INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Asthma is the most common chronic disease of young children (1), and presents a considerable burden to the child, the family, and society because of its high prevalence and lack of good control with treatment. Diagnosis of asthma is ambiguous, owing to the lack of objective measurements. The poor control of asthma in young children is partly due to a lack of validated objective methods for studying lung function and bronchial reactivity in young children, which hampers both disease monitoring and studies of pharmacotherapy.

The efficacy of inhaled corticosteroids (ICS) in young preschool children was first documented in our earlier study monitoring symptom score (SSc) and use of rescue treatment (2). Subsequent supportive trials have also been limited to such health outcomes (3), since objective measurements have not been available.

Young children under 6 yr of age can rarely perform the maneuvers needed for lung function measurements, such as forced expiration, which require active cooperation. Although single readings may occasionally be obtained, poor repeatability prevents the use of conventional methods for measuring lung function (9, 10). Recently, we successfully adapted the measurement of specific airway resistance (sRaw) by whole-body plethysmography; resistance measured with the interrupter technique (Rint); and resistance and reactance at 5 Hz (Rrs5, Xrs5) as measured with the impulse oscillation (IOS) technique for use in awake children aged 2 yr and older (11- 13). These methods require no active cooperation by the young child, are well accepted by the child, and are more sensitive than spirometry for detecting the response to methacholine (11).

Bronchial hyperresponsiveness (BHR) is an essential feature of the pathophysiology and clinical manifestation of childhood asthma (14), 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 (15). The challenge with cold, dry air has two main attractive features: the reaction probably reflects the pathophysiology of asthma better than does pharmacologic bronchoprovocation with histamine or methacholine (22), and the method is simple to perform and standardize even in children as young as 2 yr of age (23). We recently reported a sensitivity of 68% and a specificity of 93% using sRaw and cold air challenge (CACh) in asthmatic children from 2- to 5-yr old (23). Furthermore, we recently used this model to document clinically relevant bronchoprotection by the leukotriene receptor antagonist montelukast (24).

The aim of the present study was to evaluate the effect of budesonide (BUD) on symptoms, lung function (as measured through SRaw, Rint, Rrs5, and Xrs5), and BHR to CACh and methacholine challenge (MCh), with a view to evaluating whether these objective measures could serve as additional tools in the study of symptomatic asthmatic children aged 2 to 5 yr.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Patients

Asthmatic children aged 2 to 5 yr from our outpatient clinic were eligible for the study. The diagnosis of asthma was made empirically on the basis of recurrent asthma symptoms, clinical improvement with regular ICS therapy, and relapse during interruption of treatment. Only patients fully cooperating in all lung function test procedures and with CACh were considered for inclusion in the run-in period of the study. Asthma symptoms, use of rescue medication, and disturbance of parents' sleep were registered in a diary during the run-in period. Patients with a daily SSc of at least 4 (not including scoring of parents' sleep disturbance) on at least seven of 14 consecutive days were randomized.

Study Design

The study was a single-center, double-blind, parallel-group, randomized, placebo-controlled trial. Patients who fulfilled the inclusion criteria at Visit 1 entered an observational run-in period in which regular treatment was stopped and terbutaline as required was the only medication allowed. The run-in period lasted from 2 wk to a maximum of 8 wk, in which asthma symptoms, use of rescue medication, and disturbance of parents' sleep were registered in a diary. Scoring during periods with respiratory infections was suspended. Patients were excluded if they received inhaled steroids or were hospitalized for asthma during the run-in period. At randomization, both a CACh challenge test and an MCh test were performed within 72 h. Treatment medication and a new diary card, identical to the one used during the run-in period, were delivered after the last of the two challenge tests. Subjects were scheduled for a visit after 4 wk of treatment. At this visit, diary cards were checked, old medication was returned and new medication was delivered, and baseline lung function was measured. After 8 wk of treatment, CACh and MCh were repeated.

The local ethics committee (KF-02-179/96) and the national health authorities of Denmark approved the study. Written informed consent was obtained from parents or guardians of the subjects.

Randomization and Treatment

Subjects were randomly assigned to receive either two puffs of BUD 200 µg twice daily (total daily dose of 800 µg budesonide) or two puffs twice daily of placebo from a pressurized metered-dose inhaler (pMDI) via a metal spacer (Nebuchamber, AstraZeneca, Lund, Sweden). The randomization was computer generated in balanced blocks of four treatment regimens.

