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Effects of inhaled corticosteroids on sputum cell counts in stable chronic obstructive pulmonary disease:… Gan, Wen Q; Man, SF P; Sin, Don D Feb 11, 2005

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ralssBioMed CentBMC Pulmonary MedicineOpen AcceResearch articleEffects of inhaled corticosteroids on sputum cell counts in stable chronic obstructive pulmonary disease: a systematic review and a meta-analysisWen Qi Gan†, SF Paul Man and Don D Sin*†Address: From the James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul's Hospital and the Department of Medicine (Pulmonary Division), University of British Columbia, Vancouver, B.C., CanadaEmail: Wen Qi Gan - wgan@mrl.ubc.ca; SF Paul Man - pman@providencehealth.bc.ca; Don D Sin* - dsin@mrl.ubc.ca* Corresponding author    †Equal contributorsAbstractBackground: Whether inhaled corticosteroids suppress airway inflammation in chronicobstructive pulmonary disease (COPD) remains controversial. We sought to determine the effectsof inhaled corticosteroids on sputum indices of inflammation in stable COPD.Methods: We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Databases forrandomized, controlled clinical trials that used induced sputum to evaluate the effect of inhaledcorticosteroids in stable COPD. For each chosen study, we calculated the mean differences in theconcentrations of sputum cells before and after treatment in both intervention and control groups.These values were then converted into standardized mean differences to accommodate thedifferences in patient selection, clinical treatment, and biochemical procedures that were employedacross original studies. If significant heterogeneity was present (p < 0.10), then a random effectsmodel was used to pool the original data. In the absence of significant heterogeneity, a fixed effectsmodel was used.Results: We identified six original studies that met the inclusion criteria (N = 162 participants). Instudies with higher cumulative dose (≥ 60 mg) or longer duration of therapy (≥ 6 weeks), inhaledcorticosteroids were uniformly effective in reducing the total cell, neutrophil, and lymphocytecounts. In contrast, studies with lower cumulative dose (< 60 mg) or shorter duration of therapy(< 6 weeks) did not demonstrate a favorable effect of inhaled corticosteroids on these sputumindices.Conclusions: Our study suggests that prolonged therapy with inhaled corticosteroids is effectivein reducing airway inflammation in stable COPD.BackgroundChronic obstructive pulmonary disease (COPD) is charac-terized by prominent airway inflammation [1,2]. Theerbations [5]. Moreover, increased expression ofinflammatory markers in the sputum is associated withincreased risk of exacerbations [6]. The attenuation of thePublished: 11 February 2005BMC Pulmonary Medicine 2005, 5:3 doi:10.1186/1471-2466-5-3Received: 13 September 2004Accepted: 11 February 2005This article is available from: http://www.biomedcentral.com/1471-2466/5/3© 2005 Qi Gan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 14(page number not for citation purposes)intensity of the inflammation strongly correlates with dis-ease severity [3,4] and increases even further during exac-inflammatory process, on the other hand, is associatedwith improvements in lung function and airwayBMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3hyperresponsiveness in COPD [7]. It is possible thereforethat the inflammatory process is an integral component inCOPD pathogenesis and may represent an importanttherapeutic target in improving the health status and out-comes of COPD patients [1,2].One potential therapy for down-regulating the inflamma-tory process in the airways is through the use of corticos-teroids, which are potent but non-specific anti-inflammatory agents. Some in vitro studies have demon-strated that inhaled corticosteroids can modulate certainaspects of the inflammatory cascade in COPD [8,9]; how-ever, other studies have shown less favorable results[10,11]. Despite this uncertainty, large clinical trials haveshown that these medications reduce clinically relevantexacerbations by ~30% and improve health status ofpatients with moderate to severe disease [12]; their with-drawal, on the other hand, leads to increased risk of exac-erbations and worsening of health status [13]. Sinceairway inflammation is associated with exacerbations [6]and since inhaled corticosteroids reduce exacerbations[12], they may also have salutary effect on airway inflam-mation in COPD. However, to date, the clinical studies,which have addressed this issue, have been small in sizeand scope and may not have had sufficient statisticalpower (on their own) to detect subtle but important effectof these medications on inflammatory indices in the air-ways. Additionally, there may be important methodologicdifferences between