university of groningen copd exacerbations, inflammation and … · 2016-03-06 · chapter 6...

University of Groningen

COPD exacerbations, inflammation and treatmentBathoorn, Derk

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher'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.

CopyrightOther 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 theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 16-02-2020

https://www.rug.nl/research/portal/en/publications/copd-exacerbations-inflammation-and-treatment(fff05b5b-92c1-4733-912f-270ce14e54bc).html

https://www.rug.nl/research/portal/en/persons/erik-bathoorn(1a538449-e323-44ef-aed0-0160435b4d66).html

https://www.rug.nl/research/portal/en/publications/copd-exacerbations-inflammation-and-treatment(fff05b5b-92c1-4733-912f-270ce14e54bc).html

Chapter 6

Anti-inflammatory effects of combinedbudesonide/formoterol in COPD exacerbations.

Erik Bathoorn1, Jeroen Liesker1, Dirkje Postma1, MartinBoorsma2, Eva Bondesson3, Gerard Koëter1, Henk Kauffman4,Antoon van Oosterhout4 and Huib Kerstjens1.

Groningen Research Institute for Asthma and COPD (GRIAC),Department of Pulmonology1 and Laboratory of Pulmonology andAllergology4, University Medical Center Groningen, University ofGroningen, Groningen, the Netherlands, and AstraZeneca R&D,Zoetermeer, The Netherlands2 AstraZeneca R&D, Lund,Sweden3.

Submitted

93

Abstract

Systemic corticosteroids and additional short-acting ß2-agonists are commonlyused in exacerbations of chronic obstructive pulmonary disease (COPD). In thisdouble-blind study, the combination of a high dose inhaled corticosteroid with arapid-onset long-acting ß2-agonist was evaluated in the treatment of out-patientCOPD exacerbations.The primary aim was to compare 14-day treatment effects ofbudesonide/formoterol to placebo on sputum eosinophils and, secondarily, onother indices of inflammation, forced expiratory flow in one second (FEV1),symptoms, health status, and adverse events.Forty-five patients not using steroids (37 male, 21/24 current/ex smoker, medianpackyears 38, age 65 years, FEV1 61% predicted) experiencing a COPDexacerbation were treated at home with 160µg budesonide/ 4.5µg formoterol (2inhalations 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 totalsymptom scores significantly (p=0.01) compared to placebo. The increase inFEV1 by 2 weeks of treatment with budesonide/formoterol (125 ml) was notsignificantly different from that of placebo (43 ml) (p=0.07).Budesonide/formoterol treatment did not suppress morning serum cortisolcompared to placebo (-16 %; p=0.50).In conclusion, budesonide/formoterol reduces sputum eosinophils and improvessymptoms in the treatment of out-patient COPD exacerbations.

This study has been registered at http://www.clinicaltrials.gov, ID:NCT00239278.

Keywords: budesonide, chronic obstructive pulmonary disease, exacerbation,formoterol inflammation, sputum induction.

Introduction

Exacerbations of COPD are traditionally treated with systemic corticosteroidsand short-acting bronchodilators, with or without antibiotics. The effectiveness ofsystemic steroids, though used for decades, has only recently become“evidence based” 1;2. A theoretically alternative treatment of COPDexacerbations, avoiding the use of systemic corticosteroids, is treatment withinhaled corticosteroids 3. Additionally, immediate bronchodilation can also beobtained with the long-acting ß2-agonist formoterol due to its fast onset ofaction. This is an attractive option, since patients who already use combinedinhaled corticosteroids and long-acting ß2-agonists as maintenance therapy,such as budesonide/formoterol could increase their daily dose when they areexperiencing early signs of an exacerbation, thereby possibly preventing a fullblown exacerbation. Such a treatment approach has been shown to be effective

94

Anti-inflammatory effects of combined budesonide/formoterol in COPD exacerbations

in the treatment of asthma 4. Thus far, the treatment of mild to moderate COPDexacerbations with an inhaled corticosteroid and a long acting ß2-agonistcombined has not been tested in a randomised controlled trial. The combinationhas proven efficacy in preventing exacerbations of COPD 5;6.

