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(Chest. 2004;125:1693-1699.)
© 2004 American College of Chest Physicians

Leukotriene Modifier vs Inhaled Corticosteroid in Mild-to-Moderate Asthma*

Clinical and Anti-inflammatory Effects

Diahn-Warng Perng, MD, PhD, FCCP; Han-Yu Huang, MD; Yu-Chin Lee, MD, FCCP and Reury-Perng Perng, MD, PhD, FCCP

* From the Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Correspondence to: Diahn-Warng Perng, MD, PhD, FCCP, Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Rd, Taipei 11217, Taiwan; e-mail: dwperng{at}vghtpe.gov.tw


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Evidence for the anti-inflammatory activity of leukotriene receptor antagonists in humans is somewhat limited. There are also no data comparing the anti-inflammatory effects of leukotriene receptor antagonists with those of inhaled corticosteroids. This study was designed to assess the clinical efficacy and anti-inflammatory effects of leukotriene receptor antagonist plus low-dose inhaled corticosteroids compared to those of a high-dose inhaled corticosteroid in patients with mild-to-moderate asthma.

Methods: Forty-nine patients with newly diagnosed asthma were recruited. They were randomly assigned to groups that received, for a 6-week period, either (1) budesonide, 600 µg bid (1,200 µg/d) or (2) budesonide, 200 µg (400 µg/d), and zafirlukast, 20 mg bid. The variables of asthma control were recorded daily. Sputum induction and methacholine provocation tests were performed.

Results: The results indicated that the administration of a low-dose inhaled corticosteroid plus zafirlukast was as effective as that of a high-dose inhaled corticosteroid regarding clinical improvement and anti-inflammatory effects (ie, eosinophil percentage, and eosinophilic cationic protein [ECP] and cysteinyl leukotriene C4 levels in induced sputum). Nineteen (group 1, 8 patients; group 2, 11 patients) of 49 patients (38.8%) had returned to normal airway responsiveness after treatment. Among these patients, 16 patients (84.2%) had normal ECP levels and 10 patients (52.6%) had normal percentages of eosinophils. ECP level, but not the eosinophil percentage, was significantly associated with symptom scores. The peak expiratory flow rate (PEFR) showed a significant correlation with the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) instead of with symptom scores.

Conclusions: The addition of a leukotriene modifier to treatment with low-dose inhaled corticosteroids is equivalent to treatment with high-dose inhaled corticosteroids in patients with newly diagnosed mild-to-moderate asthma. In addition to symptoms and PEFR, the monitoring of ECP and PC20 may be of great value in achieving optimal control of asthma.

Key Words: asthma • induced sputum • inhaled corticosteroid • leukotriene receptor antagonist


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled corticosteroids currently are the first line of anti-inflammatory therapy for patients with asthma. They suppress airway inflammation,1 leading to decreases in airway hyperresponsiveness,2 and in the numbers of eosinophils and mast cells in the asthmatic airways.34 To manage patients with uncontrolled asthma, some asthma treatment guidelines5 recommend either increasing the dose of inhaled corticosteroids alone or in combination with the administration of sustained-release theophylline or a leukotriene modifier. However, long-term treatment with high doses of inhaled corticosteroids may result in adverse systemic effects.6

Cysteinyl leukotrienes contribute to bronchoconstriction, increased mucus secretion, and recruitment into and activation of inflammatory cells in asthmatic airways. Not surprisingly then, leukotriene receptor antagonists have been shown78 to provide clinical benefit to patients with persistent asthma. However, the evidence for anti-inflammatory activity of leukotriene receptor antagonists in humans is somewhat limited, and there are no data comparing the anti-inflammatory effects of leukotriene receptor antagonists with those of inhaled corticosteroids.

