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(Chest. 2005;128:1121-1127.)
© 2005 American College of Chest Physicians

Formoterol Added to Low-Dose Budesonide Has No Additional Antiinflammatory Effect in Asthmatic Patients*

Shelley E. Overbeek, MD, PhD; Paul G. Mulder, PhD; Sophia M. Baelemans; Henk C. Hoogsteden, MD, PhD and Jan-Bas Prins, PhD

* From the Departments of Pulmonary Medicine (Drs. Overbeek, Hoogsteden, and Prins, and Ms. Baelemans) and Epidemiology & Biostatistics (Dr. Mulder), Erasmus Medical Center, Rotterdam, the Netherlands.

Correspondence to: Shelley E. Overbeek, MD, PhD, Department of Pulmonary Medicine, SV020, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands; e-mail: s.e.overbeek{at}erasmusmc.nl


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Adding inhaled long-acting ß2-agonists to a low dose of inhaled corticosteroids (ICSs) results in better asthma control than increasing the dose of ICSs. An important, but as yet unresolved, question is whether this is due to an additional reduction of airway inflammation.

Design: Double-blind, parallel-group trial.

Patients: Forty asthma patients (FEV1, 50 to 90% predicted; provocative concentration of a substance [methacholine] causing a 20% fall in FEV1 of < 8 mg/mL; no ICSs in the last 4 weeks).

Interventions: Randomization to 8 weeks of treatment with 100 µg of budesonide bid plus placebo (BUD200) or 100 µg of budesonide bid plus 12 µg of formoterol (BUD200 + F). Then the dose of budesonide (BUD) was increased to 400 µg bid in both groups for another 8 weeks. Bronchial biopsy specimens were collected before, and after 8 and 16 weeks of treatment. Eosinophils (major basic protein [MBP]) and mast cells (tryptase) were analyzed by immunohistochemistry.

Results: BUD200 reduced the MBP staining (p = 0.008) and tryptase staining (p = 0.048) in the epithelium compared to baseline levels. There were no significant differences between the BUD200 and BUD200 + F groups. In both groups, increasing the dosage of BUD to 800 µg had no significant additional antiinflammatory effect.

Conclusions: Our results demonstrate that BUD administered at a low dose has significant antiinflammatory effects in patients with mild asthma. No significant additional antiinflammatory effects could be demonstrated either by adding formoterol or by increasing the dose of BUD.

Key Words: airway inflammation • asthma • bronchial biopsy • budesonide • formoterol


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Asthma is a chronic disease that is characterized by reversible airflow obstruction and bronchial hyperreactivity (BHR) to a variety of stimuli. Considerable evidence has been obtained to show that airway inflammation is a major factor in the pathogenesis of asthma and associated BHR. The inflammatory pattern in asthma is multicellular in nature, with mainly mast cells, eosinophils, and T lymphocytes participating in the response. An important therapeutic objective in treating asthma patients is to control the underlying inflammatory process in the airways. Current guidelines advocate the use of inhaled corticosteroids (ICSs).1 Treatment with ICSs not only leads to consistent reductions in the number and activation of mast cells and eosinophils in biopsy specimens,23 it also reduces BHR.

ICSs are generally combined with inhaled short-acting and/or long-acting (LA) ß2-agonists for symptomatic relief in patients with asthma. LA ß2-agonists are considered to be smooth muscle relaxants, while their antiinflammatory properties are still a matter of debate. Although the antiinflammatory effects of ß2-agonists have been demonstrated clearly in in vitro experiments, these have not been proven in vivo. Nevertheless, several studies456 have indicated that adding inhaled LA ß2-agonists to a low dose of ICSs results in better asthma control than increasing the dose of ICSs with respect to asthma symptoms, lung function, and the number of exacerbations. An important, but as yet unresolved, question is whether this is due to an additional reduction of airway inflammation. We set up a double-blind, parallel-group trial to answer this question. The effect of 8 weeks of treatment with 100 µg of budesonide bid plus placebo (BUD200) compared with 100 µg of budesonide bid plus 12 of µg formoterol bid (BUD200 + F), followed by another 8 weeks of treatment with 400 µg bid with or without formoterol on markers of inflammation in bronchial biopsy specimens and in exhaled air was studied.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Forty nonsmoking both atopic and nonatopic asthma patients, who were receiving a maximum dose of 800 µg of ICSs daily prior to the run-in, were selected if they met the following criteria: 18 to 55 years of age; FEV1 between 50% and 90% of predicted normal; provocative concentration of a substance (methacholine [MCh]) causing a 20% fall in FEV1 (PC20) of < 8 mg/mL, as measured by a 2-min tidal breathing method.7 Atopy was defined as having a positive radioallergosorbant test for house dust mite or at least two other common inhaled allergens. All subjects were in stable condition, were nonsmokers, and were treated according to international guidelines.8 All participants gave informed written consent to the study, which was approved by the medical ethics committee of the Erasmus Medical Center, Rotterdam, the Netherlands. The study was conducted according to the principles stated in the Declaration of Helsinki.

