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Eur Respir J 2002; 20:66-72
Copyright ©ERS Journals Ltd 2002

Comparison of anti-inflammatory and clinical effects of beclomethasone dipropionate and salmeterol in moderate asthma

E. Bacci1, A. Di Franco1, M.L. Bartoli1, S. Carnevali1, S. Cianchetti1, F.L. Dente1, D. Giannini1, B. Vagaggini1, L. Ruocco2 and P.L. Paggiaro1

1 Cardiothoracic Dept, Respiratory Unit, University of Pisa, and 2 Laboratory Unit, Cisanello Hospital, Pisa, Italy

CORRESPONDENCE: P.L. Paggiaro, Dipartimento Cardiotoracico, UO Fisiopatologia Respiratoria, Ospedale Cisanello, via Paradisa 2, 56124, Pisa, Italy. Fax: 39 050580124. E-mail: ppaggiaro@qubisoft.it

Keywords: airway inflammation, asthma, induced sputum

Received: November 6, 2000
Accepted January 23, 2002


   Abstract
TOP
 Abstract
Material and methods
 Results
 Discussion
 Acknowledgements
 References
 
Inhaled corticosteroids and long-acting ß2-agonists effectively control asthma symptoms and improve airway function. The effects of beclomethasone were compared with those of salmeterol on markers of eosinophilic inflammation in induced sputum in steroid-naïve asthmatic subjects with moderate asthma.

Fifteen moderate asthmatics were treated with either beclomethasone dipropionate (500 µg b.i.d) or salmeterol (50 µg b.i.d) for 4 weeks, according to a randomised, double-blind, parallel-group study design. All patients underwent spirometry, methacholine test, sputum induction, and blood sampling before and after 2 and 4 weeks of treatment. They also recorded daily symptoms and peak expiratory flow (PEF).

Sputum eosinophils, eosinophil cationic protein (ECP) and eosinophil protein X (EPX), and blood eosinophils, as well as the forced expiratory volume in one second (FEV1) and morning PEF, significantly improved after beclomethasone but not after salmeterol. PEF variability, the symptom score and rescue ß2-agonist use significantly improved after both treatments, although the improvement in the symptom score tended to be greater after beclomethasone. After 2 and 4 weeks of beclomethasone treatment, both serum ECP and EPX decreased. With salmeterol, only serum EPX decreased, after 4 weeks. Bronchial hyperresponsiveness to methacholine did not change after either treatment.

The authors conclude that beclomethasone, but not salmeterol, substantially improves airway inflammation in asthma. Beclomethasone also had an overall greater clinical effect, although the improvement in symptoms and peak expiratory flow variability was similar after both treatments.

It is now well established that asthma is associated with airway inflammation 1. Inhaled corticosteroids are the drug of choice in the treatment of asthma because they provide the best anti-inflammatory treatment available 2. Inhaled corticosteroids improve asthma symptoms and pulmonary function 3, 4, and have been shown to decrease airway inflammation 5, 6. Several noninvasive markers of airway inflammation have been used in past years in order to evaluate the efficacy of anti-asthma drugs 7, 8, and eosinophilia in induced sputum has been shown to be a sensitive marker of spontaneous or drug-induced changes in airway inflammation 9, 10.

Oral corticosteroids significantly reduce eosinophils in induced sputum 10. The efficacy of inhaled corticosteroids on sputum eosinophils in asthmatic subjects has been studied by several authors, showing conflicting results. While low-dose inhaled beclomethasone dipropionate or budesonide only marginally reduced sputum eosinophilia in subjects with mild-to-moderate asthma 11, 12, high-dose (1,600–2,000 µg daily) inhaled budesonide or fluticasone significantly reduced sputum eosinophilia in mild asthmatics 13, 14.

Long-acting ß2-agonists, such as salmeterol, are recommended in the treatment of moderate-to-severe asthma in addition to inhaled corticosteroids 2, because they control asthma symptoms and improve lung function in asthmatic patients 15. However, they have also been shown to have some anti-inflammatory properties in vitro 16, but whether they have the same effects in vivo is still a controversial area 17–19.

