Citation for published version (APA): Bathoorn, D. (2007). COPD exacerbations, inflammation and treatment s.n.

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1 University of Groningen COPD exacerbations, inflammation and treatment Bathoorn, Derk IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2007 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Bathoorn, D. (2007). COPD exacerbations, inflammation and treatment s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Chapter 6 Anti-inflammatory effects of combined budesonide/formoterol in COPD exacerbations. Erik Bathoorn 1, Jeroen Liesker 1, Dirkje Postma 1, Martin Boorsma2, Eva Bondesson3, Gerard Koëter1, Henk Kauffman4, Antoon van Oosterhout 4 and Huib Kerstjens 1. Groningen Research Institute for Asthma and COPD (GRIAC), Department of Pulmonology 1 and Laboratory of Pulmonology and Allergology 4, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, and AstraZeneca R&D, Zoetermeer, The Netherlands 2 AstraZeneca R&D, Lund, Sweden3. Submitted 93

3 Abstract Systemic corticosteroids and additional short-acting ß2-agonists are commonly used in exacerbations of chronic obstructive pulmonary disease (COPD). In this double-blind study, the combination of a high dose inhaled corticosteroid with a rapid-onset long-acting ß2-agonist was evaluated in the treatment of out-patient COPD exacerbations. The primary aim was to compare 14-day treatment effects of budesonide/formoterol to placebo on sputum eosinophils and, secondarily, on other indices of inflammation, forced expiratory flow in one second (FEV 1 ), symptoms, health status, and adverse events. Forty-five patients not using steroids (37 male, 21/24 current/ex smoker, median packyears 38, age 65 years, FEV1 61% predicted) experiencing a COPD exacerbation were treated at home with 160µg budesonide/ 4.5µg formoterol (2 inhalations q.i.d), prednisolone (30 mg daily), or placebo for 14 days. Sputum eosinophils were significantly reduced by budesonide/formoterol (-57%) compared to placebo (+24%) (p=0.01). Budesonide/formoterol reduced total symptom scores significantly (p=0.01) compared to placebo. The increase in FEV 1 by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p=0.07). Budesonide/formoterol treatment did not suppress morning serum cortisol compared to placebo (-16 %; p=0.50). In conclusion, budesonide/formoterol reduces sputum eosinophils and improves symptoms in the treatment of out-patient COPD exacerbations. This study has been registered at ID: NCT Keywords: budesonide, chronic obstructive pulmonary disease, exacerbation, formoterol inflammation, sputum induction. Introduction Exacerbations of COPD are traditionally treated with systemic corticosteroids and short-acting bronchodilators, with or without antibiotics. The effectiveness of systemic steroids, though used for decades, has only recently become evidence based 1;2. A theoretically alternative treatment of COPD exacerbations, avoiding the use of systemic corticosteroids, is treatment with inhaled corticosteroids 3. Additionally, immediate bronchodilation can also be obtained with the long-acting ß2-agonist formoterol due to its fast onset of action. This is an attractive option, since patients who already use combined inhaled corticosteroids and long-acting ß2-agonists as maintenance therapy, such as budesonide/formoterol could increase their daily dose when they are experiencing early signs of an exacerbation, thereby possibly preventing a full blown exacerbation. Such a treatment approach has been shown to be effective 94

