Efficacy of inhaled steroids in undiagnosed subjects at high risk for COPD: results of the detection, intervention, and monitoring of COPD and asthma program. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial The response to inhaled and oral steroids in patients with stable chronic obstructive pulmonary disease. A trial of inhaled budesonide on airway responsiveness in smokers with chronic bronchitis. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease The effect of inhaled glucocorticosteroids in emphysema due to alpha1-antitrypsin deficiency. Influence of treatment on peak expiratory flow and its relation to airway hyperresponsiveness and symptoms. The Dutch CNSLD Study Group. A randomized, double-blind study comparing the effects of beclomethasone and fluticasone on bone density over two years. Aerosolized beclomethasone in chronic bronchitis. Improved pulmonary function and diminished airway inflammation. Health status deterioration in patients with chronic obstructive pulmonary disease. Airways hyperresponsiveness, bronchodilator response, allergy and smoking predict improvement in FEV1 during long-term inhaled corticosteroid treatment. Dutch CNSLD Study Group. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results The TORCH (TOwards a Revolution in COPD Health) survival study protocol Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Randomised controlled trial of inhaled corticosteroids in patients with chronic obstructive pulmonary disease. Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study Effects of fluticasone propionate in COPD patients with bronchial hyperresponsiveness Effects of long-term treatment with corticosteroids in COPD. Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease. Effects of fluticasone propionate on inflammatory cells in COPD: an ultrastructural examination of endobronchial biopsy tissue Effect of an inhaled glucocorticoid on reactive oxygen species production by bronchoalveolar lavage cells from smoking COPD patients. Importance of total serum IgE for improvement in airways hyperresponsiveness with inhaled corticosteroids in asthma and chronic obstructive pulmonary disease. The Dutch CNSLD Study Group. Inhaled corticosteroids in stable COPD patients: do they have effects on cells and molecular mediators of airway inflammation? Lack of long-term adverse adrenal effects from inhaled triamcinolone: Lung Health Study II. Short-term treatment with budesonide does not improve hyperresponsiveness to adenosine 5'-monophosphate in COPD. Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. [Clinical study of inhaled corticosteroid in non-asthmatic chronic obstructive pulmonary disease]. Predictive value and utility of oral steroid testing for treatment of COPD in primary care: the COOPT study Impact of preventing exacerbations on deterioration of health status in COPD Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease Maintenance therapy with budesonide and formoterol in chronicobstructive pulmonary disease Inhaled budesonide therapy for patients with stable COPD. Inhaled budesonide in chronic bronchitis. Effects on respiratory impedance. Withdrawal from treatment as an outcome in the ISOLDE study of COPD. A randomized controlled trial on the effect of inhaled corticosteroids on airways inflammation in adult cigarette smokers. A double-blind comparison of oral prednisolone 40 mg/day with inhaled beclomethasone dipropionate 1500 ug/day in patients with adult onset chronic obstructive airways disease. Effect of fluticasone propionate on sputum of patients with chronic bronchitis and emphysema. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease Cardiovascular events in patients with COPD: TORCH Study results The effects of inhaled corticosteroids on chronic airflow limitation. [Inhaled budesonide for chronic obstructive pulmonary disease]. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease Inhaled beclomethasone improves the course of asthma and COPD. The influence of an inhaled steroid on quality of life in patients with asthma or COPD. [Long-term effect of inhaled budesonide in patients with mild to moderate chronic obstructive lung disease. The Osterbro Study]. Does addition of inhaled steroid to combined bronchodilator therapy affect health status in patients with COPD? Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Long-term mortality follow-up of the ISOLDE participants: causes of death during 13 years after trial completion. The effect of inhaled corticosteroids on bronchoalveolar lavage cells and IL-8 levels in stable COPD patients. Costs and effects of inhaled corticosteroids and bronchodilators in asthma and chronic obstructive pulmonary disease. Effect of adjunct fluticasone propionate on airway physiology during rest and exercise in COPD. Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Controlled Trial of Inhaled Fluticasone Propionate in Moderate to Severe COPD 
 Slowing the Deterioration of Asthma and Chronic Obstructive Pulmonary Disease Observed during Bronchodilator Therapy by Adding Inhaled Corticosteroids: A 4-Year Prospective Study Rapid Fall in Lung Density Following Smoking Cessation in COPD Reported pneumonia in patients with COPD: findings from the INSPIRE study. Effects of high dose inhaled beclomethasone dipropionate, 750 micrograms and 1500 micrograms twice daily, and 40 mg per day oral prednisolone on lung function, symptoms, and bronchial hyperresponsiveness in patients with non-asthmatic chronic airflow obstruction. Cost effectiveness of budesonide/formoterol in a single inhaler for COPD compared with each monocomponent used alone Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study. Controlled short-term trial of fluticasone propionate in ventilator-dependent patients with COPD. Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease. Compliance During Long-Term Treatment with Fluticasone Propionate in Subjects with Early Signs of Asthma or Chronic Obstructive Pulmonary Disease (COPD): Results of the Detection, Intervention, and Monitoring Program of COPD and Asthma (DIMCA) Study A double‐blind placebo‐controlled study of the effect of inhaled beclomethasone dipropionate for 2 years in patients with nonasthmatic chronic obstructive pulmonary disease Inhaled Corticosteroids as Additional Treatment in Alpha-1-Antitrypsin-Deficiency-Related COPD Loss of bone density with inhaled triamcinolone in Lung Health Study II. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Exhaled nitric oxide and hydrogen peroxide in patients with chronic obstructive pulmonary disease: effects of inhaled beclomethasone. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Time course of response to oral and inhaled corticosteroids in non-asthmatic chronic airflow obstruction. Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis. Skin manifestations of inhaled corticosteroids in COPD patients: results from Lung Health Study II. Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler® Variability of bronchodilator response and effects of inhaled corticosteroid treatment in obstructive airways disease. Dutch CNSLD Study Group. Short- and long-term efficacy of fluticasone propionate in subjects with early signs and symptoms of chronic obstructive pulmonary disease. Results of the DIMCA study. Failure of inhaled corticosteroids to modify bronchoconstrictor or bronchodilator responsiveness in middle-aged smokers with mild airflow obstruction. Gender does not influence the response to the combination of salmeterol and fluticasone propionate in COPD. The cost effectiveness of early treatment with fluticasone propionate 250 microg twice a day in subjects with obstructive airway disease. Results of the DIMCA program. Effect of single inhalation of a salbutamol, ipratropium bromide and beclomethasone on mucociliary clearance in patients with chronic obstructive airway disease. Is delayed introduction of inhaled corticosteroids harmful in patients with obstructive airways disease (asthma and COPD)? The Dutch CNSLD Study Group. The Dutch Chronic Nonspecific Lung Disease Study Groups. Additive effects of prednisolone and beclomethasone dipropionate in patients with stable chronic obstructive pulmonary disease. Response to corticosteroids in chronic airflow obstruction: relationship to emphysema and airways collapse. The efficacy and safety of inhaled fluticasone propionate/salmeterol and ipratropium/albuterol for the treatment of chronic obstructive pulmonary disease: an eight-week, multicenter, randomized, double-blind, double-dummy, parallel-group study. The European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): recruitment methods and strategies. Inhaled corticosteroids reduce neutrophilic bronchial inflammation in patients with chronic obstructive pulmonary disease The effect of high-dose inhaled beclomethasone dipropionate in patients with stable COPD. In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammation. The efficacy of inhaled corticosteroids in the management of non asthmatic chronic airflow obstruction. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): hypothesis and design. The Effect of Inhaled Corticosteroids on the Development of Emphysema in Smokers Assessed by Annual Computed Tomography Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. Steroid reversibility test followed by inhaled budesonide or placebo in outpatients with stable chronic obstructive pulmonary disease. The Danish Society of Respiratory Medicine. An observational study of inhaled corticosteroid withdrawal in stable chronic obstructive pulmonary disease. ISOLDE Study Group. Inhaled Corticosteroids May Reduce Neutrophilic Inflammation in Patients with Stable Chronic Obstructive Pulmonary Disease A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. Dutch Chronic Non-Specific Lung Disease Study Group. Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction. Beclomethasone dipropionate does not affect mucociliary clearance in patients with chronic obstructive lung disease. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial Changes in forced expiratory volume in 1 second over time in COPD.