Steroids are thought to exert their beneficial effect on exacerbations of COPDthrough their anti-inflammatory properties. Effects of systemic steroids oninflammation during exacerbations have not been reported, although somestudies document changes in stable phase COPD 7;8, effects that are alsoobserved with inhaled steroids 9-12. Effects of ß2-agonists depend largely ontheir bronchodilating properties. There are no data of anti-inflammatory effectsof ß2-agonists in COPD, but in asthma anti-inflammatory properties have beendescribed 13;14. Although inflammation assessed in sputum in stable phase ofCOPD is mainly of neutrophilic origin, several studies have indicated thatsputum eosinophils are increased during COPD exacerbations 15;16.Furthermore sputum eosinophilia predicts a better response to a short-termsteroid treatment in a stable phase of COPD 17-19. We hypothesised that theclinical response to steroids in COPD exacerbations is due to the suppressiveeffect on the eosinophilic inflammatory component and therefore designated thiscell as the primary efficacy endpoint to assess inflammatory treatment effects.

We examined whether a combination therapy with an inhaled corticosteroid andlong-acting ß2-agonist, i.e. budesonide and formoterol (B/F), as available in asingle inhaler would reduce inflammation and especially the eosinophiliccomponent occurring during exacerbations, more effectively than placebo(PLAC). We estimated that documentation of effects on clinical parameterswould require more patients and therefore pre-defined these parameters assecondary outcomes only.

Some of the results of this study have been previously reported in the form of anabstract 20;21.

Methods

Subjects

Inclusion criteria for the study were: diagnosis of COPD, age >40 years,postbronchodilator FEV1 <85% predicted but >0.7 liters, and an abnormalpostbronchodilator FEV1/slow inspiratory vital capacity (VC) (<88% predicted inmen and <89% predicted in women) 22. Patients were not allowed to use oralcorticosteroids, longacting anticholinergics, beta-blockers, or oxygen therapy, orhave a history of asthma or significant other disease that could influence theresults of the study. The study was performed in accordance with the principlesstated in the Declaration of Helsinki. The local medical ethics committeeapproved the study. Written informed consent was obtained from all patients.

95


Study design

At the inclusion visit, inhaled corticosteroids were discontinued if used. After thisvisit, the subjects had to be stable during a run-in period of 2 months. After thewash-out period, spirometry was performed followed by a sputum inductionprocedure, and long-acting ß2-agonists were withdrawn. Patients contacted theresearch facility if they experienced an exacerbation, as defined according toDavies 23: a history of increased breathlessness and at least two of the followingsymptoms for =24 hours: increased cough frequency or severity, sputum volumeor purulence, and wheeze. When presenting with an exacerbation, and providedthat postbronchodilator FEV1 < 70 % predicted and PaO2 > 8.0 kPa, patientswere randomised to a):160µg budesonide/ 4.5µg formoterol (SymbicortTurbuhaler®, AstraZeneca Sweden), 2 inhalations q.i.d., b): 30 mg prednisolone(AstraZeneca) as 6 tablets of 5 mg once daily, or c): placebo tablets andinhalations, in a double dummy set-up, for 14 days. Inhalation technique waspractised until satisfactory. All patients received a standard dose of doxycyclin,and inhaled terbutaline and ipratropium bromide as needed. For the allocation torandomised treatment we used sputum eosinophils (< or = 3%), FEV1 atexacerbation (< or = 50% of predicted), smoking status (current or ex), inhaledcorticosteroid and N-acetyl-cysteine use at start of study as stratification factorsin a minimization process (see online supplement for details on randomisationprocess).

Measurements

At randomization, and at day 3, 7, and 14, induced sputum, blood, and urinewere collected, an electrocardiogram was made and heart rate, weight, bloodpressure, and lung function were measured. Patients recorded morning andevening symptoms of breathlessness, sputum, and cough daily in a diary in thelast 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 theClinical Respiratory Questionnaire at baseline and at the and of treatment 25.FEV1, VC, forced vital capacity (FVC), and specific airways conductance (sGaw)(Masterscreen Bodybox, Jäeger, Würzburg, Germany) were measuredaccording to guidelines of the European Respiratory Society 22.

Sputum induction and processing

Sputum was induced by standard methods 26, with modifications according toPizzichini when the FEV1 was <1.5 liters 27. Messenger Ribonucleic Acid(mRNA) processing by real-time polymerase chain reaction and other methodsare described in the online supplement.

