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Maximal Airway Response in Adolescents With Long-term Asthma Remission and Persisting Airway Hypersensitivity^*

Its Profile and the Effect of Inhaled Corticosteroids

^* From the Department of Pediatrics and Clinical Research Institute, Seoul National University Hospital, Seoul; and the Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul, Korea.

Correspondence to: Young Yull Koh, MD, Department of Pediatrics, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea; e-mail: kohyy{at}plaza.snu.ac.kr

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: Many children with asthma go into long-term clinical remission at adolescence, but bronchial hyperresponsiveness (BHR) persists in some of these subjects. BHR in asthma is characterized by an increase in sensitivity and in maximal airway response to bronchoconstrictor stimuli.

Objective: The aims of this study were to compare the profiles of maximal airway response between adolescents with asthma remission and adolescents with symptomatic asthma to a similar degree of airway hypersensitivity, and to determine whether maximal airway response in adolescents with asthma remission is reduced by prolonged treatment with inhaled corticosteroids.

Methods: A high-dose methacholine inhalation test was performed in 46 adolescents with long-term asthma remission (remission group) and 44 adolescents with symptomatic asthma (symptomatic group). Subjects exhibiting a maximal response plateau in the remission group were administered inhaled budesonide (400 µg bid, budesonide/remission group, n = 15) or identical placebo (placebo/remission group, n = 15) for 6 months, and the subjects in the symptomatic group were administered the same regimen of budesonide (budesonide/symptomatic group, n = 17). The plateau level was measured after 3 months and 6 months of treatment.

Results: Thirty-four subjects (73.9%) in the remission group featured a maximal response plateau on the dose-response curve to methacholine, whereas 19 subjects (43.2%) in the symptomatic group had a plateau (p = 0.003). In neither the placebo/remission group nor the budesonide/remission group did the plateau level change significantly over the 6-month period, whereas budesonide markedly decreased the level in the budesonide/symptomatic group.

Conclusion: The difference in frequency of detection of a plateau between the remission group and the symptomatic group, as well as the difference in its response to treatment with budesonide between the two groups, suggests that inflammatory changes impact the maximal airway response in symptomatic asthmatic adolescents but not in adolescents with asthma remission.

Key Words: adolescent • airway hypersensitivity • asthma • bronchial hyperresponsiveness • clinical remission • maximal airway response • maximal response plateau

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Epidemiologic studies^{1 2} have demonstrated that many children with asthma go into long-lasting clinical remission at adolescence. Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma, and its measurement may provide a useful adjunct to the diagnosis of asthma.³ The correlation of the level of bronchial responsiveness with the clinical severity of the disease, however, is not well established. While some workers have suggested that subjects with a greater degree of bronchial responsiveness had more severe asthma,⁴ others have disagreed.⁵ Several studies^{6 7} have shown that BHR persists in a considerable proportion of adolescents with asthma in long-term clinical remission, and therefore does not fully explain symptomatology in asthma.

BHR is usually defined as an increased sensitivity of the airways to inhaled nonsensitizing bronchoconstrictor stimuli.⁸ However, there is accumulating evidence that BHR is a more complex functional abnormality that comprises more than just hypersensitivity.⁹ When exposed to high concentrations of inhaled bronchoconstrictors, normal subjects feature a maximal response plateau on the dose-response curve at mild degrees of airway narrowing, whereas asthmatic patients show an excessive airway narrowing as reflected by either an elevated or absent maximal response plateau. It has been argued that the latter is clinically a more relevant component of BHR than the former per se because it reflects the potential severity of airways obstruction in the individual patients.¹⁰

It has been shown that the maximal response of the airways increases with increasing sensitivity to methacholine in patients with symptomatic asthma, leading to unmeasurable plateau levels when the sensitivity is relatively high.¹¹ However, for airway hypersensitivity to methacholine in symptom-free and medication-free asthmatic adolescents, neither the presence of maximal response plateau nor the severity of excessive airway narrowing has been investigated so far. This is an important issue because several studies^{9 12} have suggested that the mechanisms underlying maximal airway response and airway sensitivity to methacholine are different, and that airway sensitivity is not an adequate measure of maximal airway response.

Corticosteroids are currently the most effective anti-inflammatory drugs available for the treatment of asthma.¹³ When inhaled corticosteroids are administered to symptomatic asthmatic subjects, airway sensitivity and the maximal airway response to inhaled methacholine are reduced.^{14 15} Recently, we have shown that inhaled budesonide did not cause a significant improvement in the airway hypersensitivity, as measured by the provocative concentration of methacholine causing a 20% fall in FEV₁ (PC₂₀), in adolescents with long-term asthma remission.¹⁶ It is not known, however, whether inhaled corticosteroids could reduce the maximal airway response constituting BHR in this clinical setting.