In the present study, the effects of beclomethasone were compared to those of salmeterol on markers of eosinophilic inflammation in induced sputum, in a group of steroid-naïve asthmatic subjects with symptoms of moderate asthma. The dose of inhaled steroid was as recommended by the international guidelines for asthma of moderate severity. In addition, the effects on sputum markers were compared with the effects on the same markers in blood.


   Material and methods
TOP
 Abstract
 Material and methods
Results
 Discussion
 Acknowledgements
 References
 
Subjects
A total 33 patients with symptomatic, moderate asthma, recruited from the clinics of the Cardiothoracic Dept Respiratory Unit (University of Pisa, Pisa, Italy) were screened. The diagnosis of asthma was made according to internationally accepted criteria 2, after assessing reversible airway obstruction and/or nonspecific bronchial hyperresponsiveness to methacholine. All subjects were defined as having moderate asthma according to at least one of the following criteria: daily symptoms, night-time symptoms >1·week–1, forced expiratory volume in one second (FEV1), peak expiratory flow (PEF) 60–80% of predicted, or PEF variability >30% 2. All patients had received anti-inflammatory treatment for ≤3 months in the 2 yrs preceding the study, and none in the last 3 months. At the time of the study, all patients had active symptoms and were on rescue bronchodilators only. Three patients could not expectorate at baseline evaluation and were thus excluded from the study. The remaining 30 were enrolled and produced adequate sputum samples at all subsequent inductions (table 1Go). The protocol was approved by the local ethical committee. Informed written consent was given by all patients.


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  		Table 1— Subject characteristics

 
Study design
At a screening visit, all patients underwent spirometry, and patients with FEV1 ≥70% pred had a methacholine challenge test (n=23). Every procedure was performed in the morning, at the same time of the day ±1 h. All patients recorded a daily symptom score, the use of rescue ß2-agonists, and morning and evening PEF on a diary card over the whole study period. There was a 2-week run-in period (baseline) to demonstrate the degree of asthma severity. Eligible patients then entered a randomised, double-blind, parallel-group study in which they received either beclomethasone, 500 µg b.i.d, or salmeterol, 50 µg b.i.d. The randomisation sequence was computer-generated and administered by a person who was not involved in the evaluation of patients. Methacholine challenge test and sputum induction with hypertonic saline were repeated, on 2 consecutive days, after 2 and 4 weeks of treatment. Blood samples were collected before each sputum induction.

Methods
Sputum induction
Sputum was induced according to the method described by Pin et al. 7, with a slight modification 20. Inhaled salmeterol and/or short-acting bronchodilators, but not inhaled beclomethasone, were withdrawn 24 and 8 h, respectively, before each sputum induction. No ß2-agonist was administered as a pretreatment. Hypertonic saline solution was nebulised by means of an ultrasonic nebuliser (Sirius, Technomed, Florence, Italy) with a 2.8 mL·min–1 output, and was inhaled for 5-min periods for ≤30 min. NaCl concentration was increased at intervals of 10 min from 3% to 4% to 5%. Every 5 min after the start of nebulisation, patients were asked to rinse their mouth and throat carefully and to try to cough sputum into a container. FEV1 was then measured. Nebulisation was stopped after 30 min or when FEV1 fell by ≥20% from baseline.