4 in the treatment of asthma 4. Thus far, the treatment of mild to moderate COPD exacerbations with an inhaled corticosteroid and a long acting ß2-agonist combined has not been tested in a randomised controlled trial. The combination has proven efficacy in preventing exacerbations of COPD 5;6. Steroids are thought to exert their beneficial effect on exacerbations of COPD through their anti-inflammatory properties. Effects of systemic steroids on inflammation during exacerbations have not been reported, although some studies document changes in stable phase COPD 7;8, effects that are also observed with inhaled steroids Effects of ß2-agonists depend largely on their bronchodilating properties. There are no data of anti-inflammatory effects of ß2-agonists in COPD, but in asthma anti-inflammatory properties have been described 13;14. Although inflammation assessed in sputum in stable phase of COPD is mainly of neutrophilic origin, several studies have indicated that sputum eosinophils are increased during COPD exacerbations 15;16. Furthermore sputum eosinophilia predicts a better response to a short-term steroid treatment in a stable phase of COPD We hypothesised that the clinical response to steroids in COPD exacerbations is due to the suppressive effect on the eosinophilic inflammatory component and therefore designated this cell as the primary efficacy endpoint to assess inflammatory treatment effects. We examined whether a combination therapy with an inhaled corticosteroid and long-acting ß2-agonist, i.e. budesonide and formoterol (B/F), as available in a single inhaler would reduce inflammation and especially the eosinophilic component occurring during exacerbations, more effectively than placebo (PLAC). We estimated that documentation of effects on clinical parameters would require more patients and therefore pre-defined these parameters as secondary outcomes only. Some of the results of this study have been previously reported in the form of an abstract 20;21. Methods Subjects Inclusion criteria for the study were: diagnosis of COPD, age >40 years, postbronchodilator FEV 1 <85% predicted but >0.7 liters, and an abnormal postbronchodilator FEV 1 /slow inspiratory vital capacity (VC) (<88% predicted in men and <89% predicted in women) 22. Patients were not allowed to use oral corticosteroids, longacting anticholinergics, beta-blockers, or oxygen therapy, or have a history of asthma or significant other disease that could influence the results of the study. The study was performed in accordance with the principles stated in the Declaration of Helsinki. The local medical ethics committee approved the study. Written informed consent was obtained from all patients. 95

5 Study design At the inclusion visit, inhaled corticosteroids were discontinued if used. After this visit, the subjects had to be stable during a run-in period of 2 months. After the wash-out period, spirometry was performed followed by a sputum induction procedure, and long-acting ß2-agonists were withdrawn. Patients contacted the research facility if they experienced an exacerbation, as defined according to Davies 23 : a history of increased breathlessness and at least two of the following symptoms for =24 hours: increased cough frequency or severity, sputum volume or purulence, and wheeze. When presenting with an exacerbation, and provided that postbronchodilator FEV 1 < 70 % predicted and PaO 2 > 8.0 kpa, patients were randomised to a):160µg budesonide/ 4.5µg formoterol (Symbicort Turbuhaler, AstraZeneca Sweden), 2 inhalations q.i.d., b): 30 mg prednisolone (AstraZeneca) as 6 tablets of 5 mg once daily, or c): placebo tablets and inhalations, in a double dummy set-up, for 14 days. Inhalation technique was practised until satisfactory. All patients received a standard dose of doxycyclin, and inhaled terbutaline and ipratropium bromide as needed. For the allocation to randomised treatment we used sputum eosinophils (< or = 3%), FEV 1 at exacerbation (< or = 50% of predicted), smoking status (current or ex), inhaled corticosteroid and N-acetyl-cysteine use at start of study as stratification factors in a minimization process (see online supplement for details on randomisation process). Measurements At randomization, and at day 3, 7, and 14, induced sputum, blood, and urine were collected, an electrocardiogram was made and heart rate, weight, blood pressure, and lung function were measured. Patients recorded morning and evening symptoms of breathlessness, sputum, and cough daily in a diary in the last 2 weeks of the wash-out period and during 2 weeks after randomisation 24. Patients filled in the Clinical COPD Questionnaire (CCQ) at each visit, and the Clinical Respiratory Questionnaire at baseline and at the and of treatment 25. FEV 1, VC, forced vital capacity (FVC), and specific airways conductance (sgaw) (Masterscreen Bodybox, Jäeger, Würzburg, Germany) were measured according to guidelines of the European Respiratory Society 22. Sputum induction and processing Sputum was induced by standard methods 26, with modifications according to Pizzichini when the FEV1 was <1.5 liters 27. Messenger Ribonucleic Acid (mrna) processing by real-time polymerase chain reaction and other methods are described in the online supplement. 96

6 Statistical analysis The primary endpoint was the change in % sputum eosinophils defined as the ratio of the % eosinophils at day 14 to the % eosinophils of the randomisation visit (day 1). Using GAUSS from Aptech systems inc. (kernel revision ), ratios were compared in a multiplicative analysis of variances model with the value of the randomisation visit included as a covariate. Pairwise treatment ratios and 95% confidence intervals were compared in the model using contrast. Secondary endpoints were analysed using similar methods. Power calculation was based on the change in eosinophils by steroid treatment in stable COPD in a previous study, demonstrating a change in eosinophils of 1.5% (see online supplement). Figure 1: Flow chart. B/F= Budesonide/ Formoterol; PRED= Prednisolone; PLAC= Placebo 97