Study Design
The study was a randomized, double-blind, parallel-group design. After a run-in period of 4 weeks, subjects entered an 8-week treatment period receiving 100 µg of budesonide (Pulmicort Turbuhaler; AstraZeneca; Södertälje, Sweden) bid plus placebo (ie, BUD200) or 100 µg of budesonide bid plus 12 µg of formoterol (Oxis Turbuhaler; AstraZeneca) bid (ie, BUD200 + F). Then, the dosage of budesonide (BUD) was increased to 400 µg bid in all patients for another 8 weeks (BUD800 group), while the dosage of formoterol, 12 µg bid, was continued in the randomized group (BUD800 + F).

At the start of the 4-week run-in period, all medication was stopped. Patients were allowed to receive only the inhaled short-acting ß2-agonist terbutaline (Bricanyl Turbuhaler; AstraZeneca), 0.5 mg per dose, on an as-needed basis. Treatment with terbutaline was allowed up to 8 h prior to making the study measurements.

At the start of the study period, at visit 1, a radioallergosorbant test and spirometry were performed. Reversibility was tested by measuring FEV1 relative to baseline following the inhalation of four puffs of 0.25 mg of terbutaline using a metered-dose inhaler (Nebuhaler; AstraZeneca).

At the second visit to the clinic 3 to 7 days later, exhaled nitric oxide (eNO) levels and PC20 for MCh were determined. All patients fulfilling the inclusion criteria were scheduled for bronchoscopy at least 1 week after the baseline visit. Following bronchoscopy, patients were randomized to one of the treatment regimens.

After 7 weeks of treatment, spirometry, eNO level measurement, and the determination of the PC20 for MCh were repeated. One week later, after exactly 8 weeks, a second bronchoscopy was performed. Then, the dosage of BUD was increased to 400 µg bid in all patients for another 8 weeks. After 7 weeks of the second treatment period, spirometry, eNO level measurement, and the determination of the PC20 for MCh were repeated. After exactly 8 weeks, a third bronchoscopy was performed. Eight hours prior to the pulmonary function tests, only the 0.5-mg (as needed) dose of terbutaline (Turbuhaler; AstraZeneca) was discontinued.

Bronchoprovocation
MCh was administered according to a standardized 2-min tidal-breathing method.7 The aerosols were generated using a nebulizer (model 646; DeVilbiss Health Care; Somerset, PA) [output, 0.13 mL/min].

eNO
The amount of eNO was measured by means of chemiluminescence (Aerocrine NO System; Aerocrine AB; Danderyd, Sweden).9 After complete exhalation, subjects inhaled nitric oxide-free air, via a filter (Purafil; Doraville, GA), to total lung capacity and were subsequently asked to exhale slowly at a constant flow rate between 0.075 and 0.125 L/s for 10 s. Measurements were performed at least in triplicate in order to reach an accuracy of 5 to 10% for nitric oxide levels.

Bronchial Biopsies
All bronchial biopsies were performed by the same pulmonary physician (S.E.O.). The fiberoptic bronchoscope (BF, type P20 D; Olympus; Tokyo, Japan) was introduced orally under local anesthesia. Mucosal biopsy specimens (three to six) were obtained from the segmental carinae and were embedded in a cutting compound (Tissue-Tek II Optimal Cutting Temperature compound; Sakura Finetek USA Inc; Torrance, CA), which was frozen and stored at –80°C.