96


Statistical analysisThe primary endpoint was the change in % sputum eosinophils defined as theratio of the % eosinophils at day 14 to the % eosinophils of the randomisationvisit (day 1). Using GAUSS from Aptech systems inc. (kernel revision 6.0.48),ratios were compared in a multiplicative analysis of variances model with thevalue of the randomisation visit included as a covariate. Pairwise treatmentratios and 95% confidence intervals were compared in the model using contrast.Secondary endpoints were analysed using similar methods. Power calculationwas based on the change in eosinophils by steroid treatment in stable COPD ina previous study, demonstrating a change in eosinophils of 1.5% (see onlinesupplement).

Figure 1: Flow chart. B/F= Budesonide/ Formoterol; PRED= Prednisolone; PLAC= Placebo

97


Results

Subjects

In the study 114 patients were recruited, of whom 45 patients reported anexacerbation after the run-in period and were randomised (figure 1). Thebaseline characteristics of the randomised patients are presented in table 1.Two patients were withdrawn due to treatment failure (1 in the placebo groupafter 1 day and 1 in the B/F group after 7 days of treatment) The other 43patients all completed the 2 weeks of randomised double-blind treatment.

Table 1. Patient characteristics____________________________________________________________________________

budesonide/formoterol prednisolone placebo

Number of patients 15 15 15

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), atenrolment

63.5 (13.0) 60.2 (14.4) 57.4 (12.7)

FEV1 (% ) at exacerbation 54.1 (14.3) 52.6 (16.0) 49.6 (13.4)

FEV1/VC at enrolment 46.8 (10.1) 43.8 (12.6) 45.5 (10.4)

FEV1/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 theplacebo group needed open label treatment at day 2; data of the remaining 44 patients wereused 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 inthe percentage sputum eosinophils (figure 2): the mean reduction after 2 weeks

98


was 57% for B/F compared to an increase with 24% for placebo (p=0.01) and areduction of 58% for PRED (p=0.007 versus placebo). No difference betweenthe two active treatments was found, nor were there any significant differencesin the other sputum cell differential counts or in the total cell counts between thetreatment groups (table 2). Blood eosinophil counts were not affected by eitherof the two active treatments. PRED treatment resulted in an increase in bloodleucocyte count (mean change 3.1x 109/L and blood neutrophils (mean change1.91 x109/L) which was significantly different from PLAC (p<0.001 and p=0.01respectively).

Table 2. Sputum cells


Total cells (x106/mL) day 1 7.9 (183) 16.5 (355) 7.0 (165)

Total cells (x106 mL) day 14 4.0 (153) 11.4 (749) 4.3 (178)

Eosinophil % day 1 2.6 (377) 2.0 (163) 2.4 (186)Eosinophil % day 14 0.9 (234)* 0.8 (200) † 3.5 (97)

Eosinophil (x106 /mL) day 1 0.21 (281) 0.32 (686) 0.21 (280)

Eosinophil (x106/mL) day 14 0.03 (847)* 0.09 (1274) 0.19 (204)

Neutrophils % day 1 66.3 (26) 80.6 (12) 67.1 (22)Neutrophils % day 14 69.9 (24) 80.5 (11) 68.1 (12)Macrophages % day 1 17.2 (63) 12.1 (39) 17.8 (87)Macrophages % day 14 18.6 (50) 13.0 (58) 21.5 (48)Lymphocytes % day 1 1.0 (91) 0.6 (86) 0.7 (138)

Lymphocytes % day 14 0.7(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 forcomparisons 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


Figure 2: Treatment effect on sputum eosinophil%. * On day 3, 7, and 14, the ratio of sputumeosinophil % of the visit under study to the eosinophil% at randomisation are presented. Thedifference in ratios from start to end of treatment are significant for budesonide/formoterol versusplacebo (p=0.01) and for prednisolone versus placebo (p=0.007). Data is expressed as geometricmeans. P-values for comparisons of these ratios at day 14 under budesonide/formoterol (320/9 µg4 times daily) versus prednisolone (30 mg once daily) and placebo.