The aim of this study was to assess the clinical efficacy and anti-inflammatory effects of treatment with leukotriene receptor antagonists combined with a low-dose inhaled corticosteroid compared to those of treatment with a high-dose inhaled corticosteroid in patients with newly diagnosed asthma of mild-to-moderate severity. Asthma symptom scores, peak expiratory flow rate (PEFR), and responsiveness to methacholine were determined. Airway secretions were collected directly using sputum induction to determine the characteristics of the inflammatory cells and mediators before and after treatment. From these measures, we also hoped to find a practical index to guide treatment choice and achieve effective control of asthma.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Forty-nine patients who met the criteria for asthma,5 including recurrent episodes of wheezing, troublesome cough at night, or cough, wheeze, or chest tightness after exercise or exposure to airborne allergens or pollutants, were recruited from our outpatient clinic. They were newly diagnosed asthmatic patients who were not receiving therapy with oral or inhaled corticosteroids. Twenty-five patients were men, and 24 patients were women. The ages of the patients ranged from 18 to 77 years, with a mean age of 48 years. The severity of asthma, as determined by the clinical symptoms and PEFR, was mild to moderately persistent. The numbers of patients with atopic and nonatopic types of asthma (the atopic type was defined as a positive reaction to one or more allergens in a fluoroenzyme immunoassay) were 27 and 22, respectively. The 49 healthy volunteers included 20 men and 29 women, ranging in age from 21 to 54 years, with a mean age of 37 years. All healthy subjects were nonsmokers, nonatopic, had no history of rhinitis, eczema, or spontaneous wheezing, and were not receiving any medication. All of the patients had been free from respiratory tract infections or exacerbation for 4 weeks prior to sputum induction and during the treatment period. The ethics committee of the hospital approved the study, and written informed consent was obtained from all of the subjects before the study commenced.

Study Design
Following an initial screening visit, eligible patients randomly received either budesonide, 600 µg bid (total dose, 1,200 µg/d) [Pulmicort Turbuhaler; AstraZeneca; Lund, Sweden; 200 µg per puff] (group 1) or budesonide 200 µg (20 mg bid; total dose, 400 µg/d) and zafirlukast (Accolate; AstraZeneca; 20 mg per tablet) [group 2] for a 6-week period. Clinical symptoms and PEFR were measured on waking and before the evening meal, using a peak flowmeter (mini-Wright; Clement Clarke; Harlow, UK). The values of symptom scores, the PEFR, and the use of inhaled short-acting ß2-agonists were recorded on a diary card. Four asthma symptoms (ie, wheeze, cough, daily activity, and sleep disturbance) were scored by the patients every day using a subjective score system with a scale of 0 (symptom free) to 3 (severe).5 Sputum was collected and a bronchial provocation test with methacholine was administered to all of the subjects during the screening visit, and at the end of treatment. Methacholine was delivered using hand-held nebulizers (Devilbiss Health Care; Somerset, PA) in a series of doubling concentrations (range, 0.15 to 25 mg/mL), and the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) was estimated by interpolation.

Sputum Induction and Processing
Sputum was induced by the inhalation of 3%, 4%, and then 5% hypertonic saline solution after premedication with 400 µg salbutamol, and was processed with 0.1% dithiothreitol, as described by Pin et al.9 Cytospins were stained with May-Grunwald-Giemsa stain, and 400 nonsquamous cells counted. The differential cell count was expressed as a percentage of the cell count. The supernatant of the induced sputum was aspirated and frozen at –80°C until measurement of the mediators.

Measurement of Cysteinyl Leukotriene and Eosinophilic Cationic Protein
The total level of cysteinyl leukotriene C4 (LTC4) was measured in the sputum supernatants by enzyme immunoassay, employing a polyclonal antiserum to LTC4 (Cayman Chemical; Ann Arbor, MI) after prior purification on C18 columns. The sensitivity of the enzyme-linked immunosorbent assay was 7 pg/mL. The concentration of eosinophilic cationic protein (ECP) in the supernatant was determined by double-antibody radioimmunoassay (Pharmacia and Upjohn Diagnostics; Uppsala, Sweden). The assay uses a specific antibody against human ECP raised in rabbits with 125I-labeled ECP as tracer. The lowest detectable level of ECP was 2 mg/L.

Statistical Analysis
Analysis of variation with the Bonferroni correction for multiple comparisons was applied in healthy subjects and subjects treated with different medications. Paired and independent Student t tests were performed to examine the changes in continuous outcome variables within and between the two groups. Associations among PEFR, PC20, symptom scores, and indexes of inflammation were measured using the Spearman rank correlation test. Rank correlation and p values were computed using a statistical software package (SPSS, version 10.0.1 for Windows; SPSS; Chicago, IL). A p value of < 0.05 was considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Forty-nine patients with newly diagnosed asthma were recruited into the study. Patient characteristics are shown in Table 1 . Baseline values in the treatment groups were comparable. Bronchial hyperresponsiveness to methacholine was observed in all of the asthmatic patients.


