Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness

Transcription

1 Eur Respir J 2006; 27: DOI: / CopyrightßERS Jourals Ltd 2006 Compariso of asthma treatmet give i additio to ihaled corticosteroids o airway iflammatio ad resposiveess R.H. Gree*, C.E. Brightlig*, S. McKea*, B. Hargado*, N. Neale*, D. Parker*, C. Ruse*, I.P. Hall # ad I.D. Pavord* ABSTRACT: There is icreasig evidece that the assessmet of eosiophilic airway iflammatio usig iduced sputum ad measuremet of airway hyperresposiveess provides additioal, cliically importat iformatio cocerig asthma cotrol. The aim of this study was to directly compare the effects of differet treatmets o these markers i patiets with asthma ad persistet symptoms, despite the use of low-dose ihaled corticosteroids. A double-blid four-way crossover study was performed, which compared a 1-moth treatmet with budesoide 400 mg b.i.d., additioal formoterol, additioal motelukast ad placebo i 49 patiets with ucotrolled asthma despite budesoide 100 mg b.i.d., with each treatmet separated by a 4-week washout period. The chage i sputum eosiophil cout with formoterol (2.4 to 3.8% chage, 0.6-fold reductio, 95% cofidece iterval (CI) ) differed sigificatly from placebo (2.8 to 2.5% chage, 1.1- fold reductio, 95% CI ) ad high-dose budesoide (2.7 to 1.6% chage, 1.6-fold reductio, 95% CI ). The effects of motelukast did ot differ from placebo. The chages i methacholie airway resposiveess were small ad did ot differ betwee treatmets. High-dose budesoide had the broadest rage of beeficial effects o other outcomes, icludig symptom scores, morig peak expiratory flow ad forced expiratory volume i oe secod. I coclusio, treatmet give i additio to low-dose ihaled corticosteroids results i modest beefits. Formoterol ad high-dose budesoide have cotrastig effects o eosiophilic airway iflammatio. KEYWORDS: Asthma, ihaled corticosteroids, leukotriee atagoists, log-actig b 2 -agoists, treatmet AFFILIATIONS *Istitute for Lug Health, Dept of Respiratory, Medicie ad Thoracic Surgery, Glefield Hospital, Leicester, ad # Divisio of Therapeutics, Quees Medical Cetre, Nottigham, UK. CORRESPONDENCE R.H. Gree Istitute for Lug Health Dept of Respiratory Medicie ad Thoracic Surgery Glefield Hospital Groby Road Leicester LE3 9PQ UK Fax: ruth.gree@uhl-tr.hs.uk Received: September Accepted after revisio: Jauary SUPPORT STATEMENT The study was supported by fudig from Asthma UK. A cosiderable umber of patiets with asthma remai symptomatic despite treatmet with low-dose ihaled corticosteroids. A large, primary care-based audit by NEVILLE et al. [1] showed that early half of all patiets were takig low-dose ihaled corticosteroids i additio to as required b 2 -agoists ad that 54% of these were takig more tha two puffs of a b-agoist per day, suggestig the eed for a treatmet step-up [1]. Presetly, the cliicia is faced with a icreasig umber of treatmet optios for this importat group of patiets, but relatively little data from placebo-cotrolled comparative studies to guide treatmet decisios. May of the available studies examiig the effect of treatmet optios after low-dose ihaled corticosteroids have assessed the effects of treatmet o measures of lug fuctio ad symptoms [2 6]. However, recet studies have suggested that the assessmet of eosiophilic airway iflammatio [7, 8] ad airway resposiveess [9] provides additioal, cliically importat iformatio o asthma cotrol. No placebocotrolled study has assessed the effects of differet treatmet optios after low-dose ihaled corticosteroids o these importat markers of asthma cotrol. The curret authors aims were to directly compare the effects of higher-dose budesoide, low-dose budesoide plus formoterol ad lowdose budesoide plus motelukast o the iduced sputum eosiophil cout ad methacholie airway resposiveess i a prospective, double-blid, placebo-cotrolled, four-way crossover study of patiets with symptomatic asthma who met the criteria to warrat a icrease i Europea Respiratory Joural Prit ISSN Olie ISSN VOLUME 27 NUMBER 6 EUROPEAN RESPIRATORY JOURNAL