Inhaled ₂-agonist, delivered via the pMDI and spacer, was used as rescue medication throughout the study. In the case of moderate asthma attacks, one puff of formoterol 12 µg twice daily, delivered from a pMDI and spacer, and/or a 3-d oral course of prednisolone at 1 mg/kg body weight twice daily, was allowed at the discretion of the investigator. No other antiasthma medication was allowed. All short- and long-acting ₂-agonists were stopped at 6 and 24 h, respectively, before baseline lung function measurement and bronchial provocation.

Assessments

Diary cards. Diary cards were constructed according to the method described in our previous study (7). Symptoms were scored on a scale of 0 to 3 (with a score of 0 indicating no symptoms and 1, 2, and 3 indicating mild, moderate, and severe symptoms, respectively) by one of the subject's parents in three symptom domains (wheezing, cough, and shortness of breath), in addition to scoring for use of relief medication for daytime symptoms and for nighttime symptoms individually. Furthermore, exercise-induced asthma symptoms during the daytime and parents' sleep disturbance caused by subjects' asthma during the night were scored on a scale of 0 to 3.

Pulmonary function testing. Pulmonary function testing was done with a Master Screen unit, version 4.22 (Erich 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. The methods and equipment used for pulmonary function testing have previously been described in detail (11, 12).

The children used a face mask (Astratech No. 2; ASTRA, Denmark) fitted with a flexible, noncompressible mouthpiece that supported the cheeks and provided stable access to the airways via the mouth (11).

Measurements were made during tidal breathing. Readings from duplicate measurements made with each method were used as baseline values before bronchial provocation tests. The sequence of measurements was Rint, Xrs5, Rrs5, and sRaw. The same observer made measurements at baseline and after bronchial provocation tests.

The subjects did not have clinical respiratory symptoms on the days of CACh and MCh.

sRaw. sRaw was measured in a constant-volume, whole-body plethysmograph as the relationship between simultaneous variations in respiratory flow and maximum changes in plethysmographic pressure during inspiration and expiration (11). sRaw was calculated from the S-shaped resistance loops presented graphically by the computer connected with the plethysmograph. Compensation for body temperature, barometric pressure, and water vapor-saturated (BTPS) conditions was done electronically (13). The respiratory rate was 30 to 45 breaths/min. When needed, an adult accompanied the subject during testing (11, 13). The median value of five sequential measurements of SRaw was used as the result.

Rint. Rint is based on the assumption of a simple relationship between mouth pressure at the end of interruption of airflow and the airflow after reopening of a shutter valve mounted on the pneumotachograph. At every second inspiratory phase, inspiration of 50 ml of air activated the shutter for 80 ms. Mouth pressure was measured during the last 5 ms of the interruption. Flow was measured over a 70-ms period after reopening of the shutter. The mean value of five consecutive measurements was used as the result.

Xrs5 and Rrs5. Xrs5 and Rrs5 were measured with the IOS technique. Rectangular impulses were generated mechanically by a loudspeaker and were applied to the respiratory system through the mouthpiece of the pneumotachograph. The resulting pressure and volume signals were analyzed for amplitude and phase difference to determine the Xrs and Rrs of the respiratory system. Thirty seconds of undisturbed measurements were used as the results (11, 12).

CACh. Cold, dry air was generated by a respiratory heat exchange system (RHES; Erich Jaeger). Methods and equipment used for the CACh have previously been described in detail (23). The CACh was done as a single-step, 4-min, isocapnic hyperventilation test. We used cold, dry air at 15° C, mixed with 5% CO₂. The subject breathed through a face mask fitted with a mouthpiece, which effectively secured mouth breathing and prevented inhalation of room air. The rate of ventilation was 1 L/min/kg body weight. The subject was motivated to hyperventilate by competing with a computer-animated balloon, which reflected the ventilation rate (23).

The response to hyperventilation of cold, dry air was recorded at 4 min after the end of the challenge.