Sputum mRNAThe Ct-values of the mRNA expression are shown in table 3. B/F treatmentresulted in a significantly larger decrease in interleukin-5 (IL-5) expressioncompared to placebo (p=0.02). PRED treatment resulted in a smaller increase inexpression of heme oxygenase-1 (HO-1) compared to B/F (p=0.02) and in asmaller increase in the expression of transforming growth factor- ß (TGF-ß)mRNA compared to PLAC (p=0.045).

Lung functionThe change in FEV1 is shown in figure 2. FEV1 improved during the treatmentperiod in all three groups. The increase in FEV1 by 2 weeks of treatment withbudesonide/formoterol (125 ml) was not significantly different from that ofplacebo (43 ml) (p=0.07). With PRED the FEV1 improved 27 ml (p=0.71 versusplacebo). There were no significant differences in the effects of B/F orprednisolone versus placebo after 2 weeks on other lung function parameters(table 4).

100


Table 3. mRNA expression of sputum cells


mRNA HO-1, 0.5*106 day 1 25.23 (4.2) 26.27 (3.1) 25.48 (3.9)

mRNA HO-1, 0.5*106 day 14 24.97 (5.5) 26.02 (3.3) ‡ 24.97 (3.3)

mRNA TNF-a, 0.5*106 day 1 26.80 (4.3) 25.77 (4.8) 26.27 (3.7)

mRNA TNF-a, 0.5*106day 14

26.83 (5.4) 26.05 (4.9) 26.45 (3.7)

mRNA TGF-ß, Ct day 1 25.52 (6.1) 25.41 (3.4) 24.96 (3.3)

mRNA TGF-ß, Ct day 14 24.97 (4.0) 25.23 (3.2) † 24.35 (4.2)

mRNA INF-gamma, Ct day 1 33.02 (6.0) 34.27 (9.3) 33.67 (8.5)

mRNA INF-gamma, Ct day14

33.59 (6.8) 34.78 (9.3) 34.31 (8.3)

mRNA IL-10, Ct day 1 31.09 (5.2) 29.98 (3.8) 30.14 (2.6)

mRNA IL-10, Ct day 14 31.22 (10.5) 29.66 (4.6) 30.20 (4.2)

mRNA IL-12a, Ct day 1 37.81 (10.9) 40.43 (9.3) 39.05 (9.2)

mRNA IL-12a, Ct day 14 38.20 (11.5) 40.26 (6.7) 38.31 (11.1)

mRNA IL-12b, Ct day 1 39.27 (10.5) 36.99 (6.6) 41.85 (5.2)

mRNA IL-12b, Ct day 14 41.08 (4.6) 38.97 (8.3) 40.75 (6.4)

mRNA IL-5, Ct day 1 35.89 (11.1) 38.61 (8.6) 37.77 (14.0)

mRNA IL-5, Ct day 14 40.44 (5.9)* 37.70 (8.6) 38.69 (10.0)

mRNA IL-13, Ct day 1 35.89 (11.2) 38.02 (10.3) 37.04 (10.6)

mRNA IL-13, Ct day 14 39.68 (7.9) 38.06 (10.3) 37.50 (8.7)

mRNA CCL5, Ct day 1 29.34 (7.2) 28.85 (2.9) 28.25 (3.9)

mRNA CCL5, Ct day 14 28.69 (3.7) 29.04 (3.4) 28.50 (2.4)

_______________________________________________________________________________mRNA expression of sputum cells. The Ct-values at end of treatment minus the values at start oftreatment are presented. Data presented as geometric mean and coefficient of variation (sd/mean x100%). *: p<0.05 budesonide/formoterol vs placebo. †: p<0.05 prednisolone vs placebo. ‡: p<0.05budesonide/formoterol vs prednisolone. Lower Ct-values correspond with higher mRNAexpression. Ct-values are normalised for ß2-microglobulin expression. *: P-values for comparisonsof the ratio at day 14 to day 1 under budesonide/formoterol (320/9 µg 4 times daily) versusprednisolone (30 mg once daily) and placebo. HO-1= heme ogygenase-1

101


Symptoms and health status

During both B/F and PRED treatment periods, significantly lower total symptomscores in the diaries were observed compared to the treatment period withPLAC (mean difference -1.37 and -1.03 respectively; p<0.01, p=0.048). B/Ftreatment resulted also in lower cough symptom score compared to PLAC(mean difference -0.62, p=0.015). There were trends towards lower sputumproduction scores under both B/F and PRED compared to PLAC (meandifferences –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 significantlybetween 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 wassignificantly 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 0.4points28. The health status measured by the CRQ showed similar results (meanchange B/F 0.47 and placebo 0.004, p=0.07; mean change PRED –0.06, p=0.04versus B/F).