the positive and negative studies thatcould potentially explain the discrepancy. We, therefore,conducted a systematic review and a meta-analysis todetermine whether inhaled corticosteroids do or do notsuppress airway inflammation in patients with stableCOPD and to explore the potential causes for the hetero-geneity in reports.MethodsSearch for relevant studiesMEDLINE (1966–2004), EMBASE (1980–2004),CINAHL (1982–2004), and the Cochrane Databases weresearched for randomized, controlled clinical trials thatused induced sputum to evaluate the effect of inhaled ster-oids on airway inflammation in stable COPD. The searchwas restricted on articles published in the English lan-guage, using human participants. Subject headingsincluded disease-specific search terms (COPD, lung dis-eases, pulmonary diseases, airway obstruction, obstruc-tive pulmonary disease, chronic obstructive pulmonarydisease, bronchitis, emphysema, pulmonary emphysema,or mediastinal emphysema), drug-specific search terms(glucocorticosteroids, corticosteroids, beclomethasone,budesonide, fluticasone, or triamcinolone), and labora-tory method-specific search terms (biopsy, bronchoalveo-supplement the electronic searches. We contacted the pri-mary authors for additional data and/or clarification ofdata.Study selection and data abstractionThe primary objective of this meta-analysis was to com-pare the changes in sputum inflammatory indices amongstable COPD patients before and after treatment withinhaled corticosteroids, using the control group in eachindividual studies as the referent. We chose sputum as theprimary source of the analysis because there was a markedscarcity of quality studies which had evaluated the effectof inhaled corticosteroids from bronchoalveolar lavagefluid or tissue biopsy specimens. The inflammatory indi-ces included total cell, neutrophil, macrophage, eosi-nophil, lymphocyte, and epithelial cell counts andinterleukin (IL)-8 levels. Since the actions of oral corticos-teroids may differ from those of inhaled corticosteroids,we excluded studies that evaluated the effects of oral cor-ticosteroids on sputum inflammatory indices. From eachselected article, two investigators (WQG, DDS) abstractedthe following baseline information: the source of data,study design, inclusion and exclusion criteria, concomi-tant drugs, demographics of study participants includingsample size, age, sex, current smoking status, pack-years ofsmoking history, predicted forced expiratory volume inone second (FEV1), the ratio of FEV1 to forced vital capac-ity (FVC), percent predicted reversibility with inhaledbronchodilator, the specific brand of inhaled corticoster-oids and the dose as well as the duration of therapy.Cumulative dose of inhaled corticosteroids was calculatedby multiplying the average daily dose by the total days oftreatment. All formulations were converted to beclometh-asone equivalent based on the recommendations fromthe Canadian Asthma Consensus Report [14]. Any ques-tions or discrepancies were resolved through iteration andconsensus.Statistical methodsTo accommodate any differences in patient selection, clin-ical treatment, and biochemical procedures that wereemployed across the original studies, we converted theabsolute mean differences in the concentrations of theinflammatory cells between the intervention and controlgroups into standardized mean differences. For eachstudy, standardized mean difference was derived by divid-ing the mean change in the inflammatory cell concentra-tion at follow-up visit from the baseline visit betweenintervention and control groups by a pooled standarddeviation of the mean change [15,16]. A negative stand-ardized mean difference indicated that the participantsassigned to inhaled corticosteroids had lower cell countscompared with placebo at the end of the study phase;Page 2 of 14(page number not for citation purposes)lar lavage, or sputum). We also scanned thebibliographies and reference lists of retrieved articles towhereas a positive number denoted increased cell countrelative to the control group. For each inflammatory cell,BMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3we tested the heterogeneity of results across the studies,using a Cochran Q test. If significant heterogeneity waspresent (p < 0.10), then a random effects model was used.In the absence of significant heterogeneity, a fixed effectsmodel was used [16]. We also evaluated the potentialmodifying effect of cumulative dose and the duration oftherapy of the trials. We reasoned that trials that hadhigher cumulative dose (or longer duration of therapy)defined as greater or equal to the median cumulative dose(or duration of therapy) of all the trials included in thismeta-analysis would be more "positive" than those thatused lower doses (or were shorter in duration). All analy-ses were conducted using Review Manager version 