Methacholine challenge test. The MCh test was done as a multistep challenge with a dosimetric method. Isotonic methacholine chloride solution was nebulized with a Wright nebulizer (Clement Clarke, Essex, UK) that delivered aerosol into an aerosol box that prevented entrainment of air (25). Methacholine was inhaled by tidal breathing from the aerosol box through a face mask and mouthpiece. At each step of the challenge the subject inhaled 200 ml of the aerosol per kilogram of body weight. Doubling concentrations of methacholine, from 0.0625 to a maximum of 64 mg/ml, were used. Increasing doses were inhaled until sRaw increased by 50%, the maximum methacholine dose of 64 mg/ml was reached, clinical airway obstruction was apparent, the subject complained of discomfort, or transcutaneous oxygen pressure (Tc_O2), which was monitored continuously during provocation, exhibited a decrease of  3 kPa. The heated (44° C) transcutaneous pressure electrode was placed on the middle part of the flexor side of the lower arm. Duplicate measurements of Rint were made 2 min after provocation at each step until Rint had increased by 10% or more from baseline. At that point, sRaw, Rrs5, or Xrs5 were measured in that sequence.

The response to a challenge was measured at 3 to 5 min after the end of the challenge.

Data Analysis

Study variables. Primary outcome measures were SSc and need for rescue medication. Secondary outcome measures were changes in lung function and change in response to CACh and MCh during the treatment period.

All variables from the diary cards were summarized for each patient as a run-in mean and a treatment-period mean, after excluding the first 14 d of the treatment period. Total nighttime and daytime asthma symptoms were summarized by first adding the scores for each subsymptom and then averaging the scores over the treatment periods. Total 24-h asthma symptoms were summarized by adding the nighttime and daytime mean scores. Identical periods and data were used for calculation of symptom-free days.

An asthma exacerbation was defined as at least two consecutive 24-h periods with symptoms of wheezing and the need for at least 3 puffs of rescue treatment. The exacerbation was considered ongoing as long as the two conditions were fulfilled, although for computational use, exacerbations experienced by a particular subject were separated by periods of 5 d from the last previous day of exacerbation.

The means of duplicate measurements of sRaw, Rint, Xrs5, and Rrs5 defined the baseline at each visit. Effect on lung function after treatment was calculated as the average lung function after 4 wk and 8 wk as a percent of lung function at baseline.

Predicted values based on height (in centimeters) for the lung function variables were based on a previous study of healthy controls (26). Response to CACh was quantified as the percent change from baseline. Thus, the formula used in calculating the response to CACh was 100 · (post-CACh value  baseline value)/(baseline value). The result of the MCh challenge was expressed as PCx, the provocative concentration producing a change of 50% in SRaw, 30% in Rint and Rrs5, 80% in Xrs5, and 15% in Tc_O2 (25). PCx was found through linear interpolation on a logarithmic scale. If x% change was not found after the last dose step, PCx was estimated by one-step linear extrapolation, using the last two previous values. If x% change was found after the first dose step, PCx was estimated by linear interpolation on the linear scale between 0 and the first MCh concentration used.

Statistical considerations. An analysis of variance model was applied to compare BUD and placebo, using run-in mean SSc and baseline lung function values as covariates. Ninety-five percent confidence intervals (CIs) were constructed for the differences with and without treatment. When analyzing asthma SSc, sleep disturbance, use of rescue medication, response to CA challenge, and change in lung function, we used additive models that gave arithmetic means. When analyzing lung function tests in measured units or PCx from the MCh challenge, we used multiplicative models giving geometric means, which were used to calculate treatment differences as ratios. The different subsymptoms were analyzed with a multivariate analysis of variance model, using each of the variables and baseline values as covariates.

Asthma exacerbation rates were compared for treatment versus placebo with Poisson's distribution, assuming equal exacerbation rates for all patients within a treatment group. The numbers of patients in each treatment group experiencing at least one asthma exacerbation during the treatment period were compared through Fisher's exact test.

From experience with a previous study using the same diary cards (7), we estimated that a difference of 0.6 between the treatment and placebo groups in total asthma SSc and score for use of rescue medication would be detected with 80% power with 22 patients in each treatment group.