Immunohistochemistry
Once all biopsy specimens were collected, 6-µm serial tissue sections were cut on a cryostat (model HM-560; Microm; Heidelberg, Germany). At least two sections 120 µm apart from one biopsy specimen were placed on a poly-L-lysine-coated microscopic slide (Sigma Diagnostics; St. Louis, MO). Next, sections were air-dried for 30 min and stored at –80°C until use. Immunostaining was carried out with the following substances: {alpha}-major basic protein (MBP [clone BMK13]) [Sanbio BV; Uden, the Netherlands]; and {alpha}-tryptase (Chemicon Brunschwig Chemie; Temecula, CA).10 The binding of the antibodies was detected by the immunoalkaline phosphatase antialkaline phosphatase method.

Positively stained areas in the lamina propria (depth, 100 µm below the reticular basement membrane) were quantified using an image analysis system (Quantimed; Leica; Rijswijk, the Netherlands). Images were taken at 10 x 10 magnification. A minimum area of 100,000 µm2 was analyzed per immunostaining for a given subject at a given time point. Thresholds for hue, saturation, and intensity of color were set for each immunohistochemical stain, and these were kept constant during the analysis of the entire sample set. This approach allows for a densitometric analysis. The ratio of the positive stained area divided by the total area analyzed was taken as a measure for each immunohistochemical staining. This procedure has been recorded in a standard operating procedure and was performed by at least two independent observers to minimize bias. This method has been validated by Sont et al.11

Statistical Analysis
For differences in efficacy between the two treatment groups, PC20 (log2-transformed), FEV1, and eNO (ln-transformed) were parametrically analyzed using analysis of covariance, with the baseline measurement as the covariate. Mean changes within either treatment group were tested using paired t tests.

For the inflammatory cells and markers, changes from baseline after logarithmic transformation were compared between the two treatment groups using the Mann-Whitney test. Changes within either treatment group were tested using paired Wilcoxon tests after logarithmic transformation. Nonparametric 95% confidence intervals (CIs) were estimated according to the method of Hodges and Lehmann12 for the efficacy ratio between the two treatments. The MBP-positive cells were predetermined to be the primary outcome variable. A significance level of 0.05 was used.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
All subjects who entered the study, completed it (21 men, 19 women; mean age, 28.8 years; age range, 19 to 52 years). Seventeen of 20 patients in each group were atopic. The mean reversibility rate was 16.4%. There were no significant differences for the baseline values between the groups. No adverse events were reported. Prior to the run-in period, patients used a mean dose of 520 µg of ICSs daily; only one patient had not used ICSs prior to inclusion in the study.

Spirometry
In the BUD200 group as well as in the BUD200 + F group, FEV1 (percent predicted) increased significantly after 8 weeks compared to baseline (Table 1 ). The baseline-adjusted mean difference of 3.1% points in change between the BUD200 + F and BUD200 groups was not significant (95% CI, –2.3 to 8.6; p = 0.26) [Table 2 ].


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  		Table 1. Pretreatment and Posttreatment Results in the Two Treatment Groups*

 

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  		Table 2. Point Estimate and 95% CI of the Effect Ratio BUD + F/BUD

 
Increasing BUD200 to BUD800 led to a further significant increase in FEV1, whereas increasing BUD200 + F to BUD800 + F did not produce a further significant change in FEV1. The baseline-adjusted mean difference of –3.1% shows that the difference between the treatments was not significant (95% CI, –7.8 to 1.6; p = 0.19).

Bronchoprovocation
In both the BUD200 group and the BUD200 + F group, the change in the PC20 for MCh after 8 weeks was highly significant. The baseline-adjusted mean difference in the change between the BUD200 + F and BUD200 groups was not significant (p = 0.14). Increasing the daily dose of BUD from 200 to 800 µg did not result in a further change of the mean PC20 for MCh in any of the treatment groups. The mean difference in a change of –0.7 doubling concentration between the treatments was not significant (95% CI, –1.7 to 0.3; p = 0.15).

eNO
eNO decreased significantly in both the BUD200 and the BUD200 + F groups after 8 weeks of treatment. There was no significant difference that was detectable between the two groups (p = 0.58). Increasing the dose of steroids to 800 µg resulted in a significant decrease in eNO in the BUD200 group, while there was no such effect detectable in the BUD200 + F group. There was no significant difference between the two treatment groups after increasing the dose of BUD (p = 0.74) [Fig 1 ].