This study was designed with two main aims. The first aim was to compare the profiles of maximal airway response to high doses of inhaled methacholine between adolescents with long-term asthma remission and currently symptomatic asthmatic adolescents with a similar degree of PC₂₀, and the second aim was to determine whether the maximal response plateau in adolescents with asthma remission and persisting airway hypersensitivity is reduced by prolonged treatment with inhaled corticosteroids.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
A group of adolescents with long-term remission of atopic asthma were recruited from the allergy clinic at Seoul National University Children’s Hospital. All subjects had a history of wheezing and dyspnea, and had previous diagnoses of atopic asthma according to the American Thoracic Society criteria.¹⁷ At the time of diagnosis, all had PC₂₀ levels < 18 mg/mL. Atopy was defined by at least one positive skin-prick test result to a panel of 12 common aeroallergens in the presence of positive and negative controls. Most subjects showed a positive skin reaction to house dust mites. Long-term clinical remission was assumed if the subjects reported a complete absence of wheezing and dyspnea at rest and on exertion, and they had not received any medication in order to control asthmatic symptoms for at least 24 months before the study. These subjects underwent spirometry and a methacholine inhalation test. Eligibility criteria for the study also included a FEV₁ of at least 70% of the predicted value¹⁸ and a PC₂₀ level < 18 mg/mL.

A second group of adolescents with current atopic asthma was also recruited. These patients had a history of mild symptoms (episodic wheezing or dyspnea) within the previous year, which had been controlled by an as-needed bronchodilator, and a positive skin test result. Those subjects with a history of major exacerbations requiring systemic corticosteroids or near-fatal asthma were excluded. None of the patients had used inhaled or oral corticosteroids, long-acting ß₂-agonists, leukotriene antagonists, sodium cromoglycate, or nedocromil sodium in the year prior to entry into the study. Candidates were selected, from the results of methacholine inhalation test at the initial diagnostic workup, by matching according to PC₂₀ levels with the subjects with asthma remission.

In the first phase of study, these two subject groups underwent a high-dose methacholine inhalation test, and a maximal airway response as well as the PC₂₀ was measured. None of the subjects had exhibited any symptoms of upper respiratory infection or asthma exacerbation in the month preceding the study. Given that most of the subjects were sensitized predominantly to house dust mites, it was decided to perform the test during the winter season (December to February), when the levels of house dust mites have been found to be the lowest and most constant in our country.¹⁹

In the second phase of study, only the subjects who demonstrated a maximal response plateau were studied. The subjects with asthma remission were randomly allocated into two treatment groups to receive either budesonide (two 200-µg puffs bid; total dosage, 800 µg/d: budesonide/remission group) or placebo (two 500-µg puffs bid of micronized lactose: placebo/remission group), inhaled using a dry-powder inhaler (Turbuhaler; Astra Draco; Södertälje, Sweden). The randomization, allocation, and blinding procedures used the Consolidated Standards of Reporting Trials²⁰ statement as a guide. Medications were supplied in identical devices so that patients and doctors remained unaware of a particular subject’s treatment allocation. Subjects with current asthma received inhaled budesonide at the same dosage as the budesonide/remission group (budesonide/symptomatic group). These three groups followed their assigned course of medications for 6 months, with follow-up visits, including spirometry and a methacholine challenge test, every 3 months. Subjects in the budesonide/symptomatic group were allowed to use inhaled ß₂-agonist on an as-needed basis to control their possible symptoms during the course of the study. Theophylline, which may reduce BHR,²¹ was not allowed. Subjects attended the laboratory at the same time of day on each visit, having refrained from all medications for 8 h and caffeine-containing beverages for 4 h prior. Measurements were taken only during clinically stable periods, and not within 4 weeks of viral respiratory illness. For respiratory tract infection with purulent sputum, antibiotics were administered. The dry-powder inhalation technique was checked before the start of the study and at every visit. Subjects were advised to rinse their mouth and throat after drug inhalation. Patient compliance with the recommended use of budesonide was checked by self-reported doses in diaries and by examining a red mark in the indicator window of the returned dry-powder inhaler.

