INTRODUCTION

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Asthma is the most common chronic disease in young children (1), and presents a considerable burden on the child, the child's family, and society because of the high prevalence and lack of good treatment control of this disease. The poor asthma control in young children is partly due to a lack of validated objective methods for studying lung function and bronchial reactivity in such children, which has hampered studies of pharmacotherapy for asthma.

Children less than 6 yr old can rarely perform lung function test maneuvers that require active cooperation, such as forced expiration. Although single measurements may occasionally be obtained, reproducibility is poor (2, 3). Recently, we successfully adapted whole-body plethysmography for measurements of specific airway resistance (sRaw) in children from aged 2 yr and older (4). The method requires no active cooperation, is well accepted by children, and is more sensitive than spirometry for measuring the response to methacholine(4).

Bronchial hyperresponsiveness (BHR) is an essential feature of the pathophysiology and clinical manifestation of childhood asthma (7), and is related to disease control. Bronchoconstriction induced by hyperventilation of cold, dry air is commonly found in asthmatic adults and children, and can be used to assess BHR (8, 9). Cold, dry air challenge (CACh) has two main attractive features: the reaction probably reflects the pathophysiology of asthma better than a pharmacologic bronchoprovocation with histamine or methacholine (9), and the challenge is simple to perform and standardize even in children as young as 2 yr old (10). We recently reported a sensitivity of 68% and a specificity of 93% for CACh when measuring sRaw in 2- to 5-yr-old asthmatic children (10).

CACh is hypothesized to stimulate the release of inflammatory mediators (11, 12). Suggestive evidence indicates that the cysteinyl leukotrienes (cys-LT) may be involved in the constrictor response to CACh, since inhibition of a precursor enzyme (5-lipoxygenase [5-LO]) was associated with an increased tolerance to cold, dry air in adult asthmatic individuals (13, 14).

In the present randomized trial, we evaluated the effect of the specific leukotriene receptor antagonist (LTRA) montelukast on the bronconstrictor response to CACh in 3- to 5-yr-old asthmatic children.

	METHODS

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Patients

Asthmatic children 2 to 5 yr old were eligible for the study if considered stable and well controlled. The diagnosis of asthma was empirically defined from recurrent asthmatic symptoms, clinical improvement with inhaled steroids or inhaled ₂-agonists, and relapse of symptoms after stopping of such treatment. Inhaled glucocorticosteroid treatment was allowed if maintained at a regular dose for at least 4 wk before and throughout the study. Inhaled ₂-agonist was used only as rescue treatment. No other antiasthma medication was allowed. All asthma medications were stopped 12 h before CACh. The children were without clinical symptoms on the day of CACh. Children were invited into the study if the response to CACh was considered positive.

Study Design

The study was designed as a randomized, placebo-controlled, crossover, two-period study with a washout period of at least 1 wk between the study periods. The randomization was computer generated. Montelukast in a dose of 5 mg or matching chewable placebo tablets were given between 8:00 and 9:00 A.M. daily for 2 d. CACh was performed on the third day between 8:00 and 9:00 A.M. Compliance was assured by interview. The study was repeated in six children to evaluate consistency of a treatment response.

The study was approved by the local ethics committee (KF-12073/ 99) and the National Health Authorities of Denmark (2612-1009). Written informed consent was obtained from the subjects' parents.

Pulmonary Function Testing

Pulmonary function testing was performed with a Master Screen unit, version 4.22 (Erick Jaeger GmbH, Würzburg, Germany). Flow and volume were measured with a heated pressure screen-type pneumotachograph with a resistance of 0.036 kPa · s · L¹. The equipment was calibrated daily. Methods and equipment have previously been described in detail (4).

Measurements were made during tidal breathing through a face mask (Astratech No 2; ASTRA, Copenhagen, Denmark) fitted with a flexible, noncompressible mouthpiece that ensured support of the cheeks and stable access to the airways via the mouth. The child was coached to reach a respiratory rate of 30 to 45 breaths/min.

sRaw was calculated as the relationship between simultaneous variations in respiratory flow and variations of pressure in a constant-volume, whole-body plethysmograph, on the basis of maximum pressure changes during inspiration and expiration (4). The relationship between flow and pressure was displayed on-line. The measurement was rejected if any alteration in the shape of the resistance loops was seen, since this could reflect face mask leakage, coughing, swallowing, or vocalization. Body temperature, barometric pressure at water vapor saturation (BTPS) compensation was achieved electronically (6). The median value of five sequential specific resistance loops, of similar appearance in terms of slope and shape, was retained as the outcome value.