BACKGROUND AND AIM COPD leads to a progressive decline of pulmonary function . Family physicians treat a substantial number of patients with COPD and are encouraged to start treatment at as early a stage as is possible . This study analyzed the effectiveness of early inhaled corticosteroid treatment on the decline of pulmonary function in COPD patients . PATIENTS AND SETTING Subjects with a rapid decline in lung function ( ie , FEV(1 ) decline , > 80 mL/yr ) who had never before received a diagnosis of asthma or COPD . METHODS Two-year , r and omized , controlled , double-blind clinical trial of fluticasone propionate ( 250 microg bid ; 24 patients ) or placebo ( 25 patients ) , followed by a 7-month open-label study in which all subjects received fluticasone propionate . The primary outcome was the post-bronchodilator therapy FEV(1 , ) and secondary outcomes were respiratory symptoms , exacerbations , health state , quality of life , and health-care utilization . RESULTS After 31 months , there were no statistical differences in post-bronchodilator therapy FEV(1 ) between the intervention group and the control group . No statistical differences were observed for symptoms , exacerbations , or quality of life , although tendencies were consistently in favor of treatment . There was no significant impact on the direct or indirect costs . CONCLUSIONS There are no indications that early treatment with inhaled corticosteroids modifies a rapid decline in lung function or respiratory symptoms and quality of life Background : Airway inflammation in chronic obstructive pulmonary disease ( COPD ) is characterised by infiltration of CD8 + T cells and CD68 + macrophages and an increased number of neutrophils , whereas few studies have described the presence of eosinophils . Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear , recent studies suggest that combination therapy could be beneficial . A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate ( SFC ) and fluticasone propionate ( FP ) alone on inflammatory cells in the airways of patients with COPD . Methods : Patients were treated in a r and omised , double blind , parallel group , placebo-controlled trial with either a combination of 50 µg salmeterol and 500 µg FP twice daily  ( SFC , n = 19 , 19 men , mean age 62 years ) , 500 µg FP twice daily ( n = 20 , 15 men , mean age 64 years ) or placebo  ( n = 21 , 17 men , mean age 66 years ) for 3 months . At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8 + T lymphocytes , CD68 + macrophages , neutrophils and eosinophils were measured . Results : CD8 + cells were significantly reduced by SFC compared with placebo ( difference −98.05 cells/mm2 ; 95 % CI −143.14 to −52.9 ; p<0.001 ) . Such a marked effect was not seen with FP alone ( −44.67 cells/mm2 ; 95 % CI −90.92 to 1.57 ; p = 0.06 ) . CD68 + macrophages were also reduced by SFC compared with placebo ( difference −31.68 cells/mm2 ; 95 % CI −61.07 to −2.29 ; p = 0.03 ) but not by FP . SFC did not significantly change neutrophils and eosinophils compared with placebo . Conclusions : SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone BACKGROUND A significant minority of patients with COPD have favourable response to corticosteroid treatment . In addition , the benefit of corticosteroid treatment may be outweighed by the side-effects . Long-term administration of inhaled steroids is a safe means of treatment . However , only a few studies have addressed the role of inhaled steroids in patients with COPD , with conflicting results . METHODS Forty-four patients with stable COPD were defined as ' responders to bronchodilators ' ( increase in FEV1 > or = 20 % following administration of  beta 2-agonist ) ( group A ) , and 124 as ' non-responders to bronchodilators ' ( group B ) . All patients were r and omized to receive a 6-week course of either a daily dose of 800 micrograms of inhaled budesonide or placebo , separated by 4 weeks when no medication was taken ; were r and omized again to receive a 6-week course of either 1600 micrograms day-1 of inhaled budesonide , or 800 micrograms day-1 of inhaled budesonide plus placebo ; and were r and omized once again to receive a 6-week course of either 40 mg day-1 of prednisone or placebo . All stages were performed in a double-blind cross-over design . RESULTS Following administration of 800 micrograms day-1 of inhaled budesonide , there was an increase in the mean FEV1 from 1.40 + /- 0.20 to 1.92 + /- 0.22 L ( P < 0.001 ) and a significant decrease in inhaled beta 2 agonist consumption in group A. These changes remained almost stable during the increased dose of inhaled budesonide or during prednisone treatment . The mean FEV1 did not change during the placebo period , or in group B in either treatments . CONCLUSIONS Treatment with inhaled steroids improved spirometry data and inhaled beta 2-agonist consumption in about one-quarter of patients with stable COPD , and this rate increased to about three-quarters in patients who responded to beta 2-agonist inhalation . There was no additional benefit in using a higher dose of inhaled budesonide or prednisone The aim of the present r and omized , double-blind study was to evaluate the effect of inhaled budesonide on daily symptoms , ventilatory capacity , and airway responsiveness in smokers with chronic bronchitis . Twenty-five subjects with a provocative concentration producing a 20 % fall in forced expiratory volume in one second PC20(FEV1 ) less than 2.0 mg.ml-1 , by bronchial histamine challenge , were included . Eighteen subjects accomplished the entire 12 week study , eight receiving inhaled budesonide 400 micrograms b.i.d . and ten receiving placebo .  Cough decreased significantly in the actively treated group during the treatment period , but no change could be demonstrated in expectoration , dyspnoea , or sleep disturbances . No changes in any of these symptoms were found in the placebo group , and no differences in symptoms scores were found between the groups . No significant differences in ventilatory capacity or bronchial responsiveness could be demonstrated . In conclusion , a moderately high dose of inhaled steroid in eight subjects with chronic bronchitis did not improve the symptom scores , ventilatory capacity , or airway responsiveness to any clinical ly relevant degree Background : Chronic obstructive pulmonary disease ( COPD ) is characterised by both an accelerated decline in lung function and periods of acute deterioration in symptoms termed exacerbations . The aim of this study was to investigate whether these are related . Methods : Over 4 years ,  peak expiratory flow ( PEF ) and symptoms were measured at home daily by 109 patients with COPD ( 81 men ; median ( IQR ) age 68.1 ( 63–74 ) years ; arterial oxygen tension ( Pao2 ) 9.00 ( 8.3–9.5 ) kPa , forced expiratory volume in 1 second ( FEV1 ) 1.00 ( 0.7–1.3 ) l , forced vital capacity ( FVC ) 2.51 ( 1.9–3.0 ) l ) ; of these , 32 ( 29 men ) recorded daily FEV1 . Exacerbations were identified from symptoms and the effect of frequent or infrequent exacerbations ( > or < 2.92 per year ) on lung function decline was examined using cross sectional , r and om effects models . Results : The 109 patients experienced 757 exacerbations . Patients with frequent exacerbations had a significantly faster decline in FEV1 and peak expiratory flow ( PEF ) of –40.1 ml/year ( n=16 ) and –2.9 l/min/year ( n=46 ) than infrequent exacerbators in whom FEV1 changed by –32.1 ml/year ( n=16 ) and PEF by –0.7 l/min/year ( n=63 ) . Frequent exacerbators also had a greater decline in FEV1 if allowance was made for smoking status . Patients with frequent exacerbations were more often admitted to hospital with longer length of stay . Frequent exacerbations were a consistent feature within a patient , with their number positively correlated ( between years 1 and 2 , 2 and 3 , 3 and 4 ) . Conclusions : These results suggest that the frequency of exacerbations contributes to long term decline in lung function of patients with moderate to severe COPD Despite the success of inhaled steroids in controlling asthma , the benefit in patients with chronic obstructive pulmonary disease ( COPD ) remains controversial . Five subjects with moderate to severe emphysema due to alpha 1-antitrypsin deficiency ( phenotype PiZ ) were followed with daily home spirometry in a 2 x 8 weeks , r and omized double-blind , placebo-controlled , crossover study of inhaled budesonide 0.8 mg b.i.d . In three of the five patients , there was a statistically significant increase in the mean forced expiratory volume in 1 s ( FEV1 ) , and in two of these patients , there was also a statistically significant increase in the mean forced vital capacity ( FVC ) during budesonide treatment . A significant diurnal variation in FEV1 and FVC was found in three and two patients , respectively , but did not change significantly during treatment . These findings emphasize the need for renewed evaluation of inhaled steroids in the treatment of patients with emphysema , and indicate that individual patients may have significant clinical improvement BACKGROUND --Despite effective treatments , the morbidity and mortality of obstructive airways disease ( asthma and COPD ) remains high . Home monitoring of peak expiratory flow ( PEF ) is increasingly being advocated as an aid to better management of obstructive airways disease . The few available studies describing effects of treatment on the level and variation of PEF have involved relatively small numbers of subjects and did not use control groups . METHODS -- Patients aged 18 - 60 years were selected with PC20 < or = 8 mg/ml and FEV1 < 95 % confidence interval of predicted normal . They were r and omised to receive , in addition to a beta 2 agonist , either an inhaled corticosteroid ( BA+CS ) , an anticholinergic ( BA+AC ) , or a placebo ( BA+PL ) .  