4.2(Revman; The Cochrane Collaboration, Oxford, England)ResultsA summary of the search strategy is shown in Figure 1. Theoriginal search yielded 155 and 63 citations in MEDLINEand EMBASE, respectively. CINAHL and the CochraneDatabases did not contribute to the search results. Theabstracts of these articles were selected and reviewed. Ofthese, 21 articles were retrieved for a detailed review. Weexcluded the study from Loppow and colleagues [17]because it included 6 patients with a positive skin pricktest against at least one common airborne allergen and 4patients who had FEV1/FVC > 0.7. We excluded additional14 articles because of other reasons (Figure 1). This proc-ess left 6 original studies meeting the inclusion and exclu-sion criteria, which were used for the analyses [7,18-22].Study selection processFigure 1Study selection process Search results: n=218   MEDLINE: n=155   EMBASE:  n=63 Did not meet criteria or duplicate articles: n=198   Studies retrieved: n=21 Did not meet definition of COPD: n=1Oral medication: n=4 No sputum indices reported: n=10 Studies included in analyses: n=6Page 3 of 14(page number not for citation purposes)and were two-tailed in nature. The baseline information concerning the study designs issummarized in Table 1. The relevant demographic dataBMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3are summarized in Table 2. All 162 patients were currentor ex-smokers with post-bronchodilator FEV1 <70 % pre-dicted, FEV1 to FVC ratio <0.7, and reversibility with bron-chodilator of <15%. The medications used includedsone propionate. The study period of these trials rangedfrom 2 to 12 weeks.After treatment with inhaled corticosteroids, the total cellTable 1: Baseline information on original studies included in the meta-analysis.Source Setting Design Inclusion Criteria Exclusion Criteria Concomitant drugsWithdrawal Sputum specimenSugiura et al 2003 [7]NR Randomized, placebo-controlled parallel design.FEV1/FVC < 0.7; all patients wereex-smokers who had stopped smoking for at least 1 year beforethe study.A history of perennial allergic rhinitis; positiveallergen skin prick tests and RAST assay; a history of periodicwheezing; an improvement in FEV1 of more than 12 % predicted oran absolute increase of 200 ml after inhalation of 200 µg salbutamol; had bronchial or respiratory tract infectionsin the month preceding the study; had taken systemic steroids in the 2 monthsbefore the study or inhaled steroids in the month beforethe study.NR None NRKeatings et al 1997 [18]Outpatient clinics in different hospitalsRandomized, single-blind, crossover design with 3–7 day run in period. The clinical part of the study was single-blind, but all differential cell counting and assayswere carried out in a double blind fashion.FEV1/FVC < 0.7; FEV1 < 70% predicted; reversibility with inhaled albuterol of <10% of predicted FEV1; smoking history of at least 10 pack-years; negative results on skin prick testing to four common aeroallergens.Patients who had taken inhaled or oral steroids or who had suffered an exacerbation of their airway disease in the previous 6 weeks, or patients with any history of asthma or variability in symptoms were excluded.Albuterol was allowed.2 subjects NRCulpitt et al 1999 [19]Outpatient clinicRandomized, double-blind, placebo-controlled crossover design with a run-in period of 2 weeks.FEV1/FVC < 0.7; postbronchodilat or FEV1 <85% predicted; reversibility with inhaled β2-agonist of <15% of predicted FEV1; smoking history of at least 20 pack-years.Patients who had taken inhaled or oral steroids or who had suffered an exacerbation of their airway disease in the previous 6 weeks, or patients with any history of asthma or atopy or variability in symptoms were excluded.Three subjects had concomitant treatment with albuterol (200 µg twice a day) and ipratropium bromide (40 µg twice a day), one subject with albuterol (200 µg as needed) alone.12 subjects Samples were considered adequate for analysis if there was < 50% squamous cell contamination.Confalonieri 1998 [20]Outpatient clinicRandomised, controlled, open study. The clinical parts of the study was open, but all differential cell counting was carried out in a double blind fashion.FEV1/FVC <88% of predicted in men and <89% in women; all patients were current smokers.Patients who had taken inhaled or oral steroids or had suffered a respiratory tract infection in the previous three months were excluded.None of the patients was taking theophyllines or long acting β2 agonists.None Samples were discarded if viability levels were 50% or less, or squamous contamination was 20% or more. An overall differential cell count on 500 nucleated non-squamous cells was performed by two examiners and results reported as mean of the two counts.Mirici et al 2001 [21]Outpatient clinicRandomized, double-blind, placebo-controlled parallel design.FEV1 < 70% predicted; no self-reported asthma; reversibility with inhaled terbutaline of <15% of predicted FEV1; current smokers.Long-term treatment with oral or inhaled steroids within 6 months of study entry; A respiratory tract infection in previous 3 months; pregnancy or lactation, or presence of other serious systemic diseases.