Figure 3: Treatment effect on FEV1* On day 3, 7, and 14, the ratio of FEV1 of the visit under study to the FEV1 at randomisation arepresented. Data is expressed as geometric means. P-values for comparisons of these ratios at day14 under budesonide/formoterol (320/9 µg 4 times daily) versus prednisolone (30 mg once daily)and placebo

102


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 atrandomisation are presented. The difference in means from start to end of treatment are significantfor budesonide/formoterol versus prednisolone (p=0.02) Data is expressed as means. P-values forcomparisons of the arithmetic mean changes at day 14 under budesonide/formoterol (320/9 µg 4times daily) versus prednisolone (30 mg once daily) and placebo

Adverse events and safety

No serious adverse events occurred during study treatment. One seriousadverse event (operation for a sinus maxillaris cyst) was reported during thethree months follow-up period. Eighteen patients had a treatment failure (definedas need for open label COPD treatment in the first 3 weeks after start of studytreatment) or relapse (defined as need for open label COPD treatment from 3weeks to 3 months after start of treatment) in the 3 months after start oftreatment (7 in B/F, 7 in PRED, 4 in the PLAC treatment arm). Nohospitalisations for respiratory symptoms were required. Furthermore there wereno different patterns between the treatment groups in adverse events,characteristics on electrocardiograms, or blood pressure and heart rate, thoughunder PRED QRS duration decreased compared to PLAC(-2.7 ms versus +3.6ms, p=0.0048). B/F treatment did not significantly suppress serum cortisolcompared to placebo (mean 16% lower p=0.50). By contrast, the PREDtreatment did suppress serum cortisol levels significantly versus placebo (mean45% lower; p=0.03). There were no significant differences in the changes in theserum glucose levels between the groups. The decrease in serum potassium

103


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_______________________________________________________________________________


FEV1 (L), day 1 1.56 (36) 1.57 (28) 1.45 (26)FEV1, (L), day 14 1.68 (35) 1.61 (30) 1.50 (23)IVC, (L) day 1 3.93 (27) 4.27 (25) 3.83 (20)IVC, (L) day 14 3.91 (25) 4.31 (20) 3.74 (21)

FEV1 /VC (%) day 1 40 (27) 37 (26) 38 (24)FEV1 /VC (%) day 14 43 (27) 37 (29) 41 (16)

sGaw, (kPa/L/s) day 1 0.59 (43) 0.62 (49) 0.62 (44)

sGaw, (kPa/L/s) day 14 0.70 (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 atday 14 to day 1 under budesonide/formoterol (320/9 µg 4 times daily) versus prednisolone (30 mgonce daily) and placebo.

Discussion

Treatment of COPD exacerbations with high dose budesonide/formoterol (B/F)significantly reduced sputum eosinophils compared to placebo. This reduction inairway inflammation was accompanied by an improvement in symptoms.Prednisolone (PRED) treatment also reduced airway inflammation andsymptoms. In contrast to B/F, PRED significantly suppressed plasma cortisollevels.

Several studies have reported that eosinophils increase during COPDexacerbations, both in airway biopsies and in induced sputum 15;16;29. Althoughthe effects of steroids (inhaled or oral) on inflammation during exacerbationshad not been previously studied, several studies have assessed the effects ofcorticosteroids on inflammation in stable COPD. Gan et al performed ameta-analysis of the effects of inhaled steroids in the stable phase of COPD,showing a trend towards reducing eosinophil counts in the sputum of stableCOPD patients 30. In a recent study, treatment of stable COPD with inhaledsalmeterol/ fluticasone propionate also reduced sputum eosinophil counts 31.