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  		Figure 1. Percentage of eNO before randomization, after 7 weeks in the first treatment period, and after 7 weeks in the second treatment period. The line represents the median.

 
Bronchial Biopsies
In the epithelium, MBP was significantly reduced in the BUD200 group after 8 weeks of treatment, while this was not the case in the BUD200 + F group (Table 1). The difference in the median change from baseline between the BUD200 and BUD200 + F groups was not significant (p = 0.28).

Increasing the dose of steroids to 800 µg did not significantly change MBP in either of the treatment groups. No significant difference between treatments could be detected after increasing the BUD dose to 800 µg (p = 0.86) [Fig 2 , top, A].



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  		Figure 2. Percentage of epithelium MBP (top, A) and subepithelium MBP (bottom, B) before randomization, after 8 weeks in the first treatment period, and after 8 weeks in the second treatment period. The line represents the median.

 
In the subepithelium, the median MBP decreased significantly in both the BUD200 and the BUD200 + F groups after 8 weeks. The difference in the median change from baseline between the BUD200 and BUD200 + F groups was not significant (p = 0.34). Increasing BUD200 to BUD800 in both groups did not significantly change MBP density within groups or between groups (p = 0.97) [Fig 2, bottom, B).

Concerning mast cells, BUD200 resulted in a significant reduction of tryptase in the epithelium compared to baseline, but it hardly affected tryptase staining in the subepithelium. BUD200 + F resulted in nonsignificant reductions of tryptase staining in both the epithelium and subepithelium compared to baseline (Fig 3 , top, A). No significant differences between treatments were detectable for any of the variables, or after increasing the BUD dose to 800 µg (Fig 3, bottom, B).



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  		Figure 3. Percentage of epithelium tryptase (top, A) and subepithelium tryptase (bottom, B) before randomization, after 8 weeks in the first treatment period, and after 8 weeks in the second treatment period. The line represents the median.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Several authors513 have demonstrated the clinical benefit of adding LA ß2-agonists as maintenance treatment to inhaled ICSs in asthmatic patients. The mechanism by which the addition of LA ß2-agonists leads to better control in asthma has not been fully elucidated yet but may be due to an enhanced antiinflammatory effect.

Both in vitro and in vivo animal data have suggested that LA ß2-agonists have some antiinflammatory effect. An inhibitory effect on the infiltration of inflammatory cells in the skin and lungs of guinea pigs has been demonstrated.1415 It has also been shown that the exudation of plasma from postcapillary venules, which is an important component of acute inflammation, is inhibited by LA ß2-agonists.14 Others have shown1617 additive and synergistic effects on the inflammatory properties of resident pulmonary cells, whereas some authors18 have reported interactions between ß2-agonists and glucocorticoids at the mechanistic level. A synergistic effect of BUD and formoterol was suggested.4 Our results do not support this suggestion, probably because treatment with low-dose BUD alone already resulted in a significant decrease of inflammatory cells in bronchial biopsy specimens accompanied by a significant improvement in lung function. This is underlined by the fact that we could not demonstrate an additional antiinflammatory effect even after quadrupling the ICS dose. We conclude from these findings that our patients with mild asthma who were receiving the low dose of BUD were close to the top of their dose-response curve for ICSs, allowing no room for significant improvement. Also Jatakanon et al19 have reported that treatment with low doses of steroids leads to a significant reduction in the levels of markers of inflammation.