7 Results Subjects In the study 114 patients were recruited, of whom 45 patients reported an exacerbation after the run-in period and were randomised (figure 1). The baseline characteristics of the randomised patients are presented in table 1. Two patients were withdrawn due to treatment failure (1 in the placebo group after 1 day and 1 in the B/F group after 7 days of treatment) The other 43 patients all completed the 2 weeks of randomised double-blind treatment. Table 1. Patient characteristics budesonide/formoterol prednisolone placebo Number of patients Sex (male/female) 10/5 13/2 14/1 Age (years) 61.4 (8.0) 64.8 (7.0) 64.6 (9.1) Smoking status, current/ex 6/9 8/7 7/8 Packyears 39 (28-75) 38 (30-48) 32 (19-49) Body mass index (kg/m2) 25.7 (4.3) 25.7 (3.8) 25.1 (3.1) FEV1 (% predicted), at 63.5 (13.0) 60.2 (14.4) 57.4 (12.7) enrolment FEV 1 (% ) at exacerbation 54.1 (14.3) 52.6 (16.0) 49.6 (13.4) FEV 1 /VC at enrolment 46.8 (10.1) 43.8 (12.6) 45.5 (10.4) FEV 1 /VC at exacerbation. 41 (11) 38 (10.5) 38 (8.5) Reversibility (% predicted) 8.9 (4.6) 7.7 (6.4) 9.8 (6.5) Data as actual numbers or as mean (sd). : median (interquartile range). One patient in the placebo group needed open label treatment at day 2; data of the remaining 44 patients were used for analysis. Reversibility was measured after 2 months inhaled steroid withdrawal. Inflammatory cells Treatment with B/F and PRED elicited a significant decrease versus placebo in the percentage sputum eosinophils (figure 2): the mean reduction after 2 weeks 98

8 was 57% for B/F compared to an increase with 24% for placebo (p=0.01) and a reduction of 58% for PRED (p=0.007 versus placebo). No difference between the two active treatments was found, nor were there any significant differences in the other sputum cell differential counts or in the total cell counts between the treatment groups (table 2). Blood eosinophil counts were not affected by either of the two active treatments. PRED treatment resulted in an increase in blood leucocyte count (mean change 3.1x 10 9 /L and blood neutrophils (mean change 1.91 x10 9 /L) which was significantly different from PLAC (p<0.001 and p=0.01 respectively). Table 2. Sputum cells budesonide/formoterol prednisolone placebo Total cells (x106/ml) day (183) 16.5 (355) 7.0 (165) Total cells (x10 6 ml) day (153) 11.4 (749) 4.3 (178) Eosinophil % day (377) 2.0 (163) 2.4 (186) Eosinophil % day (234)* 0.8 (200) 3.5 (97) Eosinophil (x10 6 /ml) day (281) 0.32 (686) 0.21 (280) Eosinophil (x106/ml) day (847)* 0.09 (1274) 0.19 (204) Neutrophils % day (26) 80.6 (12) 67.1 (22) Neutrophils % day (24) 80.5 (11) 68.1 (12) Macrophages % day (63) 12.1 (39) 17.8 (87) Macrophages % day (50) 13.0 (58) 21.5 (48) Lymphocytes % day (91) 0.6 (86) 0.7 (138) Lymphocytes % day (120) 0.8 (75) 0.4 (81) Data presented as geometric mean and coefficient of variation (sd/mean x 100%). *: p<0.05 budesonide/formoterol vs placebo. : p<0.05 prednisolone vs placebo. P-values for comparisons of the ratio at day 14 to day 1 under budesonide/formoterol (320/9 µg 4 times daily) versus prednisolone (30 mg once daily) and placebo. 99