One hundred and forty one of these subjects with moderately severe obstructive airways disease completed seven periods of two weeks of morning and afternoon PEF measurements at home during 18 months of blind follow up . RESULTS --Improvements in PEF occurred within the first three months of treatment with BA+CS and was subsequently maintained : the mean ( SE ) increase in morning PEF was 51 ( 8) l/min in the BA+CS group compared with no change in the other two groups . Similarly , afternoon PEF increased by 22 ( 7 ) l/min . Diurnal variation in PEF ( amplitude % mean ) decreased from 18.0 % to 10.2 % in the first three months of treatment with BA+CS . Within-subject relations between changes in diurnal variation in PEF and changes in PC20 were found to be predominantly negative ( median rho-0.40 ) but with a large scatter . Relations between diurnal variation in PEF and changes in symptom scores , FEV1 , and bronchodilator response were even weaker . CONCLUSIONS --In patients with moderately severe obstructive airways disease , PEF rates and variation are greatly improved by inhaled corticosteroids . Since the relation of diurnal PEF variation with PC20 , symptoms , FEV1 , and bronchodilator response were all weak , these markers of disease severity may all provide different information on the actual disease state . PEF measurements should be used in addition to the other markers but not instead of them Cross-sectional studies have suggested that asthmatic patients receiving high dose inhaled corticosteroids and intermittent courses of oral corticosteroids  have reduced bone mass . This prospect i ve 2-yr study was undertaken to evaluate changes in bone density of patients receiving high doses of inhaled corticosteroids . Patients ( n = 33 ) ( males aged 18 - 50 yrs , females aged 18 - 40 yrs ) on inhaled corticosteroids 1,000 - 2,000 microg x day(-1 ) , were r and omized in a double-blind fashion to either fluticasone propionate ( FP ) 1,000 microg x day(-1 ) or beclomethasone dipropionate ( BDP ) 2,000 microg x day(-1 ) . In parallel , three open control groups of the same age range were studied : asthmatics ( n = 8) receiving low dose inhaled corticosteroids ( < or = 400 microg x day(-1 ) ) ( group A ) ; chronic , severe asthmatics ( n = 8) receiving oral corticosteroids ( > or = 10 mg x day(-1 ) ( group B ) ; and healthy untreated volunteers ( n = 7 ) ( group C ) . Bone densitometry scans ( quantitative computed tomography ( QCT ) of spine ; dual X-ray absorptiometry of spine , femoral neck , and single photon absorptiometry of forearm ) were performed at baseline and after 6 , 12 and 24 months of treatment . Biochemical bone marker measurements ( serum osteocalcin , bone alkaline phosphatase , pro-collagen type 1 carboxy terminal propeptide , deoxypyridinoline and C-telopeptide of type 1 collagen ) were collected every 3 months . Fifteen FP ( mean age 36 yrs , six male ) and 9 BDP patients ( mean age 33 yrs , five male ) ; completed the study . At 0 months , mean bone mineral density ( BMD ) was lower in patients receiving inhaled corticosteroids ( both low dose and high dose ) than in normal volunteers . In the FP-treated group , mean vertebral trabecular BMD quantitative computed tomography remained stable with no evidence of decline , whereas there was some decline in the BDP-treated group . The treatment difference between FP  and BDP was statistically significant in favour of FP for quantitative computed tomography measurements after 12 months ( p = 0.006 ) and 24 months ( p = 0.004 ) . This study suggests that over 24 months , changes in bone density are minimal in patients on high-dose inhaled corticosteroids Chronic bronchitis is associated with airways obstruction and inflammation . In order to determine whether aerosolized beclomethasone can modulate airway inflammation and diminish airway obstruction , subjects with chronic bronchitis performed spirometry and underwent bronchoalveolar lavage ( BAL ) before and after receiving 6 wk of therapy ( five puffs four times a day ) with either aerosolized beclomethasone ( n = 20 ) or placebo ( n = 10 ) in a double-blinded , r and omized fashion . All subjects received aerosolized albuterol before each use of the study medications . Before BAL , the airways were visually assessed for the appearance of inflammation and assigned a score , the bronchitis index . BAL was performed by instilling five 20-ml aliquots of saline into each of three sites and pooling and separately analyzing the returns from the first aliquots to yield a " bronchial sample . " The bronchial lavages were repeated in an additional three sites to increase the volume of fluid available for analysis . The fluid was prepared for cytologic examination by cytocentrifugation . Albumin ( as a measure of epithelium permeability ) and lactoferrin and lysozyme ( as measures of serous cell activity ) were measured in unconcentrated BAL fluid by enzyme-linked immunosorbent assay , and concentrations in epithelial lining fluid were estimated using urea as an internal marker for dilution . After treatment , the beclomethasone group , but not the placebo group , showed improvement in FVC ( p = 0.02 ) , FEV1 ( p = 0.002 ) , and 25 to 75 % forced expiratory flow ( p = 0.006 ) . Associated with the improvement in spirometry , the bronchitis index fell ( 13.5 + /- 1.0 versus 10.75 + /- 1.1 , p = 0.02 ) in the beclomethasone-treated group , but not the placebo-treated group . ( ABSTRACT TRUNCATED AT 250 WORDS This study examined health status decline in patients with chronic obstructive pulmonary disease ( COPD ) . Data are from the Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) trial . After an 8-wk run-in , 751 patients ( 566 male ) , mean age 64 yr , were r and omized to receive fluticasone propionate ( FP ) 500 microg twice daily ( 376 patients ) or placebo ( 375 patients ) . Mean baseline postbronchodilator FEV1 was 50 + /- 15 % predicted . Patients completed the St George 's Respiratory Question naire ( SGRQ ) and the Short-Form 36 ( SF-36 ) at baseline and every 6 mo for 3 yr . FEV1 and smoking status were assessed at baseline and at 3-mo intervals . A total of 387 ( 212 FP ) patients completed the trial . All SGRQ components ( p = 0.03 to 0.004 ) and Physical Function , Mental Health , Energy/ Vitality , and Physical Role Limitation scales of the SF-36 ( p = 0.05 to 0.005 ) deteriorated faster in the placebo group . FEV1 and SGRQ scores correlated at baseline values ( r = -0.25 , p < 0.0001 ) , as did change in FEV1 and change in SGRQ ( Delta r = -0.24 , p < 0.0001 ) . At baseline values smokers had worse SGRQ Total , Symptoms , and Impacts scores than ex-smokers . This difference was maintained throughout the study . Smoking status did not influence the rate of decline in health status . The SGRQ Total scores of FP-treated patients took 59 % longer than placebo to deteriorate by a clinical ly significant amount . We conclude that health status decline in moderate to severe COPD can be reduced by high-dose fluticasone Although most patients with obstructive airways disease show some amelioration with long-term inhaled corticosteroid therapy , the extent of improvement may vary considerably between patients . Patients with mild to moderately severe obstructive airways disease ( asthma and COPD ) were selected if provocative concentration producing a 20 % fall in forced expiratory volume in one second ( PC20 ) < or = 8 mg.ml-1 , and forced expiratory volume in one second ( FEV1 ) < 95 % confidence intervals ( CI ) of predicted normal . The independent influences of baseline PC20FEV1 , inspiratory vital capacity ( IVC ) , bronchodilator response , smoking habits , and allergy both on the " immediate " ( within 3 months ) response in FEV1 and the change in long-term ( from 3 months onwards ) slope of FEV1 with inhaled corticosteroids were analysed . Patients had a larger " immediate " improvement in their FEV1 with inhaled corticosteroids with each doubling doses lower PC20 , with each ten-fold higher immunoglobulin E ( IgE ) , and if they did not smoke . Total IgE proved a better independent predictor of " immediate " response than specific IgE for house dust mite , skin tests , or blood eosinophils . A more favourable long-term slope of FEV1 was predicted by a larger baseline bronchodilator response , but not by smoking . In conclusion , PC20 , total IgE , and smoking habits are independent predictors of immediate treatment response to inhaled corticosteroids .  Bronchodilator response is the single independent predictor of changes in long-term slope of FEV1 with corticosteroid treatment RATIONALE Chronic obstructive pulmonary disease ( COPD ) is characterized by an accelerated decline in lung function . No drug has been shown conclusively to reduce this decline . OBJECTIVES In a post hoc analysis of the Toward a Revolution in COPD Health ( TORCH ) study , we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg , either component alone or placebo , on the rate of post-bronchodilator FEV(1 ) decline in patients with moderate or severe COPD . METHODS A r and omized , double-blind , placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries . Of 6,112 patients from the efficacy population , 5,343 were included in this analysis . MEASUREMENTS AND MAIN RESULTS Spirometry was measured every 24 weeks for 3 years . There were 26,539 on-treatment observations . The adjusted rate of decline in FEV(1 ) was 55 ml/year for placebo , 42 ml/year for salmeterol , 42 ml/year for fluticasone propionate , and 39 ml/year for salmeterol plus fluticasone propionate . Salmeterol plus fluticasone propionate reduced the rate of FEV(1 ) decline by 16 ml/year compared with placebo ( 95 % confidence interval [ CI ] , 7 - 25 ; P < 0.001 ) . The difference was smaller for fluticasone propionate and salmeterol compared with placebo ( 13 ml/year ; 95 % CI , 5 - 22 ; P = 0.003 ) . Rates of decline were similar among the active treatment arms . FEV(1 ) declined faster in current smokers and patients with a lower body mass index , and varied between world regions . Patients who exacerbated more frequently had a faster FEV(1 ) decline . CONCLUSIONS Pharmacotherapy with salmeterol plus fluticasone propionate , or the components , reduces the rate of decline of FEV(1 ) in patients with moderate-to-severe COPD , thus slowing disease progression . Clinical trial ( GSK Study Code SCO30003 ) registered with www . clinical trials.gov ( NCT00268216 ) Inhaled corticosteroids ( ICS ) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease ( COPD ) . However , little is known about the risk of associated infections . In a post hoc analysis of the TOwards a Revolution in COPD Health ( TORCH ) study , we analysed and identified potential risk factors for adverse event reports of pneumonia in this r and omised , double-blind trial comparing twice-daily inhaled salmeterol ( SAL ) 50 μg , fluticasone propionate ( FP ) 500 μg , and the combination ( SFC ) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs . Despite a higher withdrawal rate in the placebo arm , after adjusting for time on treatment , a greater rate of pneumonia was reported in the FP and SFC treatment arms ( 84 and 88 per 1,000 treatment-yrs , respectively ) compared with SAL and placebo ( 52 and 52 per 1,000 treatment-yrs , respectively ) . Risk factors for pneumonia were age ≥55 yrs , forced expiratory volume in 1 s < 50 % predicted , COPD exacerbations in the year prior to the study , worse Medical Research Council dyspnoea scores and body mass index < 25 kg·m−2 . No increase in pneumonia deaths with SFC was observed ; this could not be concluded for FP . Despite the benefits of ICS-containing regimens in COPD management , healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies Only long-term home oxygen therapy has been shown in r and omised controlled trials to increase survival in chronic obstructive pulmonary disease ( COPD ) . There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators , alone or in combination , on mortality in patients with COPD , despite their