Cold Air Challenge Test

Cold, dry air was generated by a respiratory heat exchange system (RHES; Erick Jaeger). The system was set to deliver dry air at 15° C, mixed with 5% CO₂. The temperature of the inspired air was measured 10 cm from the mouth. The test was conducted as a single-step, 4-min, isocapnic hyperventilation test. The desired level of hyperventilation was 1 L/min/kg body weight. Ventilation was measured at the exhalation valve with a pneumotachograph. The analogue signal from the pneumotachograph was displayed by computer animation. The child was coached to hyperventilate above the predetermined level, with guidance from the computer animation (10).

The mean of duplicate measurements of sRaw before CACh was taken as the baseline sRaw. The mean of duplicate measurements made 4 min after the end of a challenge defined the postchallenge sRaw. The same observer made measurements at baseline and after CACh.

Data Analysis

All children completing CACh after both treatment periods were included in the analyses of treatment effects, which were based on the intention-to-treat principle. The double-blind code was broken after source validation and data files had been locked in the computer.

The response to CACh was quantified as the percent change in sRaw from baseline. A positive response to CACh was defined as an increase in sRaw of 17%, which in healthy young children equals 2 intrasubject SDs (15).

Analyses of treatment effects were done with two-tailed paired t tests, with p < 0.05 taken as the level of significance. Central tendency was expressed by the arithmetic mean and 95% confidence interval (CI) or range.

	RESULTS

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Patients

Sixteen asthmatic children (11 boys and five girls) with a mean age of 4.5 yr (range: 3.1 to 5.7 yr) were hyperresponsive to CACh at the screening visit and were included in the study. Three children were subsequently withdrawn: one child because of refusal to take the study tablets because of their taste; one child whose family withdrew consent without reason; one child who experienced worsening of asthma 3 d before the last visit, and who was unable to reach the target flow at the final CACh. Ten of the remaining 13 patients had previously exhibited BHR to CACh; the other three children had not previously been tested.

The mean duration of asthma history was 39 mo (range: 4 to 62 mo). Seven of the 13 children had a first-degree relative with atopic disease, five had concurrent atopic dermatitis, and three had hay fever. Three children were exposed to passive smoking in their homes.

All children were tested by skin prick test or specific serum IgE assay with the 10 inhalant allergens most common in Scandinavia. Five of the 13 children had a positive test relevant to their asthma history.

Eight of the 13 children who completed the study received regular treatment with inhaled budesonide in a mean daily dose of 350 µg from a pressurized metered dose inhaler via a metal spacer (Nebuchamber; AstraZeneca, Lund, Sweden) (Table 1). All children used terbutaline as rescue treatment. Five patients used a ₂-agonist as needed as their sole prestudy treatment. The treatment regimen for all patients had remained unchanged for at least 2 mo prior to the study.

Baseline lung function at the placebo day was 129% (95% CI: 116 to 143%) of predicted lung function (15) (i.e., the children presented a significantly increased sRaw at baseline (Table 1). This baseline lung function did not change from the placebo through the montelukast treatment periods of the study.

sRaw increased by a mean of 46% (95% CI: 30 to 63%) after CACh with placebo and by a mean of 17% (95% CI: 3 to 31%) with montelukast treatment (Table 1 and Figure 1). This difference between montelukast and placebo was highly significant (p < 0.01).

View larger version (48K): [in this window] [in a new window]   Figure 1.   Percent change in sRaw in young asthmatic children after cold, dry air hyperventilation. The bronchoprotective effect of the LTRA montelukast was significantly different from that of placebo (p < 0.01). Solid line = concomittant steroid; dashed line = no concomittant steroid.

During the second test round, with six of the original children, the sRaw increased by 52% (95% CI: 28 to 75%), after CACh with placebo and by 20% (95% CI: 8 to 32%) with montelukast (Table 1), which constituted a significant difference (p = 0.02).

The individual responses did not reveal obvious nonresponders. Montelukast did not protect Patient 12 during the first test round, whereas this patient seemed protected during the second test series (Table 1). The patient was suspected of poor compliance during the study.

The bronchoprotection provided by montelukast was independent of concurrent steroid treatment (Table 1).

	DISCUSSION

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This is the first report of the effect of leukotriene modifiers in young asthmatic children. The specific LTRA montelukast significantly reduced the bronchoconstrictive response to CACh in asthmatic children 3 to 5 yr old. Airway resistance increased by 17% after treatment with the montelukast, as compared with 46% after placebo. This seems a clinically relevant degree of protection. The bronchoprotection was independent of concurrent steroid treatment.