9 Figure 2: Treatment effect on sputum eosinophil%. * On day 3, 7, and 14, the ratio of sputum eosinophil % of the visit under study to the eosinophil% at randomisation are presented. The difference in ratios from start to end of treatment are significant for budesonide/formoterol versus placebo (p=0.01) and for prednisolone versus placebo (p=0.007). Data is expressed as geometric means. P-values for comparisons of these ratios at day 14 under budesonide/formoterol (320/9 µg 4 times daily) versus prednisolone (30 mg once daily) and placebo. Sputum mrna The Ct-values of the mrna expression are shown in table 3. B/F treatment resulted in a significantly larger decrease in interleukin-5 (IL-5) expression compared to placebo (p=0.02). PRED treatment resulted in a smaller increase in expression of heme oxygenase-1 (HO-1) compared to B/F (p=0.02) and in a smaller increase in the expression of transforming growth factor- ß (TGF-ß) mrna compared to PLAC (p=0.045). Lung function The change in FEV 1 is shown in figure 2. FEV 1 improved during the treatment period in all three groups. The increase in FEV 1 by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p=0.07). With PRED the FEV 1 improved 27 ml (p=0.71 versus placebo). There were no significant differences in the effects of B/F or prednisolone versus placebo after 2 weeks on other lung function parameters (table 4). 100

10 Table 3. mrna expression of sputum cells budesonide/formoterol prednisolone placebo mrna HO-1, 0.5*10 6 day (4.2) (3.1) (3.9) mrna HO-1, 0.5*106 day (5.5) (3.3) (3.3) mrna TNF-a, 0.5*106 day (4.3) (4.8) (3.7) mrna TNF-a, 0.5* (5.4) (4.9) (3.7) day 14 mrna TGF-ß, Ct day (6.1) (3.4) (3.3) mrna TGF-ß, Ct day (4.0) (3.2) (4.2) mrna INF-gamma, Ct day (6.0) (9.3) (8.5) mrna INF-gamma, Ct day (6.8) (9.3) (8.3) mrna IL-10, Ct day (5.2) (3.8) (2.6) mrna IL-10, Ct day (10.5) (4.6) (4.2) mrna IL-12a, Ct day (10.9) (9.3) (9.2) mrna IL-12a, Ct day (11.5) (6.7) (11.1) mrna IL-12b, Ct day (10.5) (6.6) (5.2) mrna IL-12b, Ct day (4.6) (8.3) (6.4) mrna IL-5, Ct day (11.1) (8.6) (14.0) mrna IL-5, Ct day (5.9)* (8.6) (10.0) mrna IL-13, Ct day (11.2) (10.3) (10.6) mrna IL-13, Ct day (7.9) (10.3) (8.7) mrna CCL5, Ct day (7.2) (2.9) (3.9) mrna CCL5, Ct day (3.7) (3.4) (2.4) mrna expression of sputum cells. The Ct-values at end of treatment minus the values at start of treatment are presented. Data presented as geometric mean and coefficient of variation (sd/mean x 100%). *: p<0.05 budesonide/formoterol vs placebo. : p<0.05 prednisolone vs placebo. : p<0.05 budesonide/formoterol vs prednisolone. Lower Ct-values correspond with higher mrna expression. Ct-values are normalised for ß2-microglobulin expression. *: P-values for comparisons of the ratio at day 14 to day 1 under budesonide/formoterol (320/9 µg 4 times daily) versus prednisolone (30 mg once daily) and placebo. HO-1= heme ogygenase-1 101

11 Symptoms and health status During both B/F and PRED treatment periods, significantly lower total symptom scores in the diaries were observed compared to the treatment period with PLAC (mean difference and respectively; p<0.01, p=0.048). B/F treatment resulted also in lower cough symptom score compared to PLAC (mean difference -0.62, p=0.015). There were trends towards lower sputum production scores under both B/F and PRED compared to PLAC (mean differences 0.38 and 0.39 respectively, p=0.066 and p=0.058). The overall health status as measured by the CCQ did not differ significantly between B/F and PLAC (mean change 1.0 and 0.5 points, respectively: p=0.08) (figure 4). However, the improvement in overall health status with B/F was significantly greater compared to that with PRED (mean change 0.4 points, p=0.02). The minimal clinical important difference of the CCQ is a change of 0.4 points 28. The health status measured by the CRQ showed similar results (mean change B/F 0.47 and placebo 0.004, p=0.07; mean change PRED 0.06, p=0.04 versus B/F). Figure 3: Treatment effect on FEV 1 * On day 3, 7, and 14, the ratio of FEV 1 of the visit under study to the FEV 1 at randomisation are presented. Data is expressed as geometric means. P-values for comparisons of these ratios at day 14 under budesonide/formoterol (320/9 µg 4 times daily) versus prednisolone (30 mg once daily) and placebo 102