2 treatmet. A secodary aim was to idetify variables that might be associated with the respose to treatmet. METHODS Subjects Voluteers aged yrs, diagosed with asthma ad beig treated with the equivalet of f400 mg?day -1 beclomethasoe dipropioate, were ivited to participate i the study, followig advertisemets i the local media. Subjects were excluded if they were curret smokers or had a smokig history of.10 pack-yrs, had sigificat comorbidity, were receivig oral corticosteroids, log-actig b 2 -agoists, leukotriee atagoists or theophyllie, or had udergoe a asthma exacerbatio or lower respiratory tract ifectio withi the 4 weeks prior to trial etry. All patiets had symptoms cosistet with the diagosis of asthma ad oe or more of the followig: 1) a.15% icrease i forced expiratory volume i oe secod (FEV1) followig 200 mg of ihaled salbutamol; 2).20% withi-day variability i peak expiratory flow (PEF) assessed twice daily over a 2-week period; or 3) a provocative cocetratio of methacholie causig a 20% fall i FEV1 (PC20),8 mg?ml -1. Subjects were established o a stadard dose of budesoide (100 mg b.i.d. via a turbohaler) for 4 weeks before etry ad were eligible to participate i the study if they had recorded day- or ight-time asthma symptoms o their diary cards o at least 4 days i the third or fourth baselie week. The local research ethics committee approved the study ad all patiets gave writte iformed coset. Measuremets Allerge ski-prick tests were performed for Dermatophagoides pteroyssius, cat fur, grass polle ad Aspergillus fumigatus solutios with ormal salie ad histamie cotrols (Alk- Abelló, Berkshire, UK). Ed-exhaled itric oxide (NO) was measured with a chemilumiescece aalyser (Loga Research, Rochester, UK) with subjects exhalig at a flow rate of 250 ml?s -1. NO was sampled from a sidearm attached to the mouthpiece ad the mea NO value was take from the poit correspodig to the plateau of the ed-exhaled carbo dioxide readig [9]. Methacholie challege testig was performed usig the tidal breathig method with doublig cocetratios of methacholie ( mg?ml -1 ) ebulised via a Wright ebuliser [10]. FEV1 before ad 20 mi after 200 mg of salbutamol was ihaled was recorded o differet occasios, separated by at least 48 h from the methacholie challege. Symptoms over the previous week of treatmet were recorded o 100-mm visual aalogue scales (VAS) from o symptom (0 mm) to the most severe symptom (100 mm) for breathlessess, wheeze ad cough. The total VAS score (0 300 mm) was calculated as the sum of the three idividual scores [7]. The JUNIPER et al. [11] Asthma Quality of Life Questioaire (AQLQ) was used to assess asthma-specific quality of life. Sputum was iduced ad processed as previously described [12]. A experieced observer blided to the study medicatio ad cliical characteristics performed the cell couts. The cell free sputum superatat was removed ad stored at -80uC util aalysis. The cysteiyl leukotriees (LT)C 4 /LTD 4 /LTE 4 were measured i the sputum superatat usig a commercial ELISA (Cayma Chemical, A Arbor, MI, USA) with the stadard curve spiked with dithiothreitol at the same cocetratio as the ukow [13]. The itra- ad iter-assay coefficiets of variability were,10% ad the lower limit of detectio was 13 pg?ml -1 of sample. Patiets completed daily diary cards throughout the study, recordig day- ad ight-time symptoms, twice daily PEF ad rescue b 2 -agoist use. Day- ad ight-time symptom scores were recorded o a four-poit scale as previously described [2, 7]. PEF was recorded as the best of three successive readigs usig a Mii-Wright peak flow meter (Clemet Clarke Iteratioal Ltd, Harlow, UK). Compliace was assessed by tablet coutig ad by assessmet of turbohaler use; it was defied as acceptable if the subjects used.75% of the recommeded dose of study drug or placebo. I a subgroup of 37 patiets who gave their coset, the curret authors determied the geotype at the b 2 -adreoceptor by allele-specific oligoucleotide hybridisatio of geomic DNA extracted from a 5-mL sample of whole blood, as previously described [14, 15]. Study desig A radomised, double-blid, placebo-cotrolled, four-way crossover study was performed. After recruitmet, baselie measuremets were recorded ad the patiets uderwet a 1-moth ru-i period durig which they