The effect observed in this study of an LTRA on CACh suggests an effect on clinical asthma symptoms, which might make LTRAs an important addition to the pharmacotherapeutic armamentarium for asthma in young children. There are few documented efficacious treatments for asthma in this age group. Inhaled steroids are well documented to be effective for moderate to severe asthmatic symptoms in young children (16- 20). However, inhaled steroids may not be useful for mild asthmatic symptoms in young children, since a large group of young children may be expected not to comply with regular inhalation therapy. Second, young children with severe asthmatic symptoms that are not well controlled with moderate doses of inhaled steroids would benefit from a steroid-sparing agent. Third, intermittent treatment of young children with short-acting ₂-agonists may often be insufficient, since the decision to treat and drug delivery depend on a trained caretaker, who must often hand over the observation and care of the child to others for large parts of the day. Therefore, an oral nonsteroidal treatment of long duration would be of significant clinical benefit for young asthmatic children.

LTRAs specifically target cys-LT, which represents an essential component of asthma pathophysiology, and LTRAs have recently been shown to improve asthma control in children (21) and adults (22), including improvements in lung function and symptom control, and a reduced use of rescue medication. LTRAs also ameliorate the hyperreactive response to exercise in children (23) and adults (24), although apparently not the response to methacholine (24). In addition, LTRAs have some effect on the airway inflammation in asthma, as reflected by reduced peripheral (21) and mucosal eosinophilia (25) and reduced exhaled NO (26). This effect on asthmatic airway inflammation appears to make LTRAs of added value as compared with bronchodilator treatments. The antiinflammatory effect seems less potent and less comprehensive than that of steroids.

The effect of the LTRA examined in our study on CACh was independent of concurrent steroid treatment, which is in keeping with the findings of uninhibited cys-LT release in patients receiving oral (27) and inhaled steroids (28). Also, the clinical benefit seems additive to that of current steroid treatment (29), and the effect on the inflammatory marker NO was independent of current steroid treatment (26). Such evidence indicates that cys-LT is a part of the asthmatic inflammation that is unabated by steroids, which corroborates the additive effect of an LTRA to the effect of inhaled steroid found in the present study.

The bronchoprotection provided by an LTRA appeared homogeneous throughout the group of children in our study. One child had a stronger bronchoconstrictive response after LTRA treatment than after placebo during the first placebo-controlled evaluation, but was well protected by the LTRA in the repeat placebo-controlled test. This child was suspected of noncompliance during the study, yet was included in the intention-to-treat statistics. All other trends were in favor of montelukast. It has been suggested that approximately one-third of asthmatic patients are nonresponders to LTRAs, since this fraction often seems to derive little or no benefit from this treatment (30). Whether such apparent nonresponders reflect a heterogeneity in asthma pathophysiology or a simple statistical phenomenon can only be settled by designing a study showing that the group of suspected nonresponders is consistently the same with repeated testing. With this objective we designed the present study to examine the consistency of responders and nonresponders. However, we found no convincing evidence of nonresponders. The homogeneous response to an LTRA in young asthmatic children suggests that cys-LTs are essential to the asthmatic response to CACh in all asthmatic young children. Whether this applies to the effect of LTRAs in other aspects of asthma treatment should be investigated.

The dose of montelukast given in our study was 5 mg, which is the approved dose for children aged 6 to 14 yr. The effect on CACh was tested 12 h after dosing, although a prolonged effect of 20 h was seen in other pediatric studies (21, 23). The dose and timing in the present study were chosen with a view to detect all possible effects, but the dose should be titrated before clinical recommendations can be made in the 3- to 5-yr age group.

The children in this study were carefully selected on the basis of a history of recurrent asthmatic episodes, need for current antiasthmatic therapy, and relapse of asthmatic symptoms during interruption of treatment. Their baseline lung function showed a significantly increased sRaw as compared with that of healthy controls (15), which is in agreement with our previous findings in studies of young asthmatic children (10, 31). The response to CACh did not relate to the subjects' baseline lung function.

Hyperventilation of cold, dry air has been shown to be a potent stimulus to bronchoconstriction in asthma, and has been applied in several studies both in adults and school children (8, 9).

Whole-body plethysmography (sRaw) is a convenient, sensitive, and reproducible method for detecting changes in lung function in young children (4). It is possible to both identify BHR in awake young children and to distinguish asthmatic from healthy young children by using the CACh test as a provocative stimulus and measurements of sRaw to quantify the bronchial response (10).

In conclusion, the response to CACh as gauged by measurements of sRaw has proven to be a useful model for studying BHR in young asthmatic children. In the present study, this model documented clinically relevant protection from BHR with the LTRA montelukast in young asthmatic children. This suggests that LTRAs may be useful for the clinical management of asthma in young children.