All statistical tests were two sided, and values of p < 5% were considered statistically significant.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Patients

A total of 91 patients were recruited for the study, and 39 were randomized to treatment or placebo. Fifty-two patients were withdrawn prior to randomization, 50 because their SSc did not fulfil the criteria and two because of withdrawal of consent prompted by increasing symptoms after stopping of regular treatment. One patient randomized into the study had asthma exacerbations during most of the treatment period due to lack of compliance and was therefore withdrawn before analysis of the study data. Thirty-eight asthmatic children (22 boys and 16 girls; mean age 53 mo [range: 35 to 71 mo]), were analyzed as an intention-to-treat population. Baseline characteristics (Table 1), including height, atopic disposition, relevant allergy, exposure to passive smoking, SSc, use of rescue medication, and lung function were comparable in the treatment and placebo groups. The mean (range) duration of a history of recurrent asthma symptoms was 18 mo (range: 4 to 56 mo). Twenty-one (55%) subjects had a first-degree relative with atopic disease, and 18 (47%) were exposed to passive smoking at home. Twenty-two (58%) subjects had other manifestations of atopy (atopic dermatitis and/or rhinitis). All 39 randomized subjects were given skin prick tests or had assays of specific serum-IgE antibody to the 10 inhalant allergens most common in Scandinavia, and 15 of the 39 (39%) had at least one positive test relevant to a history of asthma.

Until the start of the run-in period, 33 (87%) of the subjects were undergoing treatment with ICS, consisting of BUD at 100 to 1,200 µg/d (mean: 440 µg/d) delivered via a metered-dose inhaler with a metal spacer (Nebuchamber), or fluticasone at 50 to 250 µg/d (mean: 133 µg/d) delivered via a metered dose inhaler with a plastic spacer (Babyhaler, GlaxoWellcome, Brøndby, Denmark). Short acting ₂-agonists delivered via a metered dose inhaler and spacer device were given as rescue medication. Four subjects were not treated with ICS: two were treated only with a short-acting ₂-agonist as required, one with a long-acting ₂-agonist as required, and one with sodium cromoglycate. The mean (range) duration of the run-in period, between the cessation of ICS therapy and qualification for randomization into the study, was 27 d (range: 14 to 56 d).

SSc and Rescue Medication Use

A statistically significant difference between BUD and placebo was found for nighttime asthma symptoms (p = 0.01), and a tendency toward a difference was found for daytime asthma symptoms (p = 0.07) (Figure 1). The combined 24-h SSc was significantly in favor of BUD (p = 0.03).

View larger version (16K): [in this window] [in a new window]   Figure 1.   Effect on subsymptom scores, total symptom score, and daytime and nighttime use of rescue medication of treatment with budesonide in contrast to placebo. Adjusted mean (95% CI) differences (BUD-PLAC) between changes from run in period to completion of budesonide treatment and placebo periods are shown.

All subsymptom scores were reduced during treatment, more so in the BUD than in the placebo group. Nighttime cough was significantly reduced with active treatment (p = 0.04). Borderline significance was found for a reduction in daytime cough (p = 0.09) and disturbance of parents' sleep (p = 0.06) with treatment, but no other subsymptoms were significantly reduced (Figure 1).

BUD significantly reduced daytime use of rescue medication (p = 0.01), but not its nighttime use (p = 0.09) (Figure 1).

The change with BUD and the difference between BUD and placebo in asthma-symptom-free days and nights are shown in Figure 2. There was a significant difference in the change in percentage of symptom-free days (p = 0.03) and total 24-h symptom-free periods (p = 0.01), and a tendency toward a difference in symptom-free nights (p = 0.07).

View larger version (20K): [in this window] [in a new window]   Figure 2.   Increase in percentage of symptom-free nights and days after treatment with budesonide and placebo administration.

The percentage of days with asthma exacerbations was 4.9% in the BUD group versus 19.4% in the placebo group, which was significant (p = 0.01). We found a total of 12 exacerbations in the BUD group and 29 in the placebo group, giving exacerbation rates of 3.7/yr versus 9.3/yr for BUD and placebo, respectively (p = 0.006). Nine of 19 (47%) subjects in the BUD group and 14 of 19 (74%) subjects in the placebo group (p = 0.18) experienced at least one asthma exacerbation.

Lung Function Measurements

Baseline lung function measured as sRaw and Rint at the day of randomization was 116% (95% CI: 106 to 126) and 119% (95% CI: 110 to 128), respectively, of the predicted lung function values in relation to the height of the subjects (26) (i.e., the subjects showed significantly increased airway resistance at baseline) (Table 1). Baseline measurements of Xrs5 and Rrs5 did not differ from the reference values.