took budesoide 100 mg b.i.d. via a turbohaler alog with salbutamol as required for symptom relief. The patiets the atteded the cliic for measuremet of exhaled NO, spirometry, methacholie PC20, AQLQ, VAS symptom scores ad sputum iductio (i this order). Suitable subjects were radomised to receive oe of the followig for a period of 1 moth: 1) budesoide 100 mg b.i.d. aloe; 2) budesoide 400 mg b.i.d.; 3) budesoide 100 mg b.i.d. ad oral motelukast 10 mg q.d.; ad 4) budesoide 100 mg b.i.d. ad ihaled formoterol 12 mg b.i.d. All ihaled study medicatio was delivered via a turbohaler. Blidig was maitaied by issuig two idetical turbohalers cotaiig active ad placebo formoterol ad 100 or 400 mg budesoide (AstraZeeca, Lud, Swede) ad motelukast ad placebo tablets were each prepared i a sigle white capsule (Royal Hallamshire Hospital Pharmacy Departmet, Sheffield, UK). Patiets the completed a 1-moth washout period durig which they were maitaied o budesoide 100 mg b.i.d. give via a ublided turbohaler ad as required salbutamol oly. At the ed of this time, cliical measuremets were repeated ad patiets crossed over to a secod of the above four treatmets, which they received for a further 1-moth period. The process was the repeated util the subjects had received each of the four treatmets, with a 4-week washout period betwee each. Cliical measuremets were take at the same time of day, 12 h after the last dose of each treatmet ad at least 6 h after the last dose of short-actig b 2 -agoist. The order of treatmets was radomly allocated to each patiet. Radomisatio was performed by the Glefield Hospital Pharmacy Dept Leicester, UK. Severe asthma exacerbatios were defied as a decrease i the morig PEF.30% below the baselie value o o2 cosecutive days, or deterioratio i symptoms requirig treatmet with oral corticosteroids [2]. If a severe exacerbatio occurred, this was treated with predisoloe 30 mg q.d. for 2 weeks followed by a 6-week washout period of budesoide 100 mg b.i.d. ad as required salbutamol oly. Patiets who c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER

3 Subjects recruited (=66) Subjects radomised (=49) No objective evidece of asthma (=11) No symptoms durig ru-i (=5) Developed other illess (=1) two-way ANOVA with the least sigificat differece test for multiple comparisos. Period ad order effects were ivestigated usig aalysis of covariace. The curret authors explored the relatioship betwee baselie brochodilator respose, cysteiyl-leukotriee cocetratios, sputum eosiophils ad respose to treatmet usig the Pearso correlatio coefficiet. The effect of b 2 -adreoceptor geotype ad subsequet chage i primary outcome variables was compared betwee placebo treatmet ad formoterol by a upaired t-test. The Chi-squared test was used to compare the umbers of patiets havig severe asthma exacerbatios durig each of the treatmet periods. 4-way crossover study Completed all four treatmets (=39) FIGURE 1. Trial profile. Subjects withdrew (=10) Two severe exacerbatios (=5) Chaged their mids (=4) Developed other illess (=1) experieced two severe exacerbatios were withdraw from the study. Statistical aalysis The primary outcome variables were the chage from the pretreatmet baselie i the methacholie PC20 (i doublig cocetratios), fold chage i sputum eosiophil cout ad the chage i global VAS symptom score. Secodary outcome measures were the chage from the pre-treatmet baselie i FEV1, total AQLQ score, fold chage i exhaled NO ad the chage i morig PEF calculated as the mea chage betwee the fial week of the washout period ad the fial week of treatmet. Based o a coservative estimate of withi-subject stadard deviatio of oe doublig dose, 10 mm ad two-fold differece for methacholie PC20, symptom scores ad sputum eosiophils [10, 16, 17], a total of 40 patiets were required for a 80% chace of detectig a oe doublig-dose differece i chage i methacholie PC20, a two-fold differece i sputum eosiophil cout betwee treatmet ad a 20-mm differece i total VAS symptom scores at the 5% level. Patiets who had a severe exacerbatio durig a treatmet moth were assiged the lowest observed value for the chage i each outcome measure for that treatmet. If