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  		Table 1.. Demographic Data of the Control and Treatment Groups*

 
Clinical Improvement in Symptoms and Pulmonary Function
For all of the patients, the increase in morning and evening PEFR, the fall of symptom scores, and the decrease in responsiveness to methacholine were statistically significant before and after treatment (Table 2 ). There were no significant differences in clinical efficacy between the two treatment groups (ie, budesonide vs budesonide plus zafirlukast) with respect to PEFR, symptom scores, the use of inhaled short-acting ß2-agonists, and PC20. No episode of acute exacerbation during the treatment period for all study subjects was observed.


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  		Table 2.. Comparisons of the Measures Before and After 6 Weeks of Treatment*

 
Anti-inflammatory Effects
Sputum induction was successfully completed in 41 of 49 asthmatic patients (83.6%) and 49 of 63 healthy volunteers (77.8%). Sputum eosinophilia (>= 3%) appeared in 87.5% of study subjects who had completed sputum induction. Thirty-five of 41 patients (85.4%) had ECP levels higher than normal values before the commencement of treatment. The reduction of eosinophil percentage and the levels of LTC4 and ECP were statistically significant after treatment in both groups (Table 3 ). Although the patients treated with an inhaled corticosteroid alone had a higher percentage of eosinophils and higher ECP levels, no significant differences with regard to anti-inflammatory effects between the two treatment groups were found.


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  		Table 3.. Characteristics of the Inflammatory Cells and Mediators in Induced Sputum*

 
Associations Between Asthma Symptom Scores and Airway Inflammatory Indexes
The levels of ECP, but not of LTC4, and asthma symptom scores showed a significant correlation (p < 0.05) during the screening visit (Fig 1 , top, A). The correlation between PEFR and symptom scores was not significant (Fig 1, bottom, B). The eosinophil percentage was significantly correlated with ECP levels (r = 0.59; p < 0.001), but not with LTC4 levels. However, the numbers of eosinophils were not significantly associated with the severity of asthma symptoms.



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  		Figure 1.. The correlation between symptom scores and ECP levels (top, A) and PEFR (bottom, B) in newly diagnosed asthmatic patients.

 
Correlation Between PC20 and Variables in Pulmonary Function, Asthma Symptoms, and Airway Inflammation
The mean values for the morning and evening PEFR for the first day (r = 0.352; p = 0.013) and the last 3 days (r = 0.319; p = 0.027) were significantly associated with PC20 at the beginning of the study (r = 0.453; p = 0.004) and at the end of the study (r = 0.403; p = 0.012). The initial asthma symptoms were not correlated with the levels of PC20. During the screening visit, eosinophil percentage, but not ECP level, was significantly correlated with PC20 (r = – 0.35; p = 0.014). A trend to a decreased percentage of eosinophils after treatment was observed, but it was not significantly correlated with the reduction of PC20. Nineteen (group 1, 8 patients; group 2, 11 patients) of 49 patients (38.8%) had returned to normal airway responsiveness after treatment (Fig 2 , top, A). Among these patients, 16 patients (84.2%) had normal ECP levels and 10 patients (52.6%) had normal percentages of eosinophils (Fig 2, bottom, B).



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  		Figure 2.. The relation between airway responsiveness and ECP sputum concentration (top, A), and between airway responsiveness and sputum eosinophil percentage (bottom, B).

 
Correlation Among the Changes in Variables Before and After Treatment
No significant correlation between the improvement in symptom scores and the changes in PEFR, PC20, ECP, and LTC4 levels, or eosinophil percentage was found. The correlation between the change of ECP level and eosinophil percentage was poor. The change in PC20 was not associated with the reduction of eosinophil counts and ECP levels.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this randomized study indicate that after 6 weeks of treatment, therapy with a low-dose inhaled corticosteroid (budesonide, 400 µg/d) in combination with zafirlukast was as effective as therapy with a high-dose inhaled corticosteroid (budesonide, 1,200 µg/d) regarding clinical improvement as well as the suppression of airway inflammation among newly diagnosed asthmatic patients with persistent disease and mild-to-moderate severity. Leukotriene modifiers, a new class of anti-inflammatory drugs for asthma treatment, may provide additional clinical benefit to patients concomitantly receiving therapy with inhaled corticosteroids.