Sputum processing
Sputum samples were processed as described elsewhere 20. After assessing sputum volume, whole sputum samples from all 30 patients were diluted with an equal volume of 0.1% dithiothreitol in phosphate-buffered saline (Sputasol; Unipath Ltd, Basingstoke, UK). Samples were incubated in a shaking bath at 37°C for 15 min and then pipetted up and down to further dissolve mucus plugs. At the end of incubation, samples were filtered through a 53 µm nylon gauze to remove debris. An aliquot of sputum samples was cytocentrifuged (Cytospin; Shandon Scientific, Sewickley, PA, USA) and stained with Diff-Quik (Baxter Scientific Products, Miami, FL, USA). Two investigators, blinded to the patients' codes, each counted ≥500 nonsquamous cells on each sputum slide. The interobserver agreement, expressed as intraclass correlation coefficient, was 0.92 for macrophages, 0.5 for lymphocytes, 0.82 for neutrophils, 0.98 for eosinophils. Therefore, the mean of the two readings on each sample were reported. Macrophage, lymphocyte, neutrophil and eosinophil counts were expressed as percentages of 500 inflammatory cells, excluding squamous cells. The remainder of the sputum sample was centrifuged at 450xg for 10 min. The supernatant was collected and stored at –80°C for further analysis. The cell pellets were resuspended in normal saline for total cell counts with the Türk staining and cell viability assessment by Trypan blue exclusion in a haemocytometer. Samples with cell viability <70% were discarded. In cases of low cell viability at baseline, the patient was excluded from the study. At subsequent evaluations, sputum induction was rescheduled after 24 h.

Blood processing
Blood samples were examined for total and differential cell counts. The remainder were centrifuged at 1,000xg for 10 min after 60±10 min of rest at room temperature to allow clotting. The supernatant was then centrifuged again to ensure complete cell removal. Serum was then collected and stored at –80° C for further analysis.

Eosinophil cationic protein and eosinophil protein X measurements
Eosinophil cationic protein (ECP) and eosinophil protein X (EPX) in sputum supernatant and serum were measured by means of a radioimmunoassay (Pharmacia RIA, Uppsala, Sweden) (normal values in serum: ECP 2.3–16 µg·L–1, EPX 8.2–38.2 µg·L–1; lower detection limit: <2 µg·L–1). Since ECP and EPX were higher than the upper detection limit of the method in four and seven sputum samples respectively, these samples were diluted 1:10 and the measurements were repeated. Sputum ECP and EPX measurements were corrected (multiplied by 2) for the processing dilution with dithiothreitol.

Methacholine challenge test
Inhaled salmeterol and/or short-acting bronchodilators, but not inhaled beclomethasone, were withdrawn 24 and 8 h, respectively, before each test. Methacholine (Sigma, St. Louis, MO, USA) was delivered by a DeVilbiss 646 jet nebuliser using a procedure described previously 21. The cumulative provocative dose producing a 20% fall in the FEV1 (PD20) was computed. A value of <1,000 µg of methacholine was considered positive for bronchial hyperresponsiveness.

Peak expiratory flow, symptom evaluation, rescue ß2-agonist use
Symptoms (wheezing, chest tightness, shortness of breath, cough) were rated on a scale from 0 (none) to 4 (never slept because of asthma) for night-time symptoms and 0 (none) to 5 (could not perform common daily activities because of asthma) for daytime symptoms, and were added up to give the average daily symptom score 22. Predrug morning PEF was expressed as % predicted. PEF variability, expressed as amplitude % mean, was calculated as follows:


(001)
and a value of ≥10% was considered high. Rescue ß2-agonist use was evaluated by recording the number of times that patients needed to inhale ≥1 puffs of short-acting ß2-agonists.

Analysis
Cell counts and sputum volume are expressed as median (range). The symptom score, morning PEF, daily PEF amplitude per cent mean, per cent of days with abnormal PEF amplitude per cent mean, and short-acting rescue ß2-agonist use were averaged over the last 7 days before each visit and expressed as median (range) except for morning PEF and daily PEF amplitude per cent mean, which are expressed as mean±sd. FEV1 is also expressed as mean ±sd. The provocative dose of methacholine causing a 20% fall in FEV1 (PD20) is expressed as geometric mean, and was log transformed for comparisons. The Mann-Whitney U-test and Friedman test were used to compare differential sputum cell counts, ECP and EPX, blood eosinophil percentages, serum ECP and EPX between and within treatments respectively. An unpaired t-test and analysis of variance (ANOVA) for repeated measures were used to compare FEV1 and log PD20 methacholine between and within treatments respectively.