β2 – agonists of all kinds, theophylline, and mucolytics were allowed.10 subjects Samples were discarded if viabilitylevels were 50% or less, or squamous contamination was 20% or moreYildiz et al 2000 [22]Outpatient clinicRandomized, placebo-controlled parallel design with a run-in period of 2 weeks.FEV1/FVC < 0.7; FEV1 < 70% predicted; reversibility with inhaled albuterol of <10% of predicted; smoking history of at least 10 pack-years.Patients with any history of asthma or variability in symptoms, and patients who had taken inhaled or oral steroids or had suffered a respiratory tract infection or exacerbation in the previous 6 weeks were excluded.All of the patients continued to inhale both salbutamol and ipatropium bromide. In 9 patients, sustained release theophylline was also administered.None NRAbbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; NR, not reported.Page 4 of 14(page number not for citation purposes)budesonide, beclomethasone dipropionate, and flutica- counts decreased. Overall, the standardized mean differ-ence between steroid and control groups was -0.43 unitsBMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3Table 2: The characteristics of COPD patients at baseline.Source Number of PatientsAge (year)Men (%)Current Smokers (%)Pack-yearsFEV1(% predicted)Ratio (%) Reversibility (% predicted)Drug Dose(mg/day)Duration (weeks)Cumulative dose (mg) #Sugiura [7] 18‡ 70(7) 89 0* NR 1.2(0.4)† <70 <12 Beclomethasone 0.8 4 22.4Keatings [18] 26 45–78 60 46 >10 35.1(4.7) <70 <10 Budesonide 1.6 2 28.0Culpitt [19] 26 43–73 62 69 >20 49.5(16.6) <70 <15 Fluticasone 1.0 4 56.0Confalonieri [20]34 58 (5) 59 100 NR 59.7(37.1) 67 (5) NR Beclomethasone 1.5 8 84.0Mirici [21] 40 53(10) 75 100 26.5 (16.1) 62.0(7.4) NR <15 Budesonide 0.8 12 84.0Yildiz [22] 18 64(7) 78 89 52.0 (23.4) 44.5(2.7) 57 (3) <10 Fluticasone 1.5 8 168.0† FEV1, liter;‡ 6 patients in control group* All subjects were ex-smokers and stopped smoking for at least 1 year.# Cumulative dose = daily dose × days × adjusted factor for beclomethasone equivalence [14].Continuous variables are presented as mean (SD)Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ratio, the ratio of FEV1 to FVC; NR, not reported/not calculable.Effect of inhaled corticosteroids on total cell counts in the sputum of stable COPD patientsFigure 2Effect of inhaled corticosteroids on total cell counts in the sputum of stable COPD patients-2.0 -1.6 -1.2 -0.8 -0.4 0.0 0.4 0.8 1.2 1.6 2.0Confalonieri20Keatings18Mirici21Sugiura7Yildiz22Overall Pooled SummaryPooled result (cumulative dose < 60 mg & < 6 weeks)Pooled result (cumulative dose ≥ 60 mg & ≥ 6 weeks)Culpitt19Standardized Mean Difference (95% CI) of Total Cell Count5684StudyCumulative Dose(mg)282284168Favors SteroidsFavors ControlsDuration(weeks)4248128Page 5 of 14(page number not for citation purposes)BMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3(95% confidence interval, CI, -0.75 to -0.11), indicatingthat inhaled corticosteroids had a favorable effect inreducing total count compared with controls (test for het-erogeneity, p = 0.35) (Figure 2). Importantly, the totalcumulative dose of inhaled corticosteroids calculated onthe basis of mean daily dose and duration of therapymade a material difference to the results. In the studies inwhich patients were exposed to 60 mg or greater ofbeclomethasone or its equivalent for the duration of thetrial, inhaled corticosteroids were effective in reducing thetotal sputum cell count (-0.68 units; 95% CI, -1.11 to -0.26). In contrast, trials with cumulative dose of < 60 mgdid not demonstrate a favorable effect of inhaled corticos-teroids on this sputum index (-0.11 units; 95% CI, -0.58oids for at least 6 weeks; whereas, the trials with the lowercumulative dose was uniformly less than 6 weeks induration.Inhaled corticosteroids had a salutary effect on neutrophilcounts in the sputum. As compared with the controlgroup, the standardized mean difference in those treatedwith inhaled corticosteroids was -2.16 units (95% CI, -3.81 to -0.50; test for heterogeneity, p < 0.001) (Figure 3).Similar to the findings on the total cell count, trials with acumulative dose of ≥ 60 mg of beclomethasone (or at least6 weeks of therapy) demonstrated a significant effect ofthese medications on sputum neutrophil count (-4.27units; 95% CI, -6.87 to -1.66); whereas, trials with cumu-Effect of inhaled corticosteroids on neutrophils in the sputum of stable COPD patientsFigure 3Effect of inhaled corticosteroids on neutrophils in the