Lung function was significantly improved with BUD (Table 2). The difference between BUD and placebo was reflected by Rint (p = 0.01), Rrs5 (p = 0.01), and Xrs5 (p = 0.001) at the endpoint after 8 wk of treatment, and by the average lung function through Visits 3 and 4. As shown in Table 2, Rint, Xrs5, and Rrs5 improved during active treatment and deteriorated during administration of placebo. Xrs5 and Rrs5 reflected this improvement by Visit 3. No treatment effect was reflected by SRaw (p = 0.35) (Table 2).

CACh

Responsiveness to CA challenge measured with each study method at different visits is shown as the mean percentage change from baseline (95% CI) in Figure 3. BUD significantly reduced responsiveness to CA challenge after 8 wk of treatment. This was reflected in measurements of SRaw (p < 0.001), Rint (p = 0.01), Rrs5 (p = 0.01), and Xrs5 (p = 0.07). Figure 3 shows the decrease in responsiveness in all parameters during BUD treatment and the reverse effect during placebo administration. At the final CA challenge, 11 of 19 patients in the BUD group, versus three of 19 subjects in the placebo group, reached normal responsiveness (defined as a change of < 3 SD within subject [w]) (23) measured in terms of sRaw (p = 0.02).

View larger version (45K): [in this window] [in a new window]   Figure 3.   Change (%) in measures of lung function (sRaw, Rint, Xrs5, and Rrs5) in response to CA challenge at randomization (0 W) and after 8 wk of treatment with budesonide or placebo (8 W). Mean (95% CI).

Methacholine Challenge Response

There was no statistically significant difference between BUD and placebo in any of the parameters used in the study, although a trend in favor of BUD treatment was seen in SRaw measurements (p = 0.11). The provocative concentration of MCh eliciting a 50% increase in SRaw could be computed by interpolation for all curves except two. Considerably more of the PCx values for Rint, Xrs5, Rrs5, and Tc_O2 had to be estimated as extrapolated values.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

This is the first report of the efficacy of ICS in asthmatic children aged 2 to 5 yr to be based on objective measurements of lung function and bronchial responsiveness. The study was explorative, evaluating objective measures together with conventional measures of symptoms as primary outcomes of asthma disease activity. The effect of 400 µg BUD twice daily, delivered via a pMDI with a metal spacer device, was documented by improvement in SSc, reduced consumption of rescue medication, reduced asthma exacerbation rates, and increased numbers of days and nights without symptoms, as found in previous studies (2). In addition to this expected treatment effect, the disease control with BUD was reflected in measures of lung function and responsiveness to CACh.

The design of the present study was biased by regression toward the mean, since randomization took place immediately after a period of significant symptom scoring. This was reflected by the pronounced placebo effect, and the study results should therefore be interpreted in the light of these unfavorable odds, strengthening the conclusions of the study. Also, the small sample size of only 38 patients hampered the power to uncover treatment differences in some subsymptoms, SRaw, and MCh challenge.

Previous studies of effect of ICS on asthma in young children have focused solely on subjective parameters such as SSc, exacerbation rate, and use of rescue medication (2), and all have shown an effect of ICS against moderate to severe persistent asthma symptoms. However, none of these studies used any objective parameters in children under 6 yr old. In a study of infants aged 5 to 18 mo with recurrent wheezing (27), lung function as measured with the rapid thoracoabdominal compression technique, and bronchial responsiveness assessed with histamine challenge, were used as objective measures in parallel with subjective measures. ICS was found to significantly improve bronchial responsiveness, but failed to show an effect on baseline lung function or SSc, possibly because of a lack of statistical power.

Ninety-one patients, of whom 90% were receiving regular inhaled steroid treatment, were screened for our study and stopped their steroid treatment during the run-in period. Thirty-nine patients qualified for randomization. One reason for noneligibility may have been that some of the patients did not have asthma. Alternatively, some would still have been protected at 8 wk after treatment interruption, and some had only mild asthma. Therefore, the final study group in the present study consisted of asthmatic children carefully selected on the basis of a history of recurrent asthmatic episodes, need for current antiasthmatic therapy, and relapse of asthma symptoms during interruption of treatment. From the very high percentages of days (95%) and nights (78%) with symptoms during the run-in period, it may be concluded that these patients represented a group of children with moderate to severe asthma. Their baseline lung function showed significantly increased airway resistance as compared with that of healthy controls (26), which is in agreement with our previous findings in a random group of young asthmatic children (28) and in selected groups of young asthmatic children (23, 24).