known benefit in reducing symptoms and exacerbations . The “ TOwards a Revolution in COPD Health ” ( TORCH ) survival study is aim ing to determine the impact of salmeterol/fluticasone propionate ( SFC ) combination and the individual components on the survival of COPD patients . TORCH is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled study . Approximately 6,200 patients with moderate-to-severe COPD were r and omly assigned to b.i.d . treatment with either SFC ( 50/500 µg ) , fluticasone propionate ( 500 µg ) , salmeterol ( 50 µg ) or placebo for 3 yrs . The primary end-point is all-cause mortality ; secondary end-points are COPD morbidity relating to rate of exacerbations and health status , using the St George 's Respiratory Question naire . Other end-points include other mortality and exacerbation end-points , requirement for long-term oxygen therapy , and clinic lung function . Safety end-points include adverse events , with additional information on bone fractures . The first patient was recruited in September 2000 and results should be available in 2006 . This paper describes the “ TOwards a Revolution in COPD Health ” study and explains the rationale behind it The aim of this double-blind single center study ( the COPE study ) was to investigate the effect of discontinuation of the inhaled corticosteroid fluticasone propionate ( FP ) on exacerbations and health-related quality of life in patients with chronic obstructive pulmonary disease . After 4 months of treatment with FP ( 1,000 microg/day ) , 244 patients were r and omized to either continue FP or to receive placebo for 6 months : 123 patients continued FP ( FP group ) , and 121 received placebo ( placebo group ) . In the FP group , 58 ( 47 % ) patients developed at least one exacerbation compared with 69 ( 57 % ) in the placebo group . The hazard ratio of a first exacerbation in the placebo group compared with the FP group was 1.5 ( 95 % confidence interval [ CI ] 1.1 - 2.1 ) . In the placebo group 26 patients ( 21.5 % ) experienced rapid recurrent exacerbations and were subsequently unblinded and prescribed FP compared with 6 patients ( 4.9 % ) in the FP group ( relative risk = 4.4 ; 95 % CI 1.9 - 10.3 ) . Over a 6-month period , a significant difference in favor of the FP group was observed in the total score ( + 2.48 95 % CI 0.37 - 4.58 ) , activity domain ( + 4.64 95 % CI 1.60 - 7.68 ) , and symptom domain ( + 4.58 95 % CI 1.05 - 8.10 ) of the St. George 's Respiratory Question naire . This study indicates that discontinuation of FP in patients with chronic obstructive pulmonary disease is associated with a more rapid onset and higher recurrence-risk of exacerbations and a significant deterioration in aspects of Health-Related Quality of Life BACKGROUND Inhaled corticosteroids are known to be beneficial for patients with asthma , but their role in treating patients with stable chronic obstructive pulmonary disease ( COPD ) remains controversial . A study was undertaken to determine whether inhaled corticosteroids are of functional benefit in patients who did not show improvement with a trial of oral corticosteroids . METHODS In phase I patients with stable COPD were given a two week course of oral placebo followed by two weeks of prednisone 40 mg per day in a single blind manner to distinguish between responders and non-responders to oral corticosteroids . In phase II a double blind , r and omised , parallel group trial of inhaled budesonide 1600 micrograms per day versus placebo was carried out in 79 nonresponders to oral corticosteroids .  The primary outcome measure was forced expiratory volume in one second ( FEV1 ) , and secondary outcome measures were exercise capacity , dyspnoea with exertion , quality of life , peak expiration flow rate , and respiratory symptoms . RESULTS R and omisation allocated 39 subjects to inhaled corticosteroids and 40 to placebo .  There was no difference in the change in FEV1 from baseline between the treatment and placebo groups ; mean difference -12 ml ( 95 % CI -88 to 63 ) at three months and -4 ml ( 95 % CI -95 to 87 ) at six months . The proportion of patients with a 15 % or greater improvement was no higher among those receiving inhaled corticosteroids than in the placebo group at any of the follow up visits . Changes in secondary outcomes were also no different . CONCLUSIONS Inhaled corticosteroids , even at high doses , were of no physiological or functional benefit in these patients with advanced COPD Exacerbations of chronic obstructive pulmonary disease ( COPD ) are associated with worse health and increased healthcare utilisation . The Inhaled Steroids in Obstructive Lung Disease in Europe ( ISOLDE ) study in COPD showed a 26 % reduction in the yearly rate of exacerbations in patients treated with fluticasone propionate ( FP ) compared to placebo , but did not indicate which patients showed greatest benefit . In this study the patients were stratified into mild and moderate‐to‐severe COPD using the American Thoracic Society criterion of forced expiratory volume in one second ( FEV1 ) 50 % predicted , and the total number of exacerbations and those requiring treatment with oral corticosteroids were examined . There were 391 ( 195 FP ) patients with mild COPD and 359 ( 180 FP ) patients with moderate‐to‐severe disease .  The exacerbation rate was highly skewed in mild disease , but more normally distributed in moderate‐to‐severe disease . FP reduced the overall exacerbation rate in moderate‐to‐severe disease ( FP median rate 1.47 yr−1 , placebo 1.75 yr−1 ) , but not in mild disease ( FP 0.67 yr−1 , placebo 0.92 yr−1 ) . FP use was associated with fewer patients with ≥1 exacerbation·yr−1 being treated with oral corticosteroids ( mild : FP 8 % , placebo 16 % ; moderate‐to‐severe : FP 17 % , placebo 30 % ) . Effects  of fluticasone propionate  on exacerbations were seen predominantly in patients with a postbronchodilator forced expiratory volume in one second < 50 % predicted . These data support recommendations in the Global Initiative for Chronic Obstructive Disease treatment guidelines that inhaled corticosteroids should be considered in patients with moderate‐to‐severe chronic obstructive pulmonary disease who experience recurrent exacerbations Background : A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease ( COPD ) , with the subsequent “ response ” determining the treatment selected . This approach assumes that patients can be reliably divided into responder and non-responder groups . We have assessed whether such a separation is statistically valid , which factors influence the change in forced expiratory volume in 1 second ( FEV1 ) after prednisolone , and whether the prednisolone response predicts 3 year changes in FEV1 , health status , or number of exacerbations during placebo or fluticasone propionate treatment . Methods : Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before r and omised treatment for 3 years with fluticasone propionate or placebo . Factors relating to change in FEV1 after prednisolone were investigated using multiple regression . The response to prednisolone was entered into separate mixed effects models of decline in FEV1 and health status during the 3 years of the study . Results : The post-bronchodilator FEV1 increased by a mean 60 ml ( CI 46 to 74 ) after prednisolone with a wide unimodal distribution . Current smoking was the factor most strongly associated with the change in FEV1 after prednisolone , with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers ( p<0.001 ) . There was no relationship between the change in FEV1 after prednisolone  and the response to inhaled bronchodilators , baseline FEV1 , atopic status , age , or sex . The response to prednisolone  , however expressed , was unrelated to the subsequent change in FEV1 over the following 3 years on either placebo or fluticasone propionate . Regression to the mean effects explained much of the apparent prednisolone response . The significant effect of treatment on decline in health status was not predicted by the prednisolone response . Conclusion : Patients with COPD can not be separated into discrete groups of corticosteroid responders and non-responders . Current smoking reduces the FEV1 response to prednisolone . Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients Background : Treatment of chronic obstructive pulmonary disease ( COPD ) with inhaled corticosteroids does not appear to be as effective as similar treatment of asthma . It seems that only certain subgroups of patients with COPD benefit from steroid treatment . A study was undertaken to examine whether inhaled fluticasone propionate ( FP ) had an effect on lung function and on indices of inflammation in a subgroup of COPD patients with bronchial hyperresponsiveness ( BHR ) . Methods : Twenty three patients with COPD were studied . Patients had to be persistent current smokers between 40 and 70 years of age . Non-specific BHR was defined as a PC20 for histamine of ≤8 mg/ml . Patients received either 2 × 500 μg FP or placebo for 6 months . Expiratory volumes were measured at monthly visits , BHR was determined at the start of the study and after 3 and 6 months , and bronchial biopsy specimens were taken at the start and after 6 months of treatment . Biopsy specimens from asymptomatic smokers served as controls . Results : In contrast to asthma , indices of BHR were not significantly influenced by treatment with FP  . Forced expiratory volume in 1 second ( FEV1 ) showed a steep decline in the placebo group but remained stable in patients treated with FP . FEV1/FVC , and maximal expiratory flows at 50 % and 25 % FVC ( MEF50 , MEF25 ) were significantly increased in the FP treated patients compared with the placebo group . Biopsy specimens were analysed for the presence of CD3 + , CD4 + , CD8 + , MBP+ , CD15 + , CD68 + , CD1a , and tryptase cells  . FP treatment result ed in marginal reductions in these indices of inflammation . Conclusion : In patients with COPD and BHR  , FP has a positive effect on indices of lung function  compared with placebo . Bronchial inflammation analysed in bronchial biopsy specimens is only marginally reduced STUDY OBJECTIVE To determine the effectiveness of treatment with corticosteroids in patients with COPD . METHODS In this study , we investigated the effect of a 2-year treatment with corticosteroids on clinical symptoms and the decline of lung function in 58 nonallergic patients with COPD . Subjects were treated in a double-blind , r and omized , placebo-controlled , parallel way with inhaled budesonide ( bud ) , 1,600 micrograms/d ; inhaled budesonide , 1,600 micrograms/d , plus oral prednisolone , 5 micrograms/d ( bud + pred ) ; or placebo ( plac ) .  