sputum of stable COPD patients-10.0-8.0 -6.0 -4.0 -2.0 0.0 2.0 4.0 6.0 8.0 10.0Keatings18Sugiura7Pooled result (cumulative dose < 60 mg & < 6 weeks)Culpitt19 56StudyCumulative Dose(mg)2822Duration(weeks)424Confalonieri20Mirici21Yildiz2284841688128Overall Pooled SummaryPooled result (cumulative dose ≥ 60 mg & ≥ 6 weeks)Standardized Mean Difference (95% CI) of NeutrophilsFavors SteroidsFavors ControlsPage 6 of 14(page number not for citation purposes)to 0.37). All of the trials with the higher cumulative dosehad exposed the trial participants to inhaled corticoster-lative dose of < 60 mg (or less than 6 weeks of therapy)BMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3failed to demonstrate a beneficial effect (-0.26 units; 95%CI, -0.74 to 0.22).Inhaled corticosteroids also reduced the lymphocytecounts in the sputum (standardized mean difference, -0.39 units, 95% CI, -0.74 to -0.05; test for heterogeneity,p = 0.58) (Figure 4). Trials with cumulative dose of ≥ 60mg (or at least 6 weeks of therapy) demonstrated a signif-icant effect (standardized mean difference, -0.59 units;95% CI, -1.01 to -0.17); whereas, trials with cumulativedose < 60 mg (or less than 6 weeks of therapy) failed todemonstrate a salutary effect on this endpoint (standard-ized mean difference, 0.02; 95% CI, -0.59 to 0.62).mean difference, -0.51 units, 95% CI, -0.98 to -0.05; testfor heterogeneity, p = 0.20) (Figure 5). There was an insig-nificant trend towards reducing eosinophil counts in thesputum with inhaled corticosteroid therapy (standardizedmean difference, -0.28 units, 95% CI, -0.62 to 0.07; testfor heterogeneity, p = 0.22) (Figure 6). Inhaled corticos-teroids did not appear to have any significant effect onmacrophage concentrations in the sputum (standardizedmean difference, -0.02 units, 95% CI, -0.34 to 0.29; testfor heterogeneity, p = 0.65) (Figure 7). Inhaled corticos-teroids did not have significant effect on sputum IL-8 lev-els (standardized mean difference, -0.22 units; 95% CI, -0.77 to 0.32; test for heterogeneity, p = 0.84).Effect of inhaled corticosteroids on lymphocytes in the sputum of stable COPD patientsFigure 4Effect of inhaled corticosteroids on lymphocytes in the sputum of stable COPD patients-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0Standardized Mean Difference (95% CI) of LymphocytesStudySugiura7Keatings18Cumulative Dose(mg)2822Duration(weeks)42Pooled result (cumulative dose < 60 mg & < 6 weeks)Confalonieri20Mirici21Yildiz22Overall Pooled SummaryPooled result (cumulative dose ≥ 60 mg & ≥ 6 weeks)84841688128Favors SteroidsFavors ControlsPage 7 of 14(page number not for citation purposes)These medications were also effective in reducing epithe-lial cell counts compared with the controls (standardizedTo evaluate whether the magnitude of the reduction in theinflammatory cells was modified by the absolute levels ofBMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3the inflammatory cells in the sputum at baseline, we per-formed a stratified analysis based on the total cell countsat baseline (see Table 3). No significant patterns wereobserved with any of the cell lines suggesting that baseline"cell load" in the sputum was not a predictor of responseto inhaled corticosteroids.After treatment with inhaled steroids, lung functionimproved slightly but neither the improvement in FEV1nor FVC reached statistical significance. For predictedFEV1, the overall standardized mean difference was 0.26units, 95% CI, -0.06 to 0.57 (test for heterogeneity, p =0.62) (Figure 8). For predicted FVC, the overall standard-DiscussionBy combining data across the clinical studies, weincreased statistical power to demonstrate a salutary effectof moderate to high doses of inhaled corticosteroids onsome inflammatory indices in the sputum of patients withstable COPD. Over a short term, these medicationsreduced neutrophil, lymphocyte and epithelial cell countsin the sputum of stable COPD patients. They had smaller(and insignificant) effect on sputum eosinophils and IL-8.They had little effect on sputum macrophages. Althoughthe magnitudes of these reductions were relatively small,they may explain why inhaled corticosteroids decreasecough and sputum production [23], reduce exacerbationsEffect of inhaled corticosteroids on epithelial cells in the sputum of stable COPD patientsFigure 5Effect of inhaled corticosteroids on epithelial cells in the sputum of stable COPD patients-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5Standardized Mean Difference (95% CI) of Epithelial CellsStudyCumulative Dose(mg)Duration(weeks)Favors SteroidsFavors ControlsConfalonieri20 848Mirici21 8412Overall Pooled SummaryPage 8 of 14(page number not for citation purposes)ized mean difference was 0.31 units; 95% CI, -0.09 to 0.70(test for heterogeneity, p = 0.23).