a treatmet was stopped early due to adverse effects, measuremets were take withi 12 h of the last dose of treatmet ad the results were icluded o a itetio-to-treat basis. Patiets who withdrew from the study for reasos other tha a severe exacerbatio were assiged the mea value for the chage i each outcome variable. Iduced sputum eosiophil couts, exhaled NO cocetratios ad methacholie PC20 were log 10 ormally distributed ad were expressed as the geometric mea log10 SE. Age ad age at oset were expressed as media (rage). All other baselie variables were expressed as mea SD. Primary ad secodary outcome measures were compared betwee groups usig a RESULTS A total of 66 patiets were recruited ito the study, of which 49 were radomised. Te patiets withdrew early ad therefore failed to complete oe or more of the study treatmets. Baselie demographic data ad lug fuctio are give i table 1. All subjects were judged to have acceptable compliace. There were o period or order effects ad pre-treatmet values were well matched for each outcome variable (table 2). The umber of patiets completig each treatmet is give i figure 1 ad table 3. A total of 18 severe exacerbatios occurred durig the followig treatmet periods: washout periods (57); high-dose budesoide (51); formoterol (52); motelukast (54); ad placebo (54). The differece i exacerbatio frequecy betwee treatmets was ot sigificat (p50.46). Primary outcome variables Sputum eosiophils There was a sigificat differece i the fold chage i the sputum eosiophil cout across the groups (p50.005; table 3; fig. 2.) The chage i sputum eosiophil cout with formoterol (2.4 to 3.8%; 0.6-fold reductio; 95% cofidece iterval (CI) ) differed sigificatly from placebo (2.8 to 2.5%; 1.1- fold reductio; 95% CI ; p50.03) ad high-dose budesoide (2.7 to 1.6%; 1.6-fold reductio; 95% CI ; p,0.001). TABLE 1 Baselie characteristics Baselie characteristics Patiets 49 Male 25 Age yrs 42 (19 73) Age at oset yrs 13.5 (1 67) Atopic 37 FEV1 % pred FEV1/FVC ratio % Icrease i FEV1 post-brochodilator % % icrease i FEV1 15 post-brochodilator PEF amplitude % Data are preseted as, media (rage) or mea SEM. FEV1: forced expiratory volume i oe secod; % pred: % predicted; FVC: forced vital capacity; PEF: peak expiratory flow VOLUME 27 NUMBER 6 EUROPEAN RESPIRATORY JOURNAL

4 TABLE 2 Pre-treatmet results Budesoide High-dose budesoide formeterol motelukast placebo Methacholie PC20 mg?ml -1# Sputum eosiophil cout % # Sputum eutrophil cout % Total VAS score mm Daytime symptom scores (0.08) 0.58 (0.08) 0.61 (0.09) 0.62 (0.07) Night-time symptom scores (0.08) 0.20 (0.06) 0.21 (0.07) 0.18 (0.05) Symptom free days/weeks 1.67 (0.41) 1.68 (0.39) 2.33 (0.77) 1.57 (0.39) Rescue b 2 -agoist use ihalatios?day (0.33) 1.95 (0.40) 2.09 (0.37) 1.84 (0.34) Morig PEF FEV1 L Total AQLQ score eno ppb # Data are preseted as mea SE. PC20: provocative cocetratio causig a 20% fall i forced expiratory volume i forced expiratory volume i oe secod (FEV1); VAS: visual aalogue scales; PEF: peak expiratory flow; AQLQ: Asthma Quality of Life Questioaire; eno: exhaled itric oxide. # : geometric mea log10 SE Methacholie PC20 There were o sigificat differeces i the doublig cocetratio chage i methacholie PC20 betwee ay of the treatmet groups ad placebo or across the idividual treatmets (table 3; fig. 2). Symptom scores Higher-dose budesoide resulted i a sigificat improvemet i the global VAS symptom score compared with low-dose budesoide plus placebo (mea differece 21.3 mm; 95% CI ; p50.023). Additioal motelukast ad additioal formoterol did ot result i sigificat improvemets i VAS symptom scores compared with placebo ad the differece across the four treatmet arms was of borderlie statistical sigificace (p50.05; table 3; fig. 2). There was o sigificat differece i the chage i daytime symptom scores (p50.8), ight-time symptom scores (p50.28), symptom-free days (p50.10) or rescue b 2 -agoist use (p50.16) across the four treatmet arms (table 3). Secodary outcome variables Morig peak expiratory flow Sigificat differeces i the chage i mea morig PEF over the fial week of treatmet were observed across the four treatmets (p50.019; table 3). A