Clinical assessment ( history , physical examination , and spirometry ) was carried out every 2 months . The rate of decline in FEV1 was assessed by calculating individual regression co-efficients from linear regression of FEV1 on time for each subject . RESULTS Eleven patients dropped out . The number of withdrawals due to pulmonary problems was significantly higher in the plac group ( n = 5 out of 18 ) than in the actively treated groups ( n = 2 out of 40 ) . Treatment with corticosteroids significantly reduced pulmonary symptoms . Median decline of FEV1 was 60 mL/yr in the plac group , 40 mL/yr in the bud + pred group , and 30 mL/yr in the bud group . Variation was large and differences were not statistically significant . No treatment effect was found on frequency or duration of exacerbations , possibly because of the high number of withdrawals due to pulmonary deterioration in the plac group . Treatment with a combination of inhaled plus oral corticosteroids was not more effective than inhaled corticosteroids alone . Morning plasma cortisol levels remained within the normal range in all three groups . CONCLUSIONS Our study shows beneficial effects of long-term daily treatment with inhaled corticosteroids in patients with COPD with regard to symptoms and drop out due to pulmonary problems . Lung function decline tends to decrease during treatment with inhaled corticosteroids . The observed effects are limited but warrant further studies on the effectiveness of corticosteroids in larger numbers of patients with COPD Inhaled corticosteroids are known to reduce respiratory symptoms and airway responsiveness in allergic patients with asthma . The aim of the present r and omised , double blind study was to assess the effect of eight weeks ' treatment with inhaled budesonide in non-allergic smokers with chronic obstructive lung disease . Twenty four subjects ( 23 male ) entered the study . Their ages ranged from 40 to 70 ( mean 57 ) years , with a mean of 35 ( range 9 - 80 ) pack years of smoking ; the mean FEV1 was 53 % ( range 32 - 74 % ) predicted and geometric mean PC20 ( histamine concentration causing a 20 % fall in FEV1 ) 0.96 ( range 0.07 - 7.82 ) mg/ml . After a two week washout , single blind , placebo period , 12 patients were allocated to treatment with budesonide 1600 microgram/day and 12 to placebo for eight weeks . The only additional drug to be taken was ipratropium bromide " if needed . " Twenty one patients completed the study , 10 in the budesonide group and 11 in the placebo group . The st and ard deviation of the difference between duplicate measurements of PC20 histamine and citric acid cough threshold made two weeks apart was below one doubling dose step . There was a significant reduction in dyspnoea in the budesonide group , but otherwise no change in symptom scores or use of ipratropium bromide over the eight weeks of treatment within or between the two groups . No significant differences in spirometric values , peak expiratory flow , PC20 histamine , or citric acid cough threshold were found between the groups . Although differences were not significant , some of the changes showed a trend in favour of budesonide . Whether a longer observation period would show a significant influence of inhaled corticosteroids in patients with chronic obstructive lung disease remains to be determined Background : Inhaled corticosteroids ( ICS ) markedly reduce bronchial mucosal inflammation in asthma but whether they have an anti-inflammatory effect in airway tissue in chronic obstructive pulmonary disease ( COPD ) is unknown . Methods : A study of endobronchial biopsy sample s was conducted as part of a double blind , placebo controlled , r and omised trial of parallel design . Patients had mild to moderately severe COPD ( FEV1 25–80 % of predicted ) and were given 3 months treatment with ICS , fluticasone propionate ( FP ; 500 μg twice daily , n=14 ) or placebo ( n=10 ) . Biopsy tissue taken at baseline and after treatment was examined by transmission electron microscopy to count the numbers of all ultrastructurally distinct inflammatory cells . Results : Compared with their baseline values , FP result ed in a significant decrease ( on average 65 % ) in the numbers of mucosal mast cells ( median 7.8 ( range 1–33 ) v 2.8 ( 1–14 ) , p<0.05 ) . The reductive effect of FP held true when the post-treatment values of the placebo and FP groups were compared : 8.8 ( 1–24 ) v 2.8 ( 1–14 ) ( p<0.05 ) . Unexpectedly , there were significantly more neutrophils in the FP than in the placebo group : 4.0 ( 0–23 ) v 1.7 ( 0–8 ) , respectively ( p<0.05 ) . There were no alterations to other cell types including mononuclear cells . Symptoms markedly improved in the patients treated with FP for 3 months . Conclusion : Fluticasone propionate given for 3 months to patients with COPD has selective effects on the inflammatory cells in the bronchial mucosa : the reduction in mast cell numbers may account for the improvement in symptoms over this time Oxidative stress in the lung is important in the pathogenesis of COPD . Published data indicate that glucocorticoids inhibit blood cells in their capacity to produce reactive oxygen species ( ROS ) . We investigated the effect of Fluticasone propionate ( FP ) on the ROS production capabilities of pulmonary cells . Bronchoalveolar lavage ( BAL ) was performed in smoking COPD patients , before and after a six month , placebo-controlled treatment with FP . BAL cells were stimulated with phorbol myristrate acetate ( PMA ) alone , and together with superoxide dismutase ( SOD ) . From kinetic plots of ferricytochrome-c conversion we calculated the maximal rate of superoxide production : V(max ) . We also examined BAL cell subsets and performed correlation analyses on ROS production and relevant clinical determinants . Paired results were obtained from 6 FP- and 9 placebo-treated patients . No significant change of V(max ) was found in both patient groups . Also BAL cellularity was unchanged . Correlation analyses showed a significant ( inverse ) association of V(max ) with the number of cigarettes smoked per day . We concluded that a potent inhaled glucocorticoid had no effect on the ROS production capability of BAL cells from smoking COPD patients . Apparently , heavy smoking impaired the ability of alveolar macrophages to produce ROS , which was not further decreased by FP Airways hyperresponsiveness is a hallmark of asthma , and many patients with COPD also demonstrate hyperresponsiveness . Inhaled corticosteroids improve hyperresponsiveness , but the extent of improvement may vary considerably between patients . This study was design ed to determine which patient characteristics predict these differences in response . Patients with mild to moderately severe obstructive airways disease ( asthma and COPD ) were selected if PC20 < or = 8 mg/ml and FEV1 < 95 % confidence interval of predicted normal . They were followed for 2.5 yr , during which one-third received  inhaled corticosteroids . The independent influences of baseline FEV1/IVC , bronchodilator response , PC20 , smoking habits , allergy , age , and sex on the improvement in airways hyperresponsiveness with inhaled corticosteroids were analyzed . Total serum IgE was taken as a parameter of allergy , next to specific IgE for house dust mite , skin tests , and blood eosinophils . Total serum IgE was found to be the most important and single independent predictor of change in PC20 with inhaled corticosteroids : patients with a higher IgE had a greater increase in PC20 when administered inhaled corticosteroids than those with lower IgE levels . Alternatively , patients with a higher IgE who did not receive corticosteroids had a decrease in PC20 compared with patients with a lower IgE. This effect was most prominent in asthma but was inconsistent in asthmatic bronchitis and COPD . The level of IgE can not be used to predict the response to inhaled corticosteroids in individuals accurately . Total serum IgE is the single most important predictor of change in PC20 with and without inhaled corticosteroids . ( ABSTRACT TRUNCATED AT 250 WORDS STUDY OBJECTIVE To investigate possible changes in cells and molecular mediators of airway inflammation following inhaled steroid treatment of stable COPD patients . DESIGN Six-week open preliminary prospect i ve study . SETTING A university respiratory disease clinic . PATIENTS : Stable COPD patients with mild disease . INTERVENTION Six-week treatment with inhaled beclomethasone ( 1.5 mg die ) . MEASUREMENTS The levels of interleukin (IL)-8 , myeloperoxidase , eosinophilic cationic protein and tryptase , and cell numbers in bronchial lavage specimens were determined , and the symptom score , the endoscopic bronchitis index , and functional parameters were recorded . RESULTS After treatment there were significant reductions in the lavage levels of IL-8 ( [ mean + /- SEM ] 1,603.4 + /- 331.2 vs 1,119.2 + /- 265.3 pg/mL , respectively ; p = 0 . 01 ) and myeloperoxidase ( 1,614.5 + /- 682.3 vs 511.2 + /- 144.2 microg/L , respectively ; p = 0.05 ) , in cell numbers ( 250.6 + /- 27.7 vs 186.3 + /- 11.5 cells x 10(3)/mL , respectively ; p = 0.04 ) , neutrophil proportion ( 59.7 + /- 14.3 % vs 31.5 + /- 10.1 % ; p = 0.01 ) , symptom score ( 4.5 + /- 0.6 vs 1.4 + /- 0.5 ; p = 0.01 ) , and bronchitis index ( 8.5 + /- 0.8 vs 5.5 + /- 0.7 ; p = 0.007 ) . CONCLUSIONS In stable patients with COPD , inhaled steroid treatment may induce changes on some cellular and molecular parameters of airway inflammation STUDY OBJECTIVE Inhaled corticosteroids ( ICS ) are widely used in the treatment of COPD . One of the potential adverse effects of their use is the development of adrenal suppression . Our study aim ed to determine the effects of ICS on adrenal function over 3 years of use in patients with COPD . METHODS Two hundred twenty-one subjects were recruited from the 1,116 patients already enrolled in Lung Health Study II and were r and omized to receive either triamcinolone , 1,200 microg , or placebo daily . Basal cortisol levels and cortisol levels at 30 min and 60 min following cosyntropin injection were measured at study entry and after 1 year and 3 years of participation . RESULTS Basal cortisol levels in the placebo group were higher than in those receiving active drug at all time points and rose through the study period . There was no suppression of cortisol levels after cosyntropin stimulation at any study point in any subgroup . CONCLUSION Use of inhaled triamcinolone , 1,200 microg/d , over 3 years does not suppress baseline adrenal function or diminish adrenal responsiveness to cosyntropin stimulation The role of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease ( COPD ) is unclear . We investigated the effects of budesonide on airway hyperresponsiveness ( AHR ) to methacholine ( MCh ) and adenosine 5'-monophosphate ( AMP ) , to which we hypothesized the existence of greater sensitivity . Additionally , we studied the effects of budesonide on terfenadine  and ipratropium bromide  and on serum levels of interleukin-8 ( IL-8 ) and histamine .  