[24], and hospitalizations [25].BMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3We also found that duration of therapy and total cumula-tive dose, which are related constructs, made a materialdifference to the overall results. Short trials (less than 6weeks in duration) were uniformly "negative"; whilelonger term trials (at least 6 weeks of therapy) were mostlypositive. Similarly, trials that exposed the patients tohigher cumulative dose were more "positive" than thosethat exposed patients to lower dose. This suggests thatduration of therapy and total cumulative doses may beimportant determinants of the effect of inhaled corticos-teroids on airway inflammation.Although corticosteroids delay neutrophil apoptosis andmay increase neutrophil survival [11,26], they also haveinstance, corticosteroids interfere with neutrophil chemo-taxis, adhesion, transmigration, oxidative bursts, andphagocytosis, thereby down-regulating the overall inflam-matory cascade [9,27]. Indeed, Llewellyn-Jones and co-workers [28] showed that 4 weeks of inhaled fluticasonetherapy can significantly reduce sputum chemotacticactivity for neutrophils and increase its elastase inhibitorycapacity in patients with well-characterized COPD. Thesedata suggest that inhaled corticosteroids can reducerecruitment and/or adhesion of neutrophils to the airwaysof COPD patients, thereby lowering the overall concentra-tion of these cells in COPD airways.Superficially, the present data on sputum eosinophilsEffect of inhaled corticosteroids on eosinophils in the sputum of stable COPD patientsFigure 6Effect of inhaled corticosteroids on eosinophils in the sputum of stable COPD patientsStandardized Mean Difference (95% CI) of Eosinophils-2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5StudyCumulative Dose(mg)Duration(weeks)Favors SteroidsFavors ControlsSugiura7Keatings18 282242Pooled result (cumulative dose < 60 mg & < 6 weeks)Confalonieri20Mirici21Yildiz22Overall Pooled SummaryPooled result (cumulative dose ≥ 60 mg & ≥ 6 weeks)84841688128Page 9 of 14(page number not for citation purposes)significant inhibitory action on neutrophil performance.Likely through the annexin-I (lipocortin-1) pathways, forappear to be inconsistent with the known effect of corti-costeroids in general on eosinophils. Many experimentsBMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3have shown that eosinophils are exquisitely sensitive tocorticosteroids [29,30]. The current data, however, suggestotherwise. Several studies have demonstrated that amongCOPD patients with irreversible airflow obstruction (aswas the case for a majority of patients enrolled in the orig-inal studies contained in this meta-analysis), eosinophilsare present in relatively small quantities in the sputum ofsuch patients [10,31]. In most COPD patients, eosi-nophils account for less than 2% of the total cells in thesputum. This could have introduced a "floor" biaswherein the overall signal to the noise ratio for eosi-nophils may have been too small to detect subtle butimportant effect of inhaled corticosteroids on these cells.Although by combining data from these published studiessputum, we may still have had insufficient power for anal-yses of cells with a relatively small signal. Our analysismay also have had insufficient power to assess the effectsof inhaled corticosteroids on FEV1. Although there was atrend towards improvement, we did not find a statisticallysignificant effect of inhaled corticosteroids on FEV1.Larger randomized trials have demonstrated, however,that inhaled corticosteroids significantly improve FEV1over the first three to six months of therapy [25,32-34],suggesting that for certain endpoints our present analysisstill lacked sufficient power. Therefore, the "negative"associations must be interpreted cautiously. It is alsoimportant to note that none of the studies included in thepresent review evaluated the effects of inhaled corticoster-Effect of inhaled corticosteroids on macrophages in the sputum of stable COPD patientsFigure 7Effect of inhaled corticosteroids on macrophages in the sputum of stable COPD patientsStandardized Mean Difference (95% CI) of Macrophages-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0StudyCumulative Dose(mg)Duration(weeks)Favors SteroidsFavors ControlsKeatings18Sugiura7Pooled result (cumulative dose < 60 mg & < 6 weeks)Culpitt19 562822424Confalonieri20Mirici21Yildiz2284841688128Overall Pooled SummaryPooled result (cumulative dose ≥ 60 mg & ≥ 6 weeks)Page 10 of 14(page number not for citation purposes)we increased the power of the present analysis to detectsalient changes in the inflammatory indices of theoids on the function or performance of inflammatory cellsin the airway. Thus, we can not discount the possibilityBMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3that these medications could have salutary effects on thefunctional performance of these cells.In the present review, we