To evaluate the potential effects of corticosteroids on airway inflammation, wemeasured the sputum cell mRNA expression of several cytokines that play arole in the attraction/survival of eosinophils, our primary endpoint, or may

104


contribute to the induction and resolution of COPD exacerbations. We found alarger decrease in IL-5 expression with B/F compared to placebo. Since IL-5 isinvolved in eosinophil growth and differentiation, this reduction fits well with thereduction in sputum eosinophils 32. Under placebo treatment a larger increasefrom day 1 to day 14 was observed in expression of TGF- ß compared to PREDand similar trends, though not significant, compared to B/F. This increase underplacebo may signify an increased inflammation and tissue damage due to thelack of anti-inflammatory treatment. We do not have an explanation for thesmaller increase in HO-1 expression under PRED compared to B/F. We wouldhave expected a decreased expression by both the active treatments, sinceHO-1 is a stress inducible enzyme, and we would have expected a decrease instress stimuli by treatment due to a reduction in inflammation. Perhaps thiseffect has been confounded by other stress factors such as smoking.

The beneficial effects of steroid treatment on parameters of inflammation wereaccompanied by improvements in clinical symptoms. The total symptom scoresas recorded in the daily diaries were better under both B/F and the PREDtreatment, with a significant improvement in cough for B/F and trends inimprovement in sputum production under both B/F and PRED treatment.

This study is the first to use an airway inflammatory parameter as the majorendpoint for treatment efficacy in exacerbations of COPD. A few randomisedcontrolled trials used clinical endpoints to asses the effects of oral prednisoloneon COPD exacerbations 1;2;33;34, and a meta-analysis concluded that it reducestreatment failure and the need for additional treatment, and increases the rate ofimprovement in lung function and dyspnea over the first 72 hours 35.

Maltais et al showed beneficial effects of inhaled budesonide 3, comparing 2mgnebulised budesonide every 6 hours and 30mg oral prednisolone every 12hours, and both treatments improved airflow limitation when compared withplacebo. Although we did not show a statistically significant effect on airflowlimitation between the three groups in our study, a trend was found in thecomparison between B/F and PLAC (see figure 2, p= 0.07). The lack ofsignificance is likely due to the smaller patient numbers in our study (45 versus199) since the magnitude of improvement in FEV1 was similar (125 ml versus100 ml). Our study sample size was based on power calculations with changesin eosinophil percentage as primary end point. Another difference between thestudies is the time point of evaluation, i.e. in our study at 2 weeks afterrandomisation, versus 72 hours in Maltais' study.

A great advantage of B/F therapy above PRED should be the avoidance, or atleast a reduction, of systemic side effects. Several studies have shown thatinhaled corticosteroids have fewer side effects compared to oral corticosteroids.Morice et al investigated the side effects of nebulised budesonide (2 mg twicedaily) with oral prednisolone (30 mg at once daily) in the treatment ofCOPD-exacerbations. They found that prednisolone treatment resulted in lowerurinary corticosteroid metabolites, and lower serum osteocalcin than inhaledtreatment 36. In our study we investigated serum cortisol levels. We found that

105


there was no significant suppression of serum cortisol by B/F treatmentcompared to placebo. PRED treatment did suppress serum cortisol levels asexpected 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 activetreatment arms. Such a non-inferiority trial would require more patients. Any lackof difference in statistical terms between B/F and PRED in the present studycould therefore be due to a type 2 error and should not be interpreted to signifyequal or similar effects. Nevertheless, since all parameters favoured B/F overPRED, there was no indication of inferiority of B/F versus prednisolone in thissetting.

The use of B/F for the treatment of mild to moderate exacerbations of COPD athome 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 overPRED because of less side effects, will require larger-scale efficacy studies. Aninteresting option is the possibility to treat exacerbations at home in an earlierstage of an evolving exacerbation by B/F, as was recently demonstrated to beeffective in the treatment of asthma 4. Whether this earlier institution of effectivetherapy could also prevent in COPD the development of full-blownexacerbations and thereby hospitalisations is an interesting option that should bestudied in future studies.