   Results
TOP
 Abstract
 Material and methods
 Results
Discussion
 Acknowledgements
 References
 
Inflammatory markers
Baseline sputum and blood eosinophil percentages, sputum/serum ECP and EPX levels were no different between beclomethasone and salmeterol groups (figs. 1–3GoGoGo, table 2Go). After 2 and 4 weeks of beclomethasone treatment, sputum and blood eosinophils, as well as sputum and serum ECP and EPX, significantly decreased. With salmeterol treatment, only serum EPX decreased, after 4 weeks. Sputum volume, total cell counts, and differential cell counts for macrophages, lymphocytes and neutrophils did not change after either treatment. Cell viability was >70% in all collected samples, so that no sputum induction had to be rescheduled.



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  		Fig. 1.— a) Sputum and b) blood eosinophils before (B) and 2 and 4 weeks after treatment. {square}: beclomethasone dipropionate, 500 µg b.i.d; : salmeterol, 50 µg b.i.d. *: p<0.05; **: p<0.01.

 


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  		Fig. 2.— a) Sputum and b) blood eosinophil cationic protein (ECP) before (B) and 2 and 4 weeks after treatment. {square}: beclomethasone dipropionate, 500 µg b.i.d; : salmeterol, 50 µg b.i.d. *: p<0.05.

 


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  		Fig. 3.— a) Sputum and b) blood eosinophil protein X (EPX) before (B) and 2 and 4 weeks after treatment. {square}: beclomethasone dipropionate, 500 µg b.i.d; : salmeterol, 50 µg b.i.d. *: p<0.05.

 

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  		Table 2— Induced sputum and blood indices measured before and after treatment

 
Clinical and functional data
Baseline FEV1, morning PEF, and PD20 methacholine were no different between the beclomethasone and salmeterol groups. After 2 and 4 weeks of treatment, FEV1 and morning PEF significantly improved in the beclomethasone group but not in the salmeterol group (table 3Go). PD20 methacholine tended to increase with treatment and was higher in the beclomethasone group, without reaching statistical significance (p=0.11).


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  		Table 3— Functional and clinical indices measured before and after treatment

 
Baseline daily PEF amplitude% mean, percentage of days with abnormal PEF amplitude% mean, daily symptom score and use of rescue ß2-agonist were no different between beclomethasone and salmeterol groups. After treatment, they all significantly improved in both groups, although after 4 weeks the improvement in symptom score tended to be higher in beclomethasone-treated patients (p=0.05, table 3Go).


   Discussion
TOP
 Abstract
 Material and methods
 Results
 Discussion
Acknowledgements
 References
 
In the present study it was shown that inhaled beclomethasone, at the daily dose recommended by the international guidelines for asthma treatment 2, but not salmeterol, decreased eosinophilic inflammation in sputum and blood in steroid-naïve asthmatic patients. Beclomethasone improved the symptom score, the use of rescue ß2-agonist, PEF variability, FEV1, and morning PEF values, whereas salmeterol only improved the symptom score, the use of rescue ß2-agonist, and PEF variability. Neither treatment improved methacholine responsiveness. After beclomethasone, functional data improved within 2 weeks of treatment, and paralleled the improvement in both sputum and blood eosinophilic markers.

Previous studies have reported the effect of inhaled steroids on airway inflammation in asthma. Fahy and Boushey 11 showed that low steroid doses (168 µg b.i.d) improved clinical and functional data, but had only mild effects on airway inflammation. Jatakanon et al. 13 studied a group of mild asthmatic patients treated with very high steroid doses (800 µg b.i.d), and found a significant improvement in both airway function and sputum eosinophils, but not in sputum ECP or tumour necrosis factor (TNF)-{alpha}. The lack of effect on soluble mediators was not reported, and therefore cannot be compared with the present data. In another study, the same authors compared the same group of patients with asthmatic patients of a similar degree treated with lower doses of inhaled steroid, and also found that 400 µg budesonide, but not 100 µg, significantly improved airway inflammation and lung function 12. In a study including a large number of patients, Meijer et al. 14 compared the effects of two different doses of inhaled fluticasone (1,000 or 250 µg b.i.d) and oral prednisolone (30 mg·day–1) on lung function and airway inflammation. They showed that inhaled steroids were at least as effective as oral steroids, and that the lowest dose of fluticasone had far less systemic effects than the other two treatments. Thus, it is now well established that adequate doses of inhaled steroids effectively improve eosinophilic airway inflammation.

