout period and 4 weeks of placebo therapy (subgroup I). The other 14 children started with 4 weeks of placebo therapy followed by a 2-week washout period and 4 weeks of montelukast therapy (subgroup II). There were no clinical or statistically meaningful differences between treatment subgroups for baseline characteristics (Table 1 ). Treatment (with montelukast or placebo), period (first or second period), sequence (placebo/montelukast or montelukast/placebo), and subjects (1 through 26) nested within the sequence. Sequence effect vs subjects nested within the sequence was not significant, thus the test validated the model. Therefore, the analysis was performed on the 26 patients enrolled in the study. Fifteen of 26 children had atopic dermatitis, and 17 children had a parental history of asthma or allergy. Fifty-eight percent of the patients had previously used antiinflammatory medications (inhaled corticosteroids, 12 patients; montelukast, 3 patients), but none had used these medications within the last month. All children had previously received ß2-agonists.


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  		Table 1. Patient Demographics and Baseline Characteristics and Spirometric Values*

 
Compliance with the treatment was assessed by counting the number of empty capsules returned. The average percentage of the days on which patients were fully compliant was 97%. Diary cards revealed that the children had very mild symptoms (mean daytime symptoms score, 0.98 ± 0.65 [maximum score, 5]; mean nighttime symptoms score, 0.38 ± 0.42 [maximum score, 2]). Montelukast therapy significantly reduced the daytime symptoms by 35% from a mean score of 0.98 ± 0.65 to 0.63 ± 0.46 (p = 0.033) compared to placebo. Nighttime symptoms were similarly reduced by 63% from a score of 0.38 ± 0.42 to 0.14 ± 0.27 (p = 0.022).

Nighttime mean ß2-agonist use was 4.48 ± 5.88 puffs per 28 days during the placebo period compared to 2.0 ± 3.64 puffs per 28 days during the montelukast period (p = 0.008); there was no statistically significant difference in the daytime use of ß2-agonists. None of the children experienced worsening asthma requiring oral corticosteroid rescue therapy or an unscheduled visit for asthma to a doctor’s office, an emergency department, or a hospital.

Four weeks of montelukast treatment resulted in a significant reduction of BHR compared with placebo treatment (PC20: 4.79 ± 4.69 vs 2.07 ± 2.37 mg/mL, respectively; p = 0.001). The effect of montelukast therapy on the PC20, as reflected by a ratio of PC20 for montelukast to PC20 for placebo of 2.56 (95% CI, 1.71 to 3.99) indicated a significant improvement in the MCT result (Table 2 ). Similarly, the median difference (stage with montelukast therapy – stage with placebo therapy) of one triple dose (95% CI, 0.5 to 1.5) indicated a greater improvement with montelukast therapy than with placebo. Following 4 weeks of montelukast therapy, there was a significant beneficial effect on airway reactivity in 19 of 26 patients, which was expressed as an increase of at least 1 triple dose required for the determination of PC20 (Fig 2 ).


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  		Table 2. The Effect of Montelukast on MCT*

 

Figure 2
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  		Figure 2. The in MCT step required to achieve PC20. Left: subgroup I. Right: subgroup II. Top: response to montelukast. Bottom: response of the same patient to placebo. Each step is a triple concentration of the previous dose. Each vertical bar = one patient.

 
Discussion

This study is the first to investigate the effect of montelukast therapy on bronchial reactivity as determined by PC20 in patients 3 to 6 years old with mild intermittent and persistent asthma. The study showed that 4 weeks of once-daily treatment with montelukast significantly reduced BHR compared with placebo treatment. We chose a relatively small number of children with very mild symptoms; therefore, the study was not designed to assess clinical improvement. Nevertheless, statistical improvement, albeit of minor clinical importance, was evident in asthma symptoms score and nighttime ß2-agonist usage as evaluated by the caregiver. We chose BHR as the primary outcome as it provided a tool for asthma diagnosis, the assessment of asthma severity, and the response to treatment.13 The importance of assessing BHR has been reinforced by a study conducted by Sont et al,28 in which it was found that altering therapy according to BHR resulted in better asthma control and a reduction in airway inflammation as seen on bronchial biopsy specimens. LTRAs were shown to have bronchoprotective properties in allergen, exercise, and other challenges.5293031 Wheezing in early life is a heterogeneous condition in which recurrent episodes of increased airway resistance comprise the final common pathway for the expression of different underlying mechanisms, and ultimately for different responses to treatment. Only one study8 has evaluated the effect of montelukast therapy on BHR in preschool children and showed a significant decrease in airway resistance. In that study, 13 children were challenged by hyperventilation with dry cold air and were evaluated by measured specific resistance using a plethysmograph. An MCT, as measured by PC20, is the most commonly accessible and well-established test for measuring BHR in adults and school-aged children.910111213 Recently, we have shown19 that children as young as 3 years old complied and cooperated in the determination of PC20 by spirometry. While forced expiratory volume in 0.75 s may have been be a more sensitive spirometry parameter in preschool children,21 the criterion for a positive provocation test result for this parameter has not yet been determined. We therefore adopted FEV1 as an outcome parameter for older age groups of patients.