We conclude that sputum eosinophils and symptoms of patients with mild tomoderate COPD exacerbations can be improved by a 2-week treatment with160 µg budesonide/ 4.5 µg formoterol, 2 doses q.i.d., compared to placebo. Anext study should aim to establish whether treatment of exacerbations at homewith budesonide/formoterol can replace traditional treatment with oralcorticosteroids

Acknowledgements

The authors thank Ibolya Sloots, Brigitte Dijkhuizen, Koos van de Belt, andJanneke Heimweg for all sputum measurements, Marco van der Toorn for themRNA measurements, the lung function department for the many lung functionmeasurements, and Alec Ross for the cortisol measurements (UMC St.Radboud, Nijmegen).

106


References

(1) Niewoehner DE, Erbland ML, Deupree RH et al. Effect of systemic glucocorticoids onexacerbations of chronic obstructive pulmonary disease. Department of Veterans AffairsCooperative Study Group. N Engl J Med 1999; 340(25):1941-1947.

(2) Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospitalwith exacerbations of chronic obstructive pulmonary disease: a prospective randomisedcontrolled trial. Lancet 1999; 354(9177):456-460

(3) Maltais F, Ostinelli J, Bourbeau J et al. Comparison of nebulized budesonide and oralprednisolone with placebo in the treatment of acute exacerbations of chronic obstructivepulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med 2002;165(5):698-703.

(4) O'Byrne PM, Bisgaard H, Godard PP et al. Budesonide/formoterol combination therapyas both maintenance and reliever medication in asthma. Am J Respir Crit Care Med2005; 171(2):129-136.

(5) Szafranski W, Cukier A, Ramirez A et al. Efficacy and safety of budesonide/formoterol inthe management of chronic obstructive pulmonary disease. Eur Respir J 2003;21(1):74-81.

(6) Calverley P, Pauwels R, Vestbo J et al. Combined salmeterol and fluticasone in thetreatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet2003; 361(9356):449-456.

(7) Barczyk A, Sozanska E, Trzaska M et al. Decreased levels of myeloperoxidase ininduced sputum of patients with COPD after treatment with oral glucocorticoids. Chest2004; 126(2):389-393.

(8) Culpitt SV, Rogers DF, Shah P et al. Impaired inhibition by dexamethasone of cytokinerelease by alveolar macrophages from patients with chronic obstructive pulmonarydisease. Am J Respir Crit Care Med 2003; 167(1):24-31.

(9) Confalonieri M, Mainardi E, Della Porta R et al. Inhaled corticosteroids reduceneutrophilic bronchial inflammation in patients with chronic obstructive pulmonarydisease. Thorax 1998; 53(7):583-585.

(10) Hattotuwa KL, Gizycki MJ, Ansari TW et al. The effects of inhaled fluticasone on airwayinflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlledbiopsy study. Am J Respir Crit Care Med 2002; 165(12):1592-1596.

(11) Balbi B, Majori M, Bertacco S et al. Inhaled corticosteroids in stable COPD patients: dothey have effects on cells and molecular mediators of airway inflammation? Chest 2000;117(6):1633-1637.

(12) Llewellyn-Jones CG, Harris TA, Stockley RA. Effect of fluticasone propionate on sputumof patients with chronic bronchitis and emphysema. Am J Respir Crit Care Med 1996;153(2):616-621.

107


(13) Wilson SJ, Wallin A, Della-Cioppa G et al. Effects of budesonide and formoterol onNF-kappaB, adhesion molecules, and cytokines in asthma. Am J Respir Crit Care Med2001; 164(6):1047-1052.

(14) Wallin A, Sandstrom T, Soderberg M et al. The effects of regular inhaled formoterol,budesonide, and placebo on mucosal inflammation and clinical indices in mild asthma.Am J Respir Crit Care Med 1999; 159(1):79-86.

(15) Fujimoto K, Yasuo M, Urushibata K et al. Airway inflammation during stable and acutelyexacerbated chronic obstructive pulmonary disease. Eur Respir J 2005; 25(4):640-646.

(16) Mercer PF, Shute JK, Bhowmik A et al. MMP-9, TIMP-1 and inflammatory cells in sputumfrom COPD patients during exacerbation. Respir Res 2005; 6:151.

(17) Pizzichini E, Pizzichini MM, Gibson P et al. Sputum eosinophilia predicts benefit fromprednisone in smokers with chronic obstructive bronchitis. Am J Respir Crit Care Med1998; 158(5 Pt 1):1511-1517.