High-dose methacholine inhalation tests were carried out using a modification of the method described by Chai et al.²² Briefly, methacholine (Sigma Diagnostics; St. Louis, MO) solutions were prepared at different concentrations (0.075, 0.15, 0.3, 0.625, 1.25, 2.5, 5, 10, 25, 50, 100, 150, and 200 mg/mL) in buffered saline solution (pH 7.4). A Rosenthal-French dosimeter (Laboratory for Applied Immunology; Baltimore, MD), triggered by a solenoid valve set to remain open for 0.6 s, was used to generate the aerosol from a DeVilbiss 646 nebulizer (DeVilbiss Health Care; Somerset, PA), with pressurized air at 20 pounds per square inch. Each subject inhaled five inspiratory capacity breaths of buffered saline solution and increasing concentrations of methacholine at 5-min intervals. This gave an output of 0.009 ± 0.0014 mL (mean ± SD) per inhalation. FEV₁ was measured 60 to 90 s after inhalation at each concentration level. The procedure was terminated when the FEV₁ level fell to < 50% of the postsaline solution value, or when a maximal response plateau had been established. This was considered to occur if three or more data points at the highest concentrations fell within a 5% response range.¹¹ An additional 5 or 10 inhalations of the 200 mg/mL solution were taken if the last three data points of a < 50% FEV₁ fall did not satisfy the above-mentioned criteria. For safety reasons, subjects were given the opportunity to stop the challenge test if they felt too much discomfort. Response, expressed as the percentage fall in FEV₁ from the postsaline solution value, was plotted against the log of the concentrations of inhaled methacholine. The dose-response curves were characterized by their position and maximal response, the former expressed as PC₂₀, which was calculated by log-linear interpolation between two adjacent data points, and the latter defined as the level of maximal response plateau by averaging the consecutive points on the plateau, or as the last data point of the dose-response curve if a plateau could not be obtained.

Parents gave written informed consent for their children to participate in the study. The study protocol was approved by the Hospital Ethics Committee.

Statistical Analysis
PC₂₀ values were logarithmically transformed before analysis and were expressed as a geometric mean with a range of 1 SD. Other values were presented as mean ± 1 SD. Values or prevalences between the two groups of adolescents were compared using the Student t test or the ² test. Screening of data for differences among the three treatment groups was performed using the Kruskall-Wallis test. Changes in PC₂₀ or maximal airway response with respect to the baseline values were analyzed using Wilcoxon signed-rank test. In each case, statistical significance was accepted when the two-sided p values were < 0.05.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
A total of 96 subjects (48 subjects in each group) entered the first phase of study. Of these, six subjects (two subjects with asthma remission and four subjects with symptomatic asthma) were excluded due to interruption of the test because of discomfort. The clinical characteristics of the 90 subjects who completed the initial high-dose methacholine inhalation test are shown in Table 1 . There were no differences between the two groups in terms of age, sex ratio, atopic status as assessed by total serum IgE, and the pattern of positive skin responses, body mass index, FEV₁, or PC₂₀.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Comparison of maximal airway response to methacholine between adolescents with asthma remission and adolescents with symptomatic asthma. Open circle: subject with a maximal response plateau; closed circle: subject with FEV1 fall > 50% without a plateau. Horizontal bars represent mean ± SD.

View larger version (66K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Levels of maximal airway response before (B), and after 3 months (3M) and 6 months (6M) of treatment for the three groups (budesonide/remission group, n = 15; placebo/remission group, n = 15; budesonide/symptomatic group, n = 17). Mean and 1 SD are shown. *p < 0.01 compared to the value before treatment.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

In normal subjects, the dose-response curve achieves a plateau at mild degrees of airway narrowing, whereas in asthmatic subjects increasing doses of inhaled pharmacologic agents usually lead to progressive airway narrowing without the achievement of a plateau response.²³ We have found that adolescents with asthma remission had a higher frequency of plateau on the dose-response curves to methacholine than adolescents with symptomatic asthma to a similar degree of airway sensitivity to methacholine. It is arguable that some subjects who had FEV₁ falls of > 50% without evidence of plateau might present a plateau beyond a 50% fall from baseline FEV₁. However, we do not believe that this factor had predilection for the group of adolescents with symptomatic asthma. Furthermore, the level of maximal airway response was significantly lower in adolescents with asthma remission than in those with symptomatic asthma, despite a possible underestimation of the difference between the two groups resulting from the more frequent inclusion of subjects without a plateau in the latter group. Considering the fact that mild asthma patients were chosen for the symptomatic group in order to provide a matching degree of airway sensitivity to the remission group and to minimize the risks inherent in producing an excessive fall in FEV₁, it is likely that a more balanced group of symptomatic asthmatics would have greater maximal airway response than the adolescents with asthma remission.

No published data are available on the maximal airway response to pharmacologic agents in adolescents with long-term clinical remission. The relatively mild degree of maximal airway response in adolescents with asthma remission, compared to that in adolescents with symptomatic asthma to a similar degree of airway sensitivity to methacholine, was not unexpected since the maximal airway response reflects the potential degree of airways obstruction in the individual patient irrespective of the level of sensitivity.^{23 24} Indeed, it has been demonstrated that the maximal degree of airway narrowing is associated with the severity of asthma symptoms.¹⁰ Our observation suggests that the level of maximal airway response, rather than airway sensitivity, is a more important determinant of whether asthmatic symptoms occur, and supports the hypothesis that maximal airway response is an important confounder in the relationship between airway sensitivity and the clinical expression of asthma. There are indications that the maximal airway narrowing response may be determined by mechanical factors, such as smooth-muscle contractility, airway wall thickness, and elastic loads from the surrounding parenchyma.²⁵ The factors that normally limit airway narrowing are assumed to be operative in nonasthmatic subjects.¹⁰ It is possible that airway mechanical properties involved with maximal airway response are modified in adolescents with asthma remission.