Long-acting ß2-agonists have been shown to have some anti-inflammatory effects in experimental models, including effects on sputum eosinophils 17 and blood ECP 23. However, treatment with long-acting ß2-agonists as monotherapy for longer time periods has demonstrated marginal or no effects on airway inflammation 19, 24, 25. In this study, no relevant anti-inflammatory effect of salmeterol, despite the improvement in symptoms and PEF variability, was shown. Indeed, only serum EPX significantly decreased after 4 weeks of salmeterol treatment. A similar observation has been reported previously 23 for serum ECP using a short-term course of inhaled salmeterol. The authors ascribed the decrease in serum ECP to the inhibition of eosinophil degranulation. The improvement in PEF variability is not surprising, because salmeterol reduces bronchoconstriction. The lack of improvement in FEV1 might, at least partially, be because salmeterol was withdrawn 24 h before the measurement. The lack of improvement in morning PEF may partly be due to it being measured before inhaling salmeterol, and thus the measurement was only partially affected by the latest inhalation, taken 8–10 h before PEF measurement. However, this suggests that salmeterol alone is not enough to obtain a persistent improvement in airway calibre.

Turner et al. 19 compared the effects of salmeterol and beclomethasone on mild asthma exacerbations, and found that salmeterol improved clinical parameters but not markers of eosinophilic inflammation. McIvor et al. 26 evaluated the effect of adding salmeterol to a progressive reduction in the inhaled steroid dose in patients with asthma. They observed that salmeterol controlled symptoms and airway function but not airway inflammation. Thus, salmeterol is not recommended as single therapy in asthma.

The study was designed to compare the effects of beclomethasone with those of salmeterol in controlling symptoms, respiratory function, and airway inflammation. It has been reported that airway inflammation may be present 11 and increase 26 despite good functional data and absence of symptoms, and this may lead to asthma exacerbation. It is therefore useful to know whether treatment is acting on every single aspect of the disease. While beclomethasone controls symptoms, respiratory function, and airway inflammation, salmeterol only improves clinical and functional data, and not eosinophilic inflammation. Whether adding salmeterol to low-dose inhaled corticosteroids adequately controls not only clinical but biological markers of asthma better than increasing the dose of inhaled corticosteroids is not clearly defined 27, 28.

Inhaled steroid treatment improved FEV1 but not methacholine responsiveness. This result is in agreement with the hypothesis that bronchial hyperresponsiveness depends on a wide range of factors 29, and that acute inflammation may not be the most relevant factor in the response to methacholine, which may, instead, require longer treatment duration to improve.

To conclude, it was shown that treating asthmatic patients with appropriate inhaled steroid doses, according to international guidelines, not only controls symptoms but also improves airway inflammation. By contrast, salmeterol monotherapy was effective on symptoms and peak expiratory flow variability, but only marginally affected markers of airway eosinophilic inflammation. Thus, it was confirmed that the use of salmeterol alone is not recommended for the long-term treatment of asthma.


   Acknowledgements
TOP
 Abstract
 Material and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors would like to thank. M. De Santis and E. Masino for technical assistance.


   References
TOP
 Abstract
 Material and methods
 Results
 Discussion
 Acknowledgements
 References
 

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E. Bacci, S. Cianchetti, M. Bartoli, F. L. Dente, A. Di Franco, B. Vagaggini, and P. Paggiaro
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