12 Figure 4: Treatment effect on Clinical COPD Questionnaire *On day 3, 7, and 14, the difference of CCQ-score of the visit under study from the CCQ-score at randomisation are presented. The difference in means from start to end of treatment are significant for budesonide/formoterol versus prednisolone (p=0.02) Data is expressed as means. P-values for comparisons of the arithmetic mean changes at day 14 under budesonide/formoterol (320/9 µg 4 times daily) versus prednisolone (30 mg once daily) and placebo Adverse events and safety No serious adverse events occurred during study treatment. One serious adverse event (operation for a sinus maxillaris cyst) was reported during the three months follow-up period. Eighteen patients had a treatment failure (defined as need for open label COPD treatment in the first 3 weeks after start of study treatment) or relapse (defined as need for open label COPD treatment from 3 weeks to 3 months after start of treatment) in the 3 months after start of treatment (7 in B/F, 7 in PRED, 4 in the PLAC treatment arm). No hospitalisations for respiratory symptoms were required. Furthermore there were no different patterns between the treatment groups in adverse events, characteristics on electrocardiograms, or blood pressure and heart rate, though under PRED QRS duration decreased compared to PLAC(-2.7 ms versus +3.6 ms, p=0.0048). B/F treatment did not significantly suppress serum cortisol compared to placebo (mean 16% lower p=0.50). By contrast, the PRED treatment did suppress serum cortisol levels significantly versus placebo (mean 45% lower; p=0.03). There were no significant differences in the changes in the serum glucose levels between the groups. The decrease in serum potassium 103

13 under PRED (-0.29 mmol/l) differed significantly form the increase under PLAC (+0.03 mmol/l, p=0.03). Table 4. Lung function parameters budesonide/formoterol prednisolone placebo FEV1 (L), day (36) 1.57 (28) 1.45 (26) FEV 1, (L), day (35) 1.61 (30) 1.50 (23) IVC, (L) day (27) 4.27 (25) 3.83 (20) IVC, (L) day (25) 4.31 (20) 3.74 (21) FEV 1 /VC (%) day 1 40 (27) 37 (26) 38 (24) FEV1 /VC (%) day (27) 37 (29) 41 (16) sgaw, (kpa/l/s) day (43) 0.62 (49) 0.62 (44) sgaw, (kpa/l/s) day (50) 0.67 (42) 0.76 (49) Lung function parameters. Data is expressed as geometric mean and coefficient of variation (sd/mean x 100%). All differences p>0.05. pred= predicted. p-values for comparisons of the ratio at day 14 to day 1 under budesonide/formoterol (320/9 µg 4 times daily) versus prednisolone (30 mg once daily) and placebo. Discussion Treatment of COPD exacerbations with high dose budesonide/formoterol (B/F) significantly reduced sputum eosinophils compared to placebo. This reduction in airway inflammation was accompanied by an improvement in symptoms. Prednisolone (PRED) treatment also reduced airway inflammation and symptoms. In contrast to B/F, PRED significantly suppressed plasma cortisol levels. Several studies have reported that eosinophils increase during COPD exacerbations, both in airway biopsies and in induced sputum 15;16;29. Although the effects of steroids (inhaled or oral) on inflammation during exacerbations had not been previously studied, several studies have assessed the effects of corticosteroids on inflammation in stable COPD. Gan et al performed a meta-analysis of the effects of inhaled steroids in the stable phase of COPD, showing a trend towards reducing eosinophil counts in the sputum of stable COPD patients 30. In a recent study, treatment of stable COPD with inhaled salmeterol/ fluticasone propionate also reduced sputum eosinophil counts 31. To evaluate the potential effects of corticosteroids on airway inflammation, we measured the sputum cell mrna expression of several cytokines that play a role in the attraction/survival of eosinophils, our primary endpoint, or may 104