sigificat improvemet i mea morig PEF was see with both high-dose budesoide (16.3 L?mi -1 ; 95% CI ; p50.01) ad additioal formoterol (17.2 L?mi -1 ; 95% CI ; p50.007) compared with placebo. Fold chage i exhaled itric oxide There was a sigificat differece i the fold chage i exhaled itric oxide (eno) across the groups (p50.011; table 3). The chage i eno with high-dose budesoide differed sigificatly from the chage see with placebo (mea (95% CI) differece 1.86 ( ) fold; p50.005) ad formoterol (mea (95% CI) differece 1.95 ( ) fold; p50.003). Pre-brochodilator FEV1 The differece i pre-brochodilator FEV1 across the four treatmet arms did ot reach statistical sigificace (p50.133). Chage i total AQLQ score There were o sigificat differeces i the chage i the total AQLQ score across the four treatmets (p50.81). Subgroup aalyses The respose to ay of the treatmets studied was ot iflueced by atopic status, degree of acute brochodilator reversibility, pre-treatmet sputum eosiophil couts, or pre-treatmet sputum cysteiyl-leukotriee cocetratios. Compared with heterozygotes/gly Gly homozygotes (519/ 10), homozygous Arg-16 patiets (56) respoded less well to formoterol (doublig dose chage i PC versus 1.05; mea (95% CI) differece ( ); p50.046; chage i FEV versus 0.02 L; mea differece 0.40 ( ); p50.014), but there was o differece i the chage i sputum eosiophils ( % to % compared with % to %; p50.14). I cotrast, homozygous Gl-27 patiets (515) had a better ati-iflammatory respose to high-dose ihaled steroids tha heterozygotes/glu Glu homozygotes (520/2; fold reductio i sputum eosiophils 3.01 versus 1.25; mea differece 2.40 ( cocetratio); p50.023). DISCUSSION This is the first placebo-cotrolled compariso of the treatmet optios for patiets with symptomatic asthma, despite lowdose ihaled corticosteroids ad the first to examie the effect o airway iflammatio ad airway resposiveess. Overall, the beefit provided by each of the additioal treatmets o the primary outcome measures i this group of patiets was mior; there was importat heterogeeity of treatmet respose, particularly i the effects of treatmet o eosiophilic airway iflammatio. c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER

5 Recet studies have emphasised the importace of the measures chose as the curret study s primary outcomes by showig that maagemet strategies that aim to ormalise eosiophilic airway iflammatio [7, 8] or airway hyperresposiveess [9] are associated with importat reductios i the frequecy of asthma exacerbatios. The preset study was powered to show the effects that have bee previously idetified as beig cliically sigificat [10, 17] ad are equivalet, or greater, tha have bee show to be associated with reduced exacerbatio frequecy [7, 9]. I corticosteroidaive asthma, the itroductio of ihaled corticosteroid treatmet results i 1 4 doublig dose improvemets i airway resposiveess [16, 18] ad 6 10-fold reductios i the sputum eosiophil cout [16, 19]. The much smaller effects see i this study idicate that most patiets who are symptomatic, despite takig low-dose ihaled corticosteroids, are ear the top of the dose respose curve for these variables. The VAS symptom scores ad morig PEF were more resposive i the curret study, emphasisig the complex relatioship betwee airway iflammatio, airway resposiveess, simple tests of airway calibre ad cliical expressio of the disease. It is possible that more clear evidece of efficacy would be apparet i a more symptomatic populatio, although all the preset patiets met curret criteria for a step-up i treatmet [20] ad had day- ad ight-time symptom scores ad impairmet of lug fuctio comparable to those see i the Formoterol ad Corticosteroids Establishig Therapy (FACET) study [2]. These factors suggest that the subjects icluded i the preset study are likely to be represetative of the wider populatio of patiets i whom additioal treatmet has bee evaluated. The patiets who completed the preset study had to remai free from exacerbatios for 5 moths o low-dose ihaled corticosteroids oly; this factor should be cosidered whe geeralisig the curret fidigs to a wider populatio. The relative efficacy of the treatmets differed