Forty-four hyperresponsive smokers with moderate to severe COPD participated in the study .  MCh and AMP challenges were given on three study days , after pretreatment with single doses of ipratropium bromide , terfenadine , or placebo . Thereafter , subjects were r and omized to 6 wk treatment with either 1,600 microg budesonide or placebo , and the same three study days were repeated . Budesonide , as compared with placebo , did not significantly change PC20AMP , PC20MCh , or FEV1 after placebo pretreatment . Budesonide increased PC20MCh after ipratropium bromide  pretreatment , from 5.05 to 10.20 mg/ml ( p = 0.036 ) . Budesonide decreased serum IL-8 from 9.2 + /- 3.7 to 6.2 + /- 2.1 pg/ml ( p < 0.001 ) . We conclude that AMP did not elicit greater sensitivity than MCh in assessing short-term effects of budesonide on AHR in smokers with COPD . We suggest that long-term treatment with inhaled corticosteroids might be beneficial , by reducing neutrophil load in the airways and improving the action of anticholinergic drugs Inhaled corticosteroids are widely prescribed for the treatment of stable chronic obstructive pulmonary disease ( COPD ) , despite lack of proven efficacy . Because COPD involves airway inflammation and probable protease-antiprotease imbalance , we examined the effect of high dose fluticasone propionate on markers of activity of both pathogenetic mechanisms . Thirteen patients with COPD were treated with fluticasone propionate ( 500 microg twice a day ) for 4 wk , delivered via MDI and spacer , in a double-blind crossover study . There was no clinical benefit in terms of lung function or symptom scores , and induced sputum inflammatory cells , percentage neutrophils , and IL-8 levels were unchanged . Sputum supernatant elastase activity , matrix metalloproteinase (MMP)-1 , MMP-9 , and the antiproteases secretory leukoprotease inhibitor ( SLPI ) and tissue inhibitor of metalloproteinase (TIMP)-1 were similarly unaffected by treatment . These results add to previous evidence that inhaled steroids have no anti-inflammatory action in stable COPD . Furthermore , inhaled steroids do not appear to redress the protease-antiprotease imbalance that is thought to be important in the pathogenesis of airway obstruction OBJECTIVE There is less unanimity about the effects of inhaled corticosteroid in patients with non-asthmatic chronic obstructive pulmonary disease ( COPD ) . The aim of this study is to determine whether patients with non-asthmatic COPD have favorable responses to inhaled corticosteroid ( ICS ) . METHOD A r and omized , placebo-controlled , single-blind trial of inhaled beclomethasone dipropionate(BDP 1000 micrograms daily for 6 weeks ) was carried out in 61 patients with stable non-asthmatic COPD . Before and after the therapy , the scores of clinical symptoms and the scores of quality of life were recorded , and the pulmonary function and plasma level of endothelin-1 ( ET-1 ) were measured . RESULT 58 patients finished the study . Compared with the placebo-group , after receiving 6 weeks of ICS therapy , the BDP group showed significant improvement in clinical symptoms ( P < 0.05 ) , but not in the quality of life ( P > 0.05 ) . There was also an improvement in FEV1(P < 0.001 ) , but not in MMEF ( P > 0.05 ) . The plasma concentration of ET-1 was not changed significantly in both groups . CONCLUSION The study suggested that the therapy of ICS ( 1000 micrograms daily for 6 weeks ) can improve clinical symptoms and pulmonary function in patients with stable non-asthmatic COPD , but can not affect the quality of life and the plasma concentration of ET-1 Background The oral prednisolone test is widely used to distinguish chronic obstructive pulmonary disease ( COPD ) patients who might benefit from inhaled steroid treatment . Previous studies used selected patient groups that did not represent the large COPD population in primary care . Methods The study included smokers and exsmokers with chronic bronchitis or COPD from primary care , who underwent prednisolone testing ( 30 mg for 14 days ) before r and omization in a three-year follow-up r and omized controlled trial ( COOPT Study ) .  Spirometry  was performed before and after the test . Responders and nonresponders were classified according to international criteria . Effectiveness of inhaled fluticasone relative to placebo was compared in terms of health status ( Chronic Respiratory Disease Question naire ) , exacerbations , and postbronchodilator forced expiratory volume in one second ( FEV1 ) , using repeated measurement analysis . Results Two hundred eighty-six patients recruited from 44 primary care practice s were r and omized . Nine percent to 16 % of the COPD population was classified as responder , depending on the international guideline criteria used . On average , responders did not reach the minimum clinical ly important difference in health status ( 0.29 points/year , P = 0.05 ) , although a borderline significant effect of inhaled fluticasone was noted . Possible clinical ly relevant reductions in exacerbation rate ( rate ratio 0.67 ) and FEV1 decline ( 39 mL/year ) occurred in responders , but did not reach statistical significance . Conclusions Oral steroid testing identifies a limited proportion of COPD patients , but does not reveal any clinical ly relevant benefit from inhaled steroid treatment on health status . No significant effects on exacerbation rate and lung function decline occurred Exacerbations of chronic obstuctive pulmonary disease ( COPD ) are associated with worse health status . The Inhaled Steroids in Obstructive Lung Disease in Europe ( ISOLDE ) study showed that treatment with fluticasone propionate ( FP ) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo . The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations . Rates of deterioration in St George 's Respiratory Question naire ( SGRQ ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs . Exacerbation rates were skewed and could not be normalised , therefore , patients were stratified into three exacerbation groups : none , infrequent ( < 1.65 exacerbations·yr−1 ) and frequent ( > 1.65 exacerbations·yr−1 ) . There were 91 patients with no exacerbations , 285 with infrequent exacerbations and 235 with frequent exacerbations . Frequent exacerbations were independently associated with a worse baseline SGRQ score ( p<0.0001 ) and a more rapid rate of deterioration in health status ( p=0.0003 ) . Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score . Statistical modelling showed the beneficial effect of fluticasone propionate  on deterioration in health status to be largely due to its effect on exacerbation frequency The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo , budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . In a 12-month , r and omised , double-blind , placebo-controlled , parallel-group study in 812 adults ( mean age 64 yrs , mean forced expiratory volume in one second ( FEV1 ) 36 % predicted normal ) , patients received two inhalations twice daily of either budesonide/formoterol ( Symbicort ® ) 160/4.5 µg ( delivered dose ) , budesonide 200 µg ( metered dose ) , formoterol 4.5 µg or placebo . Severe exacerbations and FEV1 ( primary variables ) , peak expiratory flow ( PEF ) , COPD symptoms , health-related quality of life ( HRQL ) , mild exacerbations , use of reliever β2‐agonist and safety variables were recorded .  Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24 % versus placebo and 23 % versus formoterol . FEV1 increased by 15 % versus placebo and 9 % versus budesonide . Morning PEF improved significantly on day 1 versus placebo and budesonide ; after 1 week , morning PEF was improved versus placebo , budesonide and formoterol . Improvements in morning and evening PEF versus comparators were maintained over 12 months . Budesonide/formoterol decreased all symptom scores and use of reliever β2‐agonists significantly versus placebo and budesonide , and improved HRQL versus placebo . All treatments were well tolerated . These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease BACKGROUND Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease ( COPD ) , whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status . We postulated that a combination of these treatments would be better than each component used alone . METHODS 1465 patients with COPD were recruited from outpatient departments in 25 countries . They were treated in a r and omised , double-blind , parallel-group , placebo-controlled study with either 50 microg salmeterol twice daily ( n=372 ) , 500 microg fluticasone twice daily ( n=374 ) , 50 microg salmeterol and 500 microg fluticasone twice daily ( n=358 ) , or placebo ( n=361 ) for 12 months . The primary outcome was the pretreatment forced expiratory volume in 1s ( FEV1 ) after 12 months treatment ' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h . Secondary outcomes were other lung function measurements , symptoms and rescue treatment use , the number of exacerbations , patient withdrawals , and disease-specific health status . We assessed adverse events , serum cortisol concentrations , skin bruising , and electrocardiograms . Analysis was as predefined in the study protocol . FINDINGS All active treatments improved lung function , symptoms , and health status and reduced use of rescue medication and frequency of exacerbations . Combination therapy improved pretreatment FEV1 significantly more than did placebo ( treatment difference 133 mL , 95 % CI 105 - 161 , p<0.0001 ) , salmeterol ( 73 mL , 46 - 101 , p<0.0001 ) , or fluticasone alone ( 95 mL , 67 - 122 , p<0.0001 ) . Combination treatment produced a clinical ly significant improvement in health status and the greatest reduction in daily symptoms . All treatments were well tolerated with no difference in the frequency of adverse events , bruising , or clinical ly significant falls in serum cortisol concentration . INTERPRETATION Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function , with no greater risk of side-effects than that with use of either component alone , this combination treatment should be considered for patients with COPD Background : Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease ( COPD ) . However , their effect on mortality is unknown . Methods : A pooled analysis , based on intention to treat , of individual patient data from seven r and omised trials ( involving 5085 patients ) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD . The end point was all-cause mortality . Results : Overall , 4 % of the participants died during a mean follow up period of 26 months . Inhaled corticosteroids reduced all-cause mortality by about 25 % relative to placebo . Stratification by individual trials and adjustments for age , sex , baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second , smoking status , and body mass index did not material ly change the results ( adjusted hazard ratio ( HR ) 0.73 ; 95 % confidence interval ( CI ) 0.55 to 0.96 ) . Although there was considerable overlap between subgroups in terms of effect sizes , the beneficial effect was especially noticeable in women ( adjusted HR 0.46 ; 95 % CI 0.24 to 0.91 ) and former smokers ( adjusted HR 0.60 ; 95 % CI 0.39 to 0.93 ) . Conclusions : Inhaled corticosteroids reduce all-cause mortality in COPD . Further studies are required to determine whether the survival benefits persist beyond 2–3 years Lung function in chronic obstructive pulmonary disease ( COPD ) can be improved acutely by oral corticosteroids and bronchodilators . Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown . COPD patients ( n=1,022 , mean prebronchodilator forced expiratory volume in one second ( FEV1 ) 36 % predicted ) initially received formoterol ( 9 µg b.i.d . ) and oral prednisolone ( 30 mg o.d . ) for 2 weeks . After this time , patients were r and omised to b.i.d . inhaled budesonide/formoterol 320/9 µg , budesonide 400 µg , formoterol 9 µg or placebo for 12 months . Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George 's Respiratory Question naire ( SGRQ ) by 4.5 units after run-in . Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide , formoterol or placebo . Budesonide/formoterol patients had a prolonged time to first exacerbation ( 254 versus 96 days ) and maintained higher FEV1 ( 99 % versus 87 % of baseline ) , both primary variables versus placebo . They had fewer exacerbations ( 1.38 versus 1.80 exacerbations per patient per year ) , had higher prebronchodilator peak expiratory flow , and showed clinical ly relevant improvements in SGRQ versus placebo ( −7.5 units ) . Budesonide/formoterol was more effective than either monocomponent in both primary variables . Budesonide/formoterol in a single inhaler ( Symbicort ® ) maintains the benefit of treatment optimisation , stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo A significant minority of patients with COPD have favorable response to corticosteroid treatment . In addition , the benefit of corticosteroid treatment may be outweighed by the side effects . Long-term administration of inhaled steroids is a safe means of treatment . We hypothesized that treatment with high-dose inhaled budesonide would improve clinical symptoms and pulmonary function in subjects with COPD , and that the response to inhaled beta 2-agonist will serve to individualize steroid responders . We compared a 6-week course of 800 micrograms/d inhaled budesonide with placebo , separated by 4 weeks when no medication was taken , in a double-blind crossover trial , in 8 patients responding to inhaled beta 2-agonist , and in 22 nonresponders with stable COPD . In six of eight " responders to beta 2-agonist , " there was a significant improvement in the FEV1 ( defined as > or = 20 % ) following inhaled budesonide , as compared with placebo . In the 22 " nonresponders to beta 2-agonist , " there was no significant improvement in the mean FEV1 ( 1.41 + /- 0.1 L before , and 1.61 + /- 0.1 L after treatment ) with inhaled budesonide or placebo . Over the 6-week course of treatment by either budesonide or placebo , the nonresponders reported similar beta 2-agonist consumption ( 4.8 + /- 0.2 and 5.0 + /- 0.1 puffs per patient per day , respectively ) . However , there was a significant difference between the two periods of treatment in the responders as for the mean daily number of beta 2-agonist inhalations ( 2.4 + /- 0.1 in the budesonide period as compared with 5.3 + /- 0.1 in the placebo period ; p < 0.005 ) . We conclude that treatment with inhaled steroids improved spirometry data and inhaled beta 2-agonist consumption in about 25 % of patients with stable COPD , and this rate is increased to about 75 % in patients who respond to beta 2-agonist inhalation In a placebo controlled study the effects of 6 weeks ' treatment with inhaled budesonide ( 1.6 mg daily ) on the impedance of the respiratory system , spirometry and symptom scores were evaluated in 35 patients with chronic bronchitis with forced expiratory volume in one second ( FEV1 ) greater than or equal to 70 % predicted . Thirty patients completed the study . No statistically significant differences in the changes in morning peak expiratory flow rate ( PEFR ) , symptom scores , use of terbutaline rescue medication and FEV1 were found between the placebo and the active treatment group . Budesonide treatment was found to result in a small decrease in resonant frequency and a less negative frequency dependence of resistance compared with the placebo group OBJECTIVES To investigate the determinants of patient withdrawal from our study , and the effect of these withdrawals on the outcome of treatment with inhaled corticosteroids in patients with COPD . DESIGN A double-blind , placebo-controlled , r and omized trial . SETTING Eighteen outpatient centers in the United Kingdom . PARTICIPANTS Seven hundred fifty-one patients with stable COPD defined clinical ly and as baseline postbronchodilator FEV(1 ) > or = 0.8 L and < 85 % predicted , FEV(1)/FVC ratio < 70 % , and FEV(1 ) change after albuterol < 10 % of predicted . INTERVENTION R and om assignment of either 500 microg bid of inhaled fluticasone propionate ( FP ) using a spacer device or an identical placebo inhaler . Treatment was continued for 3 years or until patients withdrew from follow-up . MEASUREMENTS AND RESULTS Postbronchodilator FEV(1 ) was measured on three occasions before r and omization and every 3 months thereafter . Health status was assessed by the disease-specific St. George Respiratory Question naire ( SGRQ ) and the modified short-form 36 question naire ( SF-36 ) at baseline and every 6 months . Three hundred thirty-nine patients withdrew , of whom 156 patients received FP .  Prescription of frequent courses of oral prednisolone was the most common reason for withdrawing as specified in the protocol ( 69 patients in the FP group withdrew due to respiratory symptoms , compared with 93 patients in the placebo group ) . This explained the significantly greater dropout of placebo-treated patients that was most evident when FEV(1 ) was < 50 % predicted . Patients withdrawing had a significantly more rapid decline in health status , measured by both the SGRQ and the SF-36 ( p < 0.001 ) . Those withdrawing from the placebo group had a more rapid decline in FEV(1 ) and more exacerbations than the FP-treated groups . Baseline FEV(1 ) was lower in dropouts than in patients completing the study receiving placebo , but there was no difference between the respective groups receiving FP . CONCLUSIONS Patients who withdrew from follow-up were those with the most rapidly deteriorating health status and lung function . Losing these patients from the final analysis can reduce the power of a study to achieve its primary end point STUDY OBJECTIVE To determine whether inhaled corticosteroid treatment can reduce airways inflammation in adult cigarette smokers . DESIGN This was a r and omized , placebo-controlled , double-blinded clinical trial . SETTING The subjects were recruited from the community by advertising . PARTICIPANTS Seventy-one adults with a > or = 5 pack-year history who were current smokers , had a normal FEV1 , and produced sputum daily . INTERVENTION Sixty subjects were r and omized to receive four puffs of placebo or beclomethasone dipropionate ( [ BDP ] ; total dosage , 1,000 microg/d ) using a metered-dose aerosol inhaler with a valved holding chamber ( AeroChamber ; Trudell Medical ; London , Ontario , Canada ) for 28 days . MEASUREMENTS AND RESULTS Eleven subjects were not r and omized because of poor compliance . The primary outcome was fractional airway neutrophilia , as assessed by a differential cell count of sputum . Additional outcome measures were spirometry , measurement of airway responsiveness by methacholine challenge , and lung epithelial permeability measured by the clearance of radiolabeled diethylenetriamine pentaacetic acid . There were no significant differences between the two groups in any outcome measurement after 4 weeks of treatment . CONCLUSIONS With normal spirometry , we found no benefit of treatment with inhaled BDP , 1,000 microg/d , on noninvasive measures of airways inflammation in adult smokers . This indicates that cigarette smoke-induced inflammation in its early stages ( before a demonstrable airflow obstruction ) is not steroid sensitive . This may occur because the site of involvement is not accessible to inhaled medications or because the inflammatory process is resistant to moderate doses of inhaled corticosteroids A double-blind cross-over trial was carried out on 83 sequential out- patients presenting with adult onset chronic airflow obstruction who were not clearly asthmatic . The study consisted of three treatment phases each lasting two weeks with a two week interval between each phase . The treatment phases were prednisolone 40 mg daily , beclomethasone dipropionate 500 ug three times a day and placebo , administered in a r and om order . FEV1 and FVC were measured at the end of each of the treatment phases and peak expiratory flow rate five times a day throughout . Over the study period 25 ( 30 % ) patients responded with an improvement of greater than or equal to 20 % in at least one of the parameters measured as compared with the best of either baseline or placebo measurements . A further eight patients were classified as partial responders with an improvement of greater than 15 % in any single parameter or greater than 10 % in any two parameters . A similar number responded to  beclomethasone  [ 15 ] as responded to prednisolone [ 16 ] . Only six patients , however , responded fully to both forms of steroid therapy . A number of patients responded to one form of steroid treatment only which was also comparable between the two groups ( prednisolone 10 , beclomethasone 9 ) . For full and partial responders mean improvement in FEV1 , FVC and PEFR was greater during the