did not include randomizedstudies that used bronchoalveolar lavage (BAL) or bron-chial biopsies to measure inflammatory cells in the air-ways. However, in one study, Balbi and colleagues [35]observed significant reductions in the total number ofcells, neutrophil counts, IL-8, and myeloperoxidase levelsin the BAL fluid of COPD patients after 6 weeks of inhaledbeclomethasone therapy. A similar finding was observedand reported by Thompson and coworkers [36]. Inanother experiment, Hattotuwa at al [23] randomlygroup that received fluticasone had significantly fewermast cells in the subepithelial layer as well as a reducedratio of CD8 to CD4 positive cells in the epithelial layerthan those treated with placebo. Most importantly, thefluticasone group had significant improvements in coughand sputum scores and decreased use of reliever medica-tions and experienced fewer exacerbations than did theplacebo group [23]. Verhoeven et al [37] evaluated 23patients with COPD and randomly treated 10 patients tofluticasone (1 mg/d) and the remainder to placebo. After6 months, fluticasone treatment resulted in a significantreduction in the number of MBP and CD68 positive cellsin the lamina propria and reduced tryptase levels in theEffect of inhaled corticosteroids on FEV11% predicted in stable COPD patients. Abbreviation: FEV1, forced expiratory volume in one secondFigure 8Effect of inhaled corticosteroids on FEV11% predicted in stable COPD patients. Abbreviation: FEV1, forced expiratory volume in one second-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0Standardized Mean Difference (95% CI) of FEV1% predictedStudyCumulative Dose(mg)Duration(weeks)Favors SteroidsFavors ControlsKeatings18Sugiura7Pooled result (cumulative dose < 60 mg & < 6 weeks)Culpitt19 562822424Confalonieri20Mirici21Yildiz2284841688128Overall Pooled SummaryPooled result (cumulative dose ≥ 60 mg & ≥ 6 weeks)Page 11 of 14(page number not for citation purposes)treated a group of COPD patients with 3 months ofinhaled fluticasone propionate (1 mg/d) or placebo. Theepithelium. In addition, there was a trend towards fewerCD3, CD4 CD68 positive cells in epithelium of the groupBMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3treated with fluticasone compared with the group treatedwith placebo [37]. The results from the BAL and bronchialbiopsy studies largely support data from the sputum stud-ies and are consistent with the notion that inhaled corti-costeroids reduce airway inflammation in COPD.We also did not include studies that used systemic corti-costeroids. Barcyk and colleagues [38] have reported thatoral prednisone therapy (0.5 mg/kg/d) for 2 weeks signif-icantly reduced myeloperoxidase levels in the sputum ofCOPD patients. Brightling and colleagues [39] showedthat 2 weeks of oral prednisone therapy resulted in fewereosinophils in the sputum of COPD patients. Similarfindings were reported by Fujimoto and colleagues [40].These data suggest that oral prednisone can reduce certaincomponents of airway inflammation (e.g. eosinophils) inCOPD; however, most of the studies were very short induration, which makes it difficult to compare these dataagainst those studies that used inhaled corticosteroids.Although in the present review, we could not adequatelydetermine the effects of tobacco smoke exposure on therelationship between inhaled corticosteroids and airwayinflammation, there is a growing body of evidence to sug-gest that active smoking may attenuate the effectiveness ofcorticosteroids in suppressing airway inflammation.Active smoking increases oxidative stress and up-regulatesthe production of various pro-inflammatory cytokinesincluding Il-6, IL-8, IL-1β and monocyte chemoattractantprotein-1 in airways, which may through a series of com-plex pathways lead to a state of steroid resistance [41].Additionally, cigarette smoke may reduce histone deacety-lase activity and its expression in alveolar macrophages,making these cells relatively resistant to corticosteroidssince one of the principal targets of corticosteroid actionis by switching off gene expression of inflammatory genesimportant intervention in COPD management. Inhaledcorticosteroids should be considered as a possible adjunc-tive therapy in patients who remain symptomatic despitesmoking cessation.There are certain limitations with the present analysis.First, although we used stringent entry criteria in order tominimize the heterogeneity in the research methodsemployed by each of the selected study, there were stillsome variations in the study design, the exposure medica-tions, and the target population across the original stud-ies. However, the differences in the characteristics of thestudies were relatively small and unlikely to have materi-ally affected the overall findings of the current review. Wealso contacted the primary authors to clarify any ambigu-ities or to obtain