The dose of BUD given in the study was 400 µg twice daily, which is above the pediatric dose range recommended as efficacious in young children with moderate to severe persistent asthma symptoms, and is probably on the flat part of the dose- response curve. The present study was explorative, and the high dose of BUD was chosen with a view toward not overlooking any possible effect on lung function and BHR. Importantly, despite the high dosage of BUD, it was not possible to eliminate asthma symptoms in all of the children in the study.

Whole-body plethysmography (sRaw), the interrupter technique (Rint), and impulse oscillometry (Rrs5 and Xrs5) are convenient methods for measuring lung function in young children (11). Furthermore, the CACh test as a provocative stimulus and measurement of sRaw to quantify the bronchial response can be used to disclose BHR in awake, young children, and to distinguish asthmatic and healthy children (23). In the present study we demonstrated long-term improvement in baseline lung function, attributed to treatment, as measured by the interrupter technique and impulse oscillation technique. Whole-body plethysmography seemed less sensitive in detecting long-term changes in baseline lung function.

Hyperventilation with 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 (15). We used the single-step method for CA challenge, since multistep protocols are more time consuming and identify the same subjects as hyperresponsive (21, 22). The CA challenge test is simple to perform and standardize even in children as young as 2 yr of age, and imposes no discomfort on the child (23). We recently reported a sensitivity of 68% and a specificity of 93% for measurement of SRaw and CA challenge testing in a group of 2- to 5-yr-old asthmatic children and a group of healthy children (23).

The present study is the first to demonstrate an effect of BUD on the bronchial responsiveness to CA challenge associated with improvement in symptom control in young children. Hyperventilation of cold, dry air is believed to cause airway narrowing through the release of leukotrienes (24, 29) and other mediators, and the level of responsiveness is hypothesized to reflect the degree of airway inflammation (22). We recently reported clinically relevant bronchoprotection against BHR provided by the leukotriene receptor antagonist montelukast as quantified by CA challenge and SRaw measurements in young asthmatic children (24). Previous studies of adults (30, 31) have shown an effect of ICS on bronchoconstriction induced by cold, dry air. In the present study, responsiveness improved in the group receiving active medication and deteriorated in the placebo group, probably reflecting an effect of BUD on the underlying inflammation during treatment and loss of disease control when treatment was stopped. Four children showed little or no change in responsiveness with BUD. All other children in the BUD group improved in responsiveness to CA challenge.

The importance of tailoring the dose of inhaled steroids to the degree of BHR was recently emphasized by Sont and coworkers (32). A treatment strategy in which BHR as reflected by CA challenge is used to titrate the steroid dose may provide an improvement in the long-term management of asthma in young children.

MCh has been extensively studied in children, and with success in children as young as 2 to 5 yr of age, showing satisfactory repeatability (11, 12). However, this method is time consuming and probably does not reflect the pathophysiology of asthma to the same extent as does CACh (22). In the present study we found no effect of BUD on responsiveness to MCh, in contrast to the effect found on CACh. Inadequate duration of treatment may explain the lack of effect on MCh responsiveness. Furthermore, it has been suggested that ICS may provide greater protection against constrictor stimuli that act indirectly, such as CA, than those that act directly, such as MCh. It has also been found that in asthmatic children, the airway reactivities induced by cold, dry air and methacholine challenge have no significant relationship (33).

The present study found a concordant treatment response to BUD in both subjective parameters and objective parameters such as lung function and bronchial responsiveness in young asthmatic children. This suggests that measurement of these objective parameters could be implemented and applied in future studies of the clinical management of asthma in young children. Furthermore, a dose-response study of ICS on symptoms, lung function, and BHR in a larger number of young asthma patients is needed.

In conclusion, inhaled BUD at a total dose of 800 µg daily significantly improved SSc, asthma exacerbation rates, lung function, and BHR as assessed by CA challenge in young asthmatic children aged 2 to 5 yr.