Another major finding of this study was that inhaled budesonide did not cause a significant reduction in the level of the maximal response plateau in adolescents with asthma remission. However, inhaled budesonide was observed to reduce it in patients with symptomatic asthma, in accordance with previous studies.^{15 26} This is the first study to evaluate the effects of inhaled corticosteroids on the level of maximal airway response to inhaled methacholine, among symptom-free asthmatic adolescents with persistent BHR. A randomized placebo-controlled design enabled the examination of the longitudinal changes in maximal response during adolescence. Although some fluctuations occurred in individual subjects, a small but nonsignificant improvement was observed in the placebo/remission group. A similar trend was observed in the budesonide/remission group, and there was no significant difference in these observed changes between the two groups. It is unlikely that the potential for reduction was limited by confounding factors, such as allergen exposure,²⁷ or viral respiratory infections,²⁸ since the methacholine challenges were timed to avoid the peak house dust mite season and were not performed within 4 weeks of viral respiratory infection. The absence of significant improvement with corticosteroid treatment might be attributable to inadequate budesonide dosing or duration. However, this is also unlikely, since the same treatment regimen significantly reduced the maximal response in the budesonide/symptomatic group. Meanwhile, another study has demonstrated a marked effect with the same dose of budesonide and over a period as short as 4 weeks in patients with symptomatic asthma.¹⁵ Other factors that might have reduced the effect of budesonide include insufficient bioavailability of the drug, poor patient compliance with therapy, and relatively mild degree of maximal response in our subjects. Because we used the novel multiple-dose dry-powder inhaler, insufficient bioavailability of budesonide seems unlikely.²⁹ Following a careful check of the degree of compliance with the recommended use of budesonide, the subjects with poor compliance were excluded. Finally, it can be argued that the potential benefits of inhaled budesonide on the maximal airway response may be more evident in subjects with unlimited airway narrowing, rather than in those with maximal response plateau. However, the selection of subjects with maximal response plateau was necessary to allow estimation of change in repeated measurements.

It is not known whether persistent BHR in adolescents with asthma remission is associated with airway inflammation or is linked to another mechanism. The only study on the presence of airway inflammation in BHR of this clinical setting was performed by Van den Toorn et al,³⁰ who showed that adolescents with atopic asthma in clinical remission had an increased exhaled nitric oxide level, like that of symptomatic asthmatics. However, this does not provide definite evidence for ongoing airway inflammation, since atopic status independent of asthma diagnosis may be an important determinant of increased nitric oxide production in the airways.³¹ Reduction of airway sensitivity or maximal airway response to methacholine through inhaled corticosteroid treatment is mainly a result of improvements in various measures of airway inflammation.^{15 32} The lack of improvement in either maximal airway response or airway hypersensitivity with inhaled corticosteroid treatment therefore may suggest that airway inflammation does not play an important role in persisting BHR in adolescents with clinical remission. It has been shown that BHR may be the result of a chronic inflammatory process, with increased airway wall thickness and hypertrophy of the airway smooth muscle.³³ BHR caused by such airway remodeling would not be influenced by corticosteroids. However, genetic factors could offer another possible explanation. The importance of a familial predisposition, and therefore a possible genetic transmission of BHR, has been demonstrated by several studies.^{34 35} Inasmuch as this genetic factor exists in subjects, it could explain the observed lack of improvement in BHR with inhaled corticosteroids.

In conclusion, adolescents with asthma remission showed a relatively low level of maximal airway response, compared to symptomatic asthmatic adolescents with a similar degree of airway sensitivity to methacholine. Budesonide inhaled regularly for 6 months did not lead to a significant improvement in maximal airway response in adolescents with asthma remission. These findings suggest that the mechanism underlying bronchial hyperresponsiveness in this clinical setting may be different from that in symptomatic asthma.

	Footnotes

 
Abbreviations: BHR = bronchial hyperresponsiveness; PC₂₀ = provocative concentration of methacholine causing a 20% fall in FEV₁

Supported in part by BK 21 Human Life Sciences, Seoul National University.

Received for publication October 22, 2001. Accepted for publication March 27, 2002.

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Koh, Y. Y. Articles by Kim, C. K. Search for Related Content PubMed PubMed Citation Articles by Koh, Y. Y. Articles by Kim, C. K.