Inhaled corticosteroids are currently the most effective medications available for the treatment of persistent asthma of any degree of severity.5 Data from some studies8 have shown that zafirlukast has significant additive anti-inflammatory effects to therapy with low-dose inhaled corticosteroid, but not to therapies with a medium-dose inhaled corticosteroid, indicating that the anti-inflammatory property of zafirlukast could be masked while using a higher dose of an inhaled corticosteroid. Pauwels et al10 has reported that in treating persistent asthma (mean FEV1, > 75% predicted), the higher dose of budesonide (800 µg/d) was associated with a significant increase in peak expiratory flow and better control of symptoms than the lower dose (200 µg/d). Budesonide also was associated with a dose-response effect in adults and children with moderate-to-severe asthma.11 With respect to cost-effectiveness, optimizing the dose of inhaled corticosteroids as monotherapy, which is consistent with current guidelines, might be more logical than a combination therapy in the management of asthma. However, caution must be taken in the long-term treatment of patients with a high-dose inhaled corticosteroid as systemic side effects may occur.

One long-term prospective intervention study12 demonstrated associations among airway inflammation, hyperresponsiveness, and remodeling, and suggested the need for early and long-term intervention with inhaled corticosteroids, even in patients with relatively mild asthma. After 6 weeks of treatment, nearly 40% of our patients had regained normal airway responsiveness, and most of them had normal ECP levels, suggesting a silent inflammatory status in the airways. It is unclear when airway inflammation and hyperresponsiveness will develop again in those patients. It is also unclear whether asthmatic patients with normal airway responsiveness and normal ECP levels or eosinophil counts should continue inhaled corticosteroid therapy. More large-scale and long-term follow-up studies are needed to address these questions.

Asthma is a complex inflammatory disorder with various clinical presentations. It is difficult to use a single parameter to assess the severity of asthma, the response to treatment, or the clinical outcome. Sputum induction is a simple and relatively safe procedure to obtain airway secretions. The analysis of induced sputum can yield information that is qualitatively similar to that obtained by an analysis of bronchial wash and BAL fluid.13 In this study, most of the newly diagnosed asthmatic patients had ECP levels in induced sputum that were higher than normal values before the commencement of treatment, and ECP level appeared to be more strongly correlated with the severity of symptoms than with other parameters such as sputum eosinophil percentage, PC20, or PEFR. The ECP level in induced sputum has been reported14 to be helpful in the diagnosis of asthma and could serve as a useful marker for evaluating airway inflammation.15 In assessing exacerbations of asthma, ECP level is considered to be more accurate than eosinophil percentage.16 Nevertheless, ECP level is not a potential marker to assess treatment response. For instance, a patient who experienced improvements in asthma symptoms and responsiveness to methacholine after treatment may have ECP levels above the normal range, or sometimes even higher than the pretreatment baseline level. The clinical improvement in symptoms is not proportional to the reduction of ECP levels observed in this study.

PEFR and symptom scores are commonly used to monitor the severity of asthma. We found that the PEFR was significantly correlated with PC20 instead of with symptom scores. Airway hyperresponsiveness has been shown to have an inverse relationship with baseline lung function.1718 Methacholine responsiveness may reflect multiple and variable features of airway inflammation, and is recognized as an indicator for the long-term monitoring of asthma.19 Clinically, ongoing airway inflammation is likely to be neglected because of normal pulmonary function and insignificant symptoms, especially in patients with intermittent or mild persistent asthma. Long-term airway inflammation may lead to airway remodeling and impaired pulmonary function. It has been reported that for the long-term treatment of asthma, the outcome can be substantially improved not only by using symptom score and pulmonary function as guides, but also by monitoring airway hyperresponsiveness.20

In conclusion, the effect of therapy with a leukotriene receptor antagonist plus a low-dose inhaled corticosteroid is the same as that of a high-dose inhaled corticosteroid in the management of patients with mild-to-moderate persistent asthma. In addition to clinical symptoms and pulmonary function, the monitoring of airway hyperresponsiveness and ECP concentrations in induced sputum may be of great value in achieving optimal control of asthma.


   Footnotes
 
Abbreviations: ECP = eosinophilic cationic protein; LTC4 = cysteinyl leukotriene C4; PC20 = provocative concentration of a methacholine causing a 20% fall in FEV1; PEFR = peak expiratory flow rate

Drs. D-W. Perng and Huang made equal contributions to this study.

This work was supported by research grants from Taipei Veterans General Hospital (VGH91-210).

Received for publication June 10, 2003. Accepted for publication December 17, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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