cosiderably with the differet outcome variables studied. The most strikig example of this ca be see with the cotrastig effects of formoterol ad high-dose budesoide o markers of eosiophilic airway iflammatio. The curret fidigs with formoterol cotrast with those of KIPS et al. [21], who studied the effects of low-dose budesoide plus formoterol versus highdose budesoide o sputum iflammatory cells i a subset of the participats of the FACET study. They foud a slight icrease i the sputum eosiophil cout i the budesoide plus formoterol group compared with the groups treated with higher-dose budesoide. This icrease did ot reach statistical sigificace, although there were cliically importat differeces i the level of eosiophilic airway iflammatio i the two groups at baselie, which complicate the iterpretatio of these data. Brochial biopsy studies of the effects of logactig b 2 -agoists o airway iflammatio i asthma have either show a icrease i mucosal eosiophil umbers or cosistet evidece of ati-iflammatory effects [22 24]. Oe way to recocile the curret fidigs with those of the brochial biopsy studies is that b 2 -agoists icrease traffickig of eosiophils away from the airway mucosa ito the airway lume rather tha a icrease i eosiophilic airway iflammatio per se. Eosiophilic airway iflammatio has bee implicated i the pathophysiology of severe asthma exacerbatios [7, 25]. There were o sigificat differeces i exacerbatio frequecy betwee the treatmet arms i the preset study, although it was ot powered to show this. However, there is cosiderable evidece from appropriately desiged studies that the additio of formoterol to ihaled corticosteroids is associated with a reductio i the frequecy of asthma exacerbatios [2, 3]. I cotrast, the regular use of short-actig b 2 -agoists has bee associated with icreased eosiophilic airway iflammatio [26] ad exacerbatio frequecy i some [27], but ot all TABLE 3 Chage from baselie i primary ad secodary outcome variables Budesoide High-dose formeterol motelukast placebo Patiets completig treatmet Methacholie PC20 doublig dose 0.4 ( ) 0.2 ( ) 0.4( ) 0.1 ( ) Sputum eosiophils fold reductio 1.6 ( ) 0.6 ( ) 0.8 ( ) 1.1 ( ) Daytime symptom score ( ) ( ) ( ) ( ) Night-time symptom score ( ) ( ) ( ) 0.05 ( ) Symptom free days/weeks 0.45 ( ) 1.35 ( ) 1.29 ( ) 0.21 ( ) Rescue b 2 -agoist use ihalatios?day ( ) ( ) ( ) 0.90 ( ) VAS symptom score mm ( )* -3.5 ( ) 10.1 ( ) 5.5 ( ) Morig PEF 15.2 ( )* 16.4 ( )* 4.9 ( ) -1.3 ( ) FEV1 L 0.07 ( )* ( ) ( ) ( ) Total AQLQ 0.2 ( ) 0.1 ( ) 0.2 ( ) 0.0 ( ) eno fold reductio 1.3( )* 0.7 ( ) 0.9 ( ) 0.7 ( ) Data are preseted as or mea (95% cofidece itervals). PC20: provocative cocetratio causig a 20% fall i forced expiratory volume i oe secod (FEV1); VAS: visual aalogue scales; PEF: peak expiratory flow; AQLQ: Asthma Quality of Life Questioaire; eno: exhaled itric oxide. *: p,0.05 ANOVA VOLUME 27 NUMBER 6 EUROPEAN RESPIRATORY JOURNAL

6 a) Chage i VAS score mm b) Doublig dose chage i methacholie PC20 c) Fold reductio i sputum eosiophil cout High-dose budesoide studies [28]. The absece of a deleterious effect of formoterol o exacerbatio frequecy i earlier, appropriately powered studies [2, 3] suggests that the chages i sputum eosiophil cout observed with formoterol treatmet i the preset study are ot cliically relevat. However, the curret authors could ot discout the possibility that log-actig b 2 -agoists are associated with a icrease i the frequecy of exacerbatios that are particularly associated with icreased eosiophilic airway iflammatio ad a reductio i the frequecy of other evets that are less depedet o airway iflammatio [29]. Low-dose budesoide plus formoterol Low-dose budesoide plus motelukast FIGURE 2. Mea et chage i primary outcome compared with chage i placebo. Vertical lies represet 95% cofidece itervals. VAS: visual aalogue scales; PC20: provocative cocetratio causig a 20% fall i forced expiratory. The curret authors have cosidered whether the icreased eosiophilic iflammatio that was observed with formoterol i the preset study is due to patiets reducig their ihaled corticosteroid dose because of improved cotrol of symptoms. It is thought to