14 contribute to the induction and resolution of COPD exacerbations. We found a larger decrease in IL-5 expression with B/F compared to placebo. Since IL-5 is involved in eosinophil growth and differentiation, this reduction fits well with the reduction in sputum eosinophils 32. Under placebo treatment a larger increase from day 1 to day 14 was observed in expression of TGF- ß compared to PRED and similar trends, though not significant, compared to B/F. This increase under placebo may signify an increased inflammation and tissue damage due to the lack of anti-inflammatory treatment. We do not have an explanation for the smaller increase in HO-1 expression under PRED compared to B/F. We would have expected a decreased expression by both the active treatments, since HO-1 is a stress inducible enzyme, and we would have expected a decrease in stress stimuli by treatment due to a reduction in inflammation. Perhaps this effect has been confounded by other stress factors such as smoking. The beneficial effects of steroid treatment on parameters of inflammation were accompanied by improvements in clinical symptoms. The total symptom scores as recorded in the daily diaries were better under both B/F and the PRED treatment, with a significant improvement in cough for B/F and trends in improvement in sputum production under both B/F and PRED treatment. This study is the first to use an airway inflammatory parameter as the major endpoint for treatment efficacy in exacerbations of COPD. A few randomised controlled trials used clinical endpoints to asses the effects of oral prednisolone on COPD exacerbations 1;2;33;34, and a meta-analysis concluded that it reduces treatment failure and the need for additional treatment, and increases the rate of improvement in lung function and dyspnea over the first 72 hours 35. Maltais et al showed beneficial effects of inhaled budesonide 3, comparing 2mg nebulised budesonide every 6 hours and 30mg oral prednisolone every 12 hours, and both treatments improved airflow limitation when compared with placebo. Although we did not show a statistically significant effect on airflow limitation between the three groups in our study, a trend was found in the comparison between B/F and PLAC (see figure 2, p= 0.07). The lack of significance is likely due to the smaller patient numbers in our study (45 versus 199) since the magnitude of improvement in FEV1 was similar (125 ml versus 100 ml). Our study sample size was based on power calculations with changes in eosinophil percentage as primary end point. Another difference between the studies is the time point of evaluation, i.e. in our study at 2 weeks after randomisation, versus 72 hours in Maltais' study. A great advantage of B/F therapy above PRED should be the avoidance, or at least a reduction, of systemic side effects. Several studies have shown that inhaled corticosteroids have fewer side effects compared to oral corticosteroids. Morice et al investigated the side effects of nebulised budesonide (2 mg twice daily) with oral prednisolone (30 mg at once daily) in the treatment of COPD-exacerbations. They found that prednisolone treatment resulted in lower urinary corticosteroid metabolites, and lower serum osteocalcin than inhaled treatment 36. In our study we investigated serum cortisol levels. We found that 105

15 there was no significant suppression of serum cortisol by B/F treatment compared to placebo. PRED treatment did suppress serum cortisol levels as expected and this aspect favours the treatment with B/F over prednisolone. Our study was not powered to assess equality of clinical effects of the two active treatment arms. Such a non-inferiority trial would require more patients. Any lack of difference in statistical terms between B/F and PRED in the present study could therefore be due to a type 2 error and should not be interpreted to signify equal or similar effects. Nevertheless, since all parameters favoured B/F over PRED, there was no indication of inferiority of B/F versus prednisolone in this setting. The use of B/F for the treatment of mild to moderate exacerbations of COPD at home improved both inflammation and symptoms and was well tolerated. Whether B/F treatment is as effective as PRED and is to be favoured B/F over PRED because of less side effects, will require larger-scale efficacy studies. An interesting option is the possibility to treat exacerbations at home in an earlier stage of an evolving exacerbation by B/F, as was recently demonstrated to be effective in the treatment of asthma 4. Whether this earlier institution of effective therapy could also prevent in COPD the development of full-blown exacerbations and thereby hospitalisations is an interesting option that should be studied in future studies. We conclude that sputum eosinophils and symptoms of patients with mild to moderate COPD exacerbations can be improved by a 2-week treatment with 160 µg budesonide/ 4.5 µg formoterol, 2 doses q.i.d., compared to placebo. A next study should aim to establish whether treatment of exacerbations at home with budesonide/formoterol can replace traditional treatment with oral corticosteroids Acknowledgements The authors thank Ibolya Sloots, Brigitte Dijkhuizen, Koos van de Belt, and Janneke Heimweg for all sputum measurements, Marco van der Toorn for the mrna measurements, the lung function department for the many lung function measurements, and Alec Ross for the cortisol measurements (UMC St. Radboud, Nijmegen). 106

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