additional data, where necessary, tofurther minimize the "noise" inherent to meta-analyses.Moreover, to accommodate various differences in themethodology of data collection and laboratory tech-niques employed across the original studies, we convertedthe individual data into standardized mean estimates,which enhanced the comparability of data across the orig-inal studies. Second, it is possible that corticosteroid ther-apy could have affected the volume of sputum recovery,decreasing the total sputum cell counts in those patientsexposed to this therapy. To mitigate this possibility, thecell counts were expressed as cells per volume of sputumrecovered.ConclusionsIn summary, the present meta-analysis suggests thatinhaled corticosteroids when used for longer than 6 weekscan significantly reduce neutrophil counts and otherinflammatory indices in the sputum of patients withstable COPD. Large randomized controlled trials areneeded in the future to confirm these early findings and toTable 3: Total and differential cell counts at baseline and the standard mean difference (SMD) in cell counts between intervention group and placebo group after treatment.Source Total cells Neutrophils Lymphocytes Eosinophils MacrophagesNumber (× 104/mL)SMD (95% CI) Number (× 104/mL)SMD (95% CI) Number (× 104/mL)SMD (95% CI) Number (× 104/mL)SMD (95% CI) Number (× 104/mL)SMD (95% CI)Yildiz [22] 350.0 -0.6 (-1.6 to 0.4) 260.0 -2.2 (-3.4 to -1.0) 3.5 -0.5 (-1.4 to 0.5) 7.0 -1.1 (-2.1 to -0.1) 80.0 0.2 (-0.5 to 0.9)Confalonieri [20]219.0 -0.4 (-1.1 to 0.3) 158.8 -3.4 (-4.5 to -2.3) 6.6 -0.5 (-1.2 to 0.2) 6.2 -0.6 (-1.3 to 0.1) 45.0 -0.3 (-0.9 to 0.3)Mirici [21] 196.5 -1.0 (-1.7 to -0.3) 146.5 -7.5 (-9.3 to -5.6) 1.6 -0.7 (-1.4 to -0.1) 1.6 0.2 (-0.4 to 0.8) 38.2 0.5 (-0.5 to 1.5)Sugiura [7] 165.7 0.2 (-0.8 to 1.2) 102.9 0.1 (-0.9 to 1.1) 6.1 0.04 (-0.9 to 1.0) 4.5 -0.2 (-1.2 to 0.8) 52.0 -0.3 (-1.1 to 0.5)Culpitt [19] 165.0 -0.3 (-1.1 to 0.5) 145.0 -0.4 (-1.2 to 0.4) NR NR NR NR 25.0 -0.2 (-0.9 to 0.6)Keatings [18] 6.3* -0.1 (-0.9 to 0.7) 4.3* -0.4 (-1.1 to 0.4) 6.0* 0.0 (-0.7 to 0.8) 0.2* -0.2 (-1.0 to 0.6) 1.8* 0.2 (-0.7 to 1.2)Pooled Summary-0.4 (-0.8 to -0.1) -2.2 (-3.8 to -0.5) -0.4 (-0.7 to -0.1) -0.3 (-0.6 to 0.1) -0.02 (-0.3 to 0.3)* cell count/mlAbbreviations: NR, not reported/not calculable.Page 12 of 14(page number not for citation purposes)through the recruitment of histone deacetylases [41].Therefore smoking cessation remains the single mostdetermine whether these salutary effects persist longerthan 3 to 4 months of therapy.BMC Pulmonary Medicine 2005, 5:3 http://www.biomedcentral.com/1471-2466/5/3AbbreviationsCOPD chronic obstructive pulmonary diseaseFEV1 forced expiratory volume in 1 secondFVC forced vital capacitySD standard deviationIL-8 interleukin-8Competing interestsDDS and SFP have received honoraria for speakingengagements from GlaxoSmithKline (GSK) & Astra-Zeneca, and have received consultation fees and researchfunding from GSK. However, no part of this work wasfinanced by these companies. This work was funded byCanada Research Chair and a Michael Smith/St. Paul'sHospital Foundation Professorship in COPD.Authors' contributionsAll the authors contributed to the design and implemen-tation of the study. Data analyses were performed byWQG and DDS. All authors contributed to the write-up ofthe manuscript.AcknowledgementsThe authors thank Dr. Füsu Yildiz, Dr. Hisatoshi Sugiura, and Dr. Arzu Mir-ici for providing additional data for this study.DDS is supported by a Canada Research Chair (Respiration) and a Michael Smith/St. Paul's Hospital Foundation Professorship in COPD.References1. Calverley PM, Walker P: Chronic obstructive pulmonarydisease. Lancet 2003, 362:1053-1061.2. Barnes PJ, Shapiro SD, Pauwels RA: Chronic obstructive pulmo-nary disease: molecular and cellular mechanisms. Eur Respir J2003, 22:672-688.3. 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Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, WardlawAJ, Pavord ID, Brightling CE, Monteiro W, Ward R, Parker D, MorganMD, Wardlaw AJ, Pavord ID: Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pul-monary disease: a randomised controlled trial. Lancet 2000,356:1480-1485.40. Fujimoto K, Kubo K, Yamamoto H, Yamaguchi S, Matsuzawa Y: Eosi-nophilic inflammation in the airway is related to glucocorti-coid reversibility in patients with pulmonary emphysema.Chest 1999, 115:697-702.41. Barnes PJ, Ito K, Adcock IM: Corticosteroid resistance in chronicobstructive pulmonary disease: inactivation of histonedeacetylase. Lancet 2004, 363:731-733.Pre-publication historyThe pre-publication history for this paper can be accessedhere:http://www.biomedcentral.com/1471-2466/5/3/prepubyours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralPage 14 of 14(page number not for citation purposes)

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