be ulikely, sice all treatmet was give double blid ad compliace was carefully assessed throughout the study. However, this may be a issue whe ihaled corticosteroids ad log-actig b 2 -agoists are used separately i the commuity. Recet studies have show that regular treatmet with ihaled salbutamol i patiets who are homozygous for Arg Arg at positio 16 leads to a deterioratio i lug fuctio [30] ad is associated with a icreased risk of asthma exacerbatios [31]. I the preset study, patiets carryig this geotype respoded less well to formoterol i terms of lug fuctio ad airway hyperresposiveess, although the icreased eosiophilic airway iflammatio observed with formoterol was ot cofied to this group. However, due to the small umbers, the preset authors caot exclude the possibility that icreased airway iflammatio with regular b 2 -agoists is a particular problem i patiets with the Arg Arg geotype; further studies are eeded to ivestigate this possibility. The demostratio of a improved ati-iflammatory effect i homozygous Gl-27 patiets was uexpected. The preset authors recogise that multiple outcomes were studied i this report ad this differece may have emerged by chace. Further work is required to determie whether this effect is real ad to ivestigate the mechaism. Previous studies of log-actig b 2 agoists [2 5] or motelukast [6, 32] give to patiets who remai symptomatic despite low-dose ihaled corticosteroids have reported greater improvemets i symptoms ad morig PEF tha those see i the preset study. I cotrast, the curret authors have demostrated rather greater beefits from a high dose of ihaled corticosteroids tha has previously bee reported [2 5]. The preset study ivolved shorter treatmet periods tha other studies, but this is ulikely to have biased the results i favour of ihaled corticosteroids sice motelukast ad formoterol reach their maximum effect earlier tha ihaled corticosteroids [2, 6, 32]. The possibility that the maskig of motelukast i a capsule reduced its bioavailability caot be excluded, although there is o strog biological ratioale for such a effect. A more likely explaatio for these discrepacies betwee studies is the patiet populatio studied. Ulike previous studies, the curret study was ot cofied to recruitig subjects who demostrated a marked acute brochodilator respose, a populatio who might be particularly likely to respod to a log-actig b 2 -agoist [33]. The fact that the oly other study that had etry criteria similar to the preset study showed o sigificat improvemet i FEV1, methacholie airway resposiveess, symptom scores or exacerbatio rates whe salmeterol was added to beclomethasoe supports this iterpretatio [34]. The curret authors did ot fid a relatioship betwee brochodilator respose (or ideed ay other of the variables measured) ad the effect of treatmet, although this was a relatively small study ad the treatmet effects were small so the power to demostrate such a relatioship was low. I coclusio, the treatmet over 4 weeks give i additio to low-dose ihaled corticosteroids resulted i modest beefits i c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER

7 patiets who met the criteria for a step-up i treatmet. Furthermore, the respose to idividual treatmets appears to differ with the outcome variable, particularly with markers of eosiophilic airway iflammatio. The curret fidigs emphasise the complex relatioship betwee differet pathophysiological aspects of asthma. Further studies addressig the effects of treatmet o a rage of outcome variables i larger umbers of uselected patiets are required. ACKNOWLEDGEMENTS The authors would like to thak the voluteers who participated i the study, C. Burs of the Leicester Mercury for help with patiet recruitmet, AstraZeeca for providig active ad placebo ihalers, the Glefield Hospital Pharmacy Dept for performig the radomisatio, W. Moteiro for performig the cysteiyl leukotriee aalyses, M. Hibbert for assistace with computer database desig, ad A. Wardlaw for his helpful advice. REFERENCES 1 Neville RG, Pearso MG, Richards N, et al. A cost aalysis o the patter of asthma prescribig i the UK. 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