(18) Brightling CE, Monteiro W, Ward R et al. Sputum eosinophilia and short-term response toprednisolone in chronic obstructive pulmonary disease: a randomised controlled trial.Lancet 2000; 356(9240):1480-1485.

(19) Brightling CE, McKenna S, Hargadon B et al. Sputum eosinophilia and the short termresponse to inhaled mometasone in chronic obstructive pulmonary disease. Thorax 2005;60(3):193-198.

(20) Bathoorn D, Liesker JJW, Postma DS, Bondesson E, Koëter GH, van Oosterhout AJM,Kerstjens HAM. Anti-inflammatory effect of combined budesonide/formoterol treatment inCOPD exacerbations. Proceedings of the American Thoracic Society 2006; 3:A605

(21) Bathoorn D, Liesker JJW, Postma DS, Koëter GH, Kerstjens HAM. Change ininflammation during COPD exacerbations. Eur Respir J 2005; 26 Suppl. 49: 15s.

(22) Quanjer PH, Tammeling GJ, Cotes JE et al. Lung volumes and forced ventilatory flows.Report Working Party Standardization of Lung Function Tests, European Community forSteel and Coal. Official Statement of the European Respiratory Society. Eur Respir JSuppl 1993; 16:5-40.

(23) Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospitalwith exacerbations of chronic obstructive pulmonary disease: a prospective randomisedcontrolled trial. Lancet 1999; 354(9177):456-460.

(24) Leidy NK, Schmier JK, Jones MK et al. Evaluating symptoms in chronic obstructivepulmonary disease: validation of the Breathlessness, Cough and Sputum Scale. RespirMed 2003; 97 Suppl A:S59-S70.

(25) van der Molen T, Willemse BW, Schokker S et al. Development, validity andresponsiveness of the Clinical COPD Questionnaire. Health Qual Life Outcomes 2003;1(1):13.

(26) Rutgers SR, Timens W, Kaufmann HF et al. Comparison of induced sputum withbronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD. Eur Respir J2000; 15(1):109-115.

108


(27) Pizzichini MM, Pizzichini E, Clelland L et al. Sputum in severe exacerbations of asthma:kinetics of inflammatory indices after prednisone treatment. Am J Respir Crit Care Med1997; 155(5):1501-1508.

(28) Kocks JW, Tuinenga MG, Uil SM et al. Health status measurement in COPD: the minimalclinically important difference of the clinical COPD questionnaire. Respir Res 2006; 7:62.

(29) Saetta M, Di Stefano A, Maestrelli P et al. Airway eosinophilia in chronic bronchitis duringexacerbations. Am J Respir Crit Care Med 1994; 150(6 Pt 1):1646-1652.

(30) Gan WQ, Man SF, Sin DD. Effects of inhaled corticosteroids on sputum cell counts instable chronic obstructive pulmonary disease: a systematic review and a meta-analysis.BMC Pulm Med 2005; 5(1):3.

(31) Barnes NC, Qiu YS, Pavord ID et al. Antiinflammatory effects of salmeterol/fluticasonepropionate in chronic obstructive lung disease. Am J Respir Crit Care Med 2006;173(7):736-743.

(32) Takatsu K. Interleukin 5 (IL-5) and its receptor. Microbiol Immunol 1991; 35(8):593-606.

(33) Emerman CL, Connors AF, Lukens TW et al. A randomized controlled trial ofmethylprednisolone in the emergency treatment of acute exacerbations of COPD. Chest1989; 95(3):563-567.

(34) Albert RK, Martin TR, Lewis SW. Controlled clinical trial of methylprednisolone in patientswith chronic bronchitis and acute respiratory insufficiency. Ann Intern Med 1980;92(6):753-758.

(35) Wood-Baker RR, Gibson PG, Hannay M et al. Systemic corticosteroids for acuteexacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev2005;(1):CD001288.

(36) Morice AH, Morris D, Lawson-Matthew P. A comparison of nebulized budesonide withoral prednisolone in the treatment of exacerbations of obstructive pulmonary disease.Clin Pharmacol Ther 1996; 60(6):675-678.

109


university of groningen copd exacerbations, inflammation and … · 2016-03-06 · chapter 6...

Documents