In the present study, we compared the effect of treatment with LTRAs on BHR in preschool children with treatment with placebo. The study had a crossover design with a washout period of 2 weeks. Such a washout period is appropriate because the effect of antiinflammatory medications on asthma patients is short-lived. This is evidenced by the return of airway reactivity to baseline and the increase of exhaled nitric oxide levels to baseline after the discontinuation of montelukast therapy for 1 and 2 weeks, respectively.3233

Similarly, airway reactivity returned to baseline after the discontinuation of therapy with inhaled corticosteroids for 2 weeks.34 For ethical reasons, we chose a group of patients with very mild asthma so that a placebo treatment period and bronchial provocation tests would not pose a risk to them. The mean PC20 value of 3.18 ± 3.47 mg/mL found in our group reflects a very mild degree of BHR. All of the children had normal spirometry values; therefore, the improvement of spirometric indexes could not be used as an outcome measure. Each patient underwent three MCT studies that required the presence of a parent and a loss of working time. In addition, the MCT required the full cooperation of the children with repetitive spirometry measurements. As shown in Figure 2, 19 of 26 patients had a significantly beneficial effect on bronchial reactivity, as shown by an increase of at least one triple dose required for the determination of the PC20. This improvement was not achieved in one third of the patients. The lack of improvement in one third of the patients is probably not due to compliance, although compliance assessment by empty capsule counting is notoriously inaccurate. The lack of improvement could be due to the heterogeneity of the presentation of preschool asthma. The variability of the clinical response to LTRAs may also depend on the individual’s genetic background in its being related to polymorphisms in the leukotriene pathway candidate genes.35

Cysteinyl leukotrienes play an important role in the cascade of asthmatic airway inflammation, and lead to increased mucus secretion, epithelial cell damage, smooth muscle proliferation, constriction, edema, and the influx of inflammatory cells.36 LTRAs blocks the effects of cysteinyl leukotrienes.37 Montelukast has been shown to be a potential antiinflammatory drug in school children with asthma. Therapy with LTRAs may be advantageous over that with inhaled steroids, particularly in young children, due to their oral and easy administration.36

However, studies in this age group have been hampered by a lack of objective measurements for both disease monitoring and pharmacotherapy studies. Montelukast therapy significantly decreased the rate of asthma exacerbations and increased the time to exacerbation in patients 2 to 5 years old who had mild asthma.6 It also had a positive effect on lung function and airway inflammation as measured by nitric oxide levels and airway resistance in preschool children.38 Only one study8 has evaluated the effect of montelukast (Singulair; Merck; Whitehouse Station, NJ) on bronchial reactivity in preschool children and has demonstrated a clinically significant bronchoprotection against the effect of hyperventilation due to breathing cold dry air.

In the present study, we used PC20 as a tool for assessing the response to treatment and found a benefit of one triple dose in two thirds of the patients. Although the patients had mild asthma, a significantly improved symptom score and decreased ß2-agonist use were observed in addition to an improvement in BHR. Recently, a favorable response to montelukast compared to fluticasone was found to be associated with younger age and shorter disease duration.39 The study protocol was cumbersome for both parents and children. BHR was not determined after a washout period just prior to the second phase of the study as it was considered to pose an additional unacceptable inconvenience and was of questionable ethical justification. Airway reactivity has seasonal variability; however, as the conditions of most patients improved after receiving montelukast while those of most patients deteriorated after receiving placebo, seasonal improvement seems unlikely.

In summary, this study demonstrated that, when compared with treatment with placebo, 4 weeks of treatment with montelukast was associated with a significant increase in the PC20. Larger scale studies are required to correlate improvement in BHR and clinical parameters, and to compare the effect of therapy with inhaled corticosteroids with montelukast therapy on PC20 in preschool children.

Footnotes

Abbreviations: BHR = bronchial hyperreactivity; CI = confidence interval; FEFV = forced expiratory flow volume; LTRA = leukotriene receptor antagonist; MCT = methacholine challenge test; PC20 = provocative concentration of a substance causing a 20% fall in FEV1;

This study was funded by the Israel Lung Association, Tel-Aviv, Israel.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication June 3, 2006. Accepted for publication July 25, 2006.

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