Previously, other investigators13 have demonstrated similar effects of low-dose ICSs in steroid-naïve patients with mild asthma. However, they were able to show13 an additive clinical effect of formoterol in the group of asthma patients receiving low doses of ICSs. In line with this finding, it was demonstrated that the addition of salmeterol resulted in a greater improvement in lung function and symptom control than did doubling the dose of beclomethasone dipropionate.5 Our patients were atopic asthma patients using up to 800 µg of ICSs daily prior to the run-in period during which they were taken off steroid therapy. While not receiving steroids, it is fair to assume that the condition of the airways deteriorated and the inflammation increased at the same time. At the end of the run-in period, the severity of the airway inflammation had reached a level at which a low dose of BUD was sufficient to reduce the airway inflammation to such a degree that no further reduction could be expected.

The Formoterol and Corticosteroids Establishing Therapy study420 looked at the number of exacerbations that occurred during a 12-month study in which formoterol was added to both low-dose and high-dose BUD in patients with asthma. The addition of formoterol decreased the incidence of mild and severe exacerbations in both groups. These studies demonstrated the clinical effects of the addition of an LA ß2-agonist to ICSs. Their findings are in line with those of Zetterstrom et al21 who showed that during the first 30 days of treatment therapy with BUD and formoterol in a single inhaler tended to show more rapid improvement in lung function and symptom score compared to therapy with the same drugs in separate inhalers. It is unclear, however, whether these improvements in lung function were accompanied by a reduction of inflammation.

Only a few authors have investigated the antiinflammatory effect of LA ß2-agonists in humans. In patients with mild asthma, 8 weeks of monotherapy with formoterol significantly reduced the number of submucosal mast cells.22 It has been reported23 that 2 weeks of treatment with formoterol significantly reduced the number of eosinophils (EG2+) in the submucosa and epithelium in patients with mild atopic asthma. Other investigators6 could not confirm such an antiinflammatory effect as measured in induced sputum when they compared 1 year of treatment with formoterol and 200 µg of BUD with 800 µg of BUD. Clinical asthma control was not significantly different between the two groups.

eNO as a noninvasive marker of airway inflammation has been shown2425 to be useful in monitoring disease activity and the effectiveness of antiinflammatory treatment. Although eNO decreased significantly after treatment with both BUD200 and BUD200 + F, we found no differences between the two treatments or after increasing the BUD dose to 800 µg/d, which was in line with the decrease in inflammatory cells in the bronchial mucosa.

In contrast to some other studies, only a limited number of patients could be included in this study due its invasive nature, requiring multiple biopsies within a relatively short period of time. Therefore, a parallel-group design was considered to be a statistically valid approach. Since our main objective was to look at the change in inflammatory marker levels, neither symptom scores nor rescue ß2-agonist medication were recorded by the patients.

In summary, treatment with BUD at a low dose already has significant antiinflammatory effects in the bronchial mucosa of patients with mild asthma. No significant additional antiinflammatory effects (on the inflammatory markers analyzed in this study) could be demonstrated either by adding formoterol or by increasing the dose of BUD.


   Acknowledgements
 
The authors thank the Lung Function Laboratory and coworkers of the Pulmonary Research Department of the Erasmus Medical Center Rotterdam for their valuable participation in this study. The authors thank Dr. Huib Kerstjens for reading the manuscript, and for his constructive suggestions and comments.


   Footnotes
 
Abbreviations: BHR = bronchial hyperreactivity; BUD = budesonide; BUD200 = 100 µg of budesonide bid plus placebo; BUD200 + F = 100 µg of budesonide bid plus 12 µg of formoterol bid; BUD800 = 400 µg of budesonide bid; BUD800 + F = 400 µg of budesonide bid plus 12 µg of formoterol bid; CI = confidence interval; eNO = exhaled nitric oxide; ICS = inhaled corticosteroid; LA = long-acting; MBP = major basic protein; MCh = methacholine; PC20 = provocative concentration of a substance causing a 20% fall in FEV1

All authors have disclosed all pertinent involvement in AstraZeneca, which has a direct financial interest in the subject of the manuscript. This study was supported by AstraZeneca, the Netherlands (study BN-00P-0059).

Received for publication August 5, 2004. Accepted for publication February 14, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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J G Koopmans, R Lutter, H M Jansen, and J S van der Zee
Adding salmeterol to an inhaled corticosteroid: long term effects on bronchial inflammation in asthma
Thorax, April 1, 2006; 61(4): 306 - 313.
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