prednisolone phase than during the beclomethasone phase , however , the difference did not achieve statistical significance The effects of fluticasone propionate ( FP ) on sputum chemotactic activity , elastase inhibitory potential , albumin concentrations , and peripheral neutrophil function were studied in a group of patients with clinical ly stable , smoking-related chronic bronchitis and emphysema . Seventeen patients ( 50 to 75 yr of age ) were entered into a double-blind , placebo-controlled study of 1.5 mg inhaled FP/d for 8 wk . Following treatment with FP the chemotactic activity of the sputum sol phase was lower than the corresponding values for the placebo group ( p < 0.01 ) . Values fell from a mean of 21.75 ( + /- 1.58 ) during the run-in period to 18.37 ( + /- 1.46 ; p < 0.01 ) after 4 wk and 17.63 ( + /- 1.86 ; p < 0.05 ) after 8 wk treatment returning to 22.08 ( + /- 1.26 ) cell/field after the washout period . The neutrophil elastase inhibitory capacity of the sputum sol phase increased ( p < 0.025 ) with treatment from a mean of 0.177 microM elastase inhibited/L ( + /- 0.05 ) pretreatment to 0.413 microM ( + /- 0.054 ) after 4 wk and 0.415 microM ( + /- 0.054 ) after 8 wk returning to 0.270 microM ( + /- 0.07 ) after the washout period . Treatment with FP did not result in a change in the peripheral neutrophil functions studied or sputum albumin and myeloperoxidase concentrations . The results suggest that FP may play a protective role in these patients through a reduction in the chemotactic activity of lung secretions and potentially a reduction in the recruitment of neutrophils to the lung , and also by directly affecting the proteinase/antiproteinase balance , in favor of antiproteinases , within lung secretions BACKGROUND The efficacy of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease ( COPD ) remains controversial because of a lack of placebo-controlled studies . We compared the effect of inhaled fluticasone propionate with placebo in the treatment of patients with COPD . METHODS We used a r and omised , double-blind , placebo-controlled design . We enrolled from 13 European countries , New Zeal and , and South Africa , 281 outpatient current or ex-smokers , aged between 50 and 75 years . They had a forced expiratory volume in 1 s ( FEV1 ) of between 35 % and 90 % of predicted normal values , a ratio of FEV1 to forced vital capacity of 70 % or less and bronchodilator reversibility of less than 15 % , as well as a history of chronic bronchitis . Patients were r and omly assigned fluticasone propionate 500 microg ( n=142 ) or placebo ( n=139 ) twice daily via a metered-dose inhaler for 6 months . The main outcome measures were the number of patients who had at least one exacerbation by the end of treatment , the number and severity of exacerbations , clinic lung function , diary card symptoms and peak expiratory flow and 6 min walking distance . FINDINGS 51 ( 37 % ) patients in the placebo group compared with 45 ( 32 % ) in the fluticasone propionate group had had at least one exacerbation by the end of treatment ( p=0.449 ) . Significantly more patients had moderate or severe exacerbations in the placebo group than in the fluticasone propionate group ( 86 % vs 60 % , p<0.001 ) . Diary-card and clinic morning peak expiratory flows improved significantly in the fluticasone propionate group ( p<0.001 , p=0.048 , respectively ) , as did clinic FEV1 ( p<0.001 ) , forced vital capacity ( p<0.001 ) , and mid-expiratory flow ( p=0.01 ) . Symptom scores for median daily cough and sputum volume were significantly lower with fluticasone propionate treatment than with placebo ( p=0.004 and p=0.016 , respectively ) . At the end of treatment , patients on fluticasone propionate had increased their 6 min walking distance significantly more than those on placebo ( p=0.032 ) . Fluticasone propionate was tolerated as well as placebo , with few adverse effects and without a clinical ly important effect on mean serum cortisol concentration . INTERPRETATION Fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months .  Inhaled corticosteroids may have an important role in the long-term treatment of COPD Background Previous studies have suggested that long-term use of β agonists to treat chronic obstructive pulmonary disease ( COPD ) may increase the risk of cardiovascular adverse events . In this post hoc analysis , data from the TOwards a Revolution in COPD Health ( TORCH ) study were used to investigate whether use of the long-acting β2 agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD . Methods TORCH was a r and omised , double-blind , placebo controlled study conducted at 444 centres in 42 countries . Patients ( n=6184 ; safety population ) received twice daily combined salmeterol 50 μg plus fluticasone propionate 500 μg ( SFC ) , either component alone , or placebo . Adverse events were recorded every 12 weeks for 3 years . Results The probability of having a cardiovascular adverse event by 3 years was 24.2 % for placebo , 22.7 % for salmeterol , 24.3 % for fluticasone propionate and 20.8 % for SFC . Although a history of myocardial infa rct ion doubled the probability of cardiovascular adverse events , the event rates remained similar across treatment groups . Conclusion Post hoc analysis of the 3-year TORCH data set showed that salmeterol alone or in combination ( SFC ) did not increase the risk of cardiovascular events in patients with moderate to severe COPD A placebo-controlled , double blind , cross-over study of inhaled budesonide was carried out to examine its effectiveness in the treatment of  chronic airflow limitation ( CAL ) . Fourteen patients ( 11 males , mean age 66 years ) with stable CAL received placebo treatment for four weeks followed by inhaled budesonide 400 micrograms BD for eight weeks . Response was assessed by measuring forced expiratory volume in one second ( FEV1 ) . There was no significant improvement in the overall spirometric measurements and symptom scores except a reduction in daily peak expiratory flow rate fluctuation ( p < 0.05 ) . However , individual patients showed significant increase in FEV1 . Two patients ( 14 % ) had greater than 30 % increase in FEV1 in response to inhaled corticosteroids . This response could not be predicted from history of allergy , skin test , bronchial challenge test , peripheral blood or sputum eosinophilia . We conclude that only a minority of patients with stable CAL may respond to inhaled budesonide . Nonetheless , patients who are symptomatic despite treatment with maximum doses of bronchodilators may have a trial of inhaled corticosteroids in order to demonstrate any additional benefit A significant , large minority of patients with chronic obstructive pulmonary disease ( COPD ) respond favorably to corticosteroid treatment ; but the benefit may be outweighed by its side effects . Long-term administration of inhaled steroids is a safe means of treatment . We hypothesized that treatment with inhaled budesonide would improve clinical symptoms and pulmonary function in subjects with COPD , and that the response to an inhaled B2-agonist would individualize steroid responders . In 44 patients with stable COPD in a double- blind crossover trial , we compared a 6-week course of inhalations of 800 micrograms/d budesonide with a placebo , separated by a 4-week interval when no medication was taken . In 33 out of 42 responders to the B2-agonist who remained in the study , there was a significant improvement in FEV1 of greater than 20 % following budesonide inhalation , as compared to placebo . There was also a significant difference between the 2 periods of treatment as to the mean number of B2-agonist inhalations . We conclude that about 1/4 of patients with stable COPD respond to bronchodilators , and treatment with inhaled steroids improves spirometry data and inhaled B2-agonist consumption in about 3/4 The role of glucocorticoids in the treatment of chronic obstructive pulmonary disease ( COPD ) is controversial . We have previously described high numbers of neutrophils and high concentrations of the inflammatory cytokines interleukin-8 ( IL-8 ) and tumor necrosis factor-alpha ( TNF-alpha ) , and of the cell activation markers eosinophil cationic protein ( ECP ) , eosinophil peroxidase ( EPO ) , myeloperoxidase ( MPO ) , and human neutrophil lipocalin ( HNL ) in COPD patients as compared with controls , and have postulated that the cytokines TNF-alpha and IL-8 play a role in propagating the inflammatory response in COPD . We have now studied the effects of inhaled and oral glucocorticoids on these inflammatory indices in induced sputum . Initially , we studied the effect of a 2-wk course of inhaled budesonide ( 800 mg twice daily for 2 wk ) in 13 patients with severe COPD ( mean FDV1 : 35 % predicted ) . There was no clinical benefit in either lung function or symptom scores , and no significant change in the inflammatory indices as measured by total and differential cell counts and concentrations of TNF-alpha eosinophil activation markers ECP and EPO , and neutrophil activation markers MPO and HNL . Because the lack of anti-inflammatory effect might have been due to poor drug delivery as a result of severe airflow limitation , we undertook a study examining the antiinflammatory effect of oral prednisolone ( 30 mg daily for 2 wk ) in patients with COPD and undertook the same measurements in 10 patients with atopic asthma .  Sputum eosinophil numbers , ECP , and EPO were significantly reduced in the asthmatic patients but were not modified in COPD . This confirms the clinical impression that inhaled steroids have little antiinflammatory effect , at least in the short term in this group of patients , and suggests that the inflammatory process in COPD is resistant to the antiinflammatory effect of glucocorticoids Background : Combined treatment with inhaled corticosteroids and long acting β2 agonists is approved for the treatment of chronic obstructive pulmonary disease ( COPD ) , but little is known about the onset of effect of the combination . Methods : Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow ( PEF ) and symptom scores . Results : PEF was significantly higher after 1 day in patients treated with salmeterol 50 μg twice daily or the salmeterol/fluticasone propionate combination 50/500 μg twice daily than placebo . In patients treated with fluticasone propionate 500 μg twice daily alone , PEF differed from placebo after 2 days . The differences after 2 weeks compared with placebo were 16 l/min ( 95 % confidence interval ( CI ) 11 to 21 ) , 11 l/min ( 95 % CI 6 to 16 ) , and 27 l/min ( 95 % CI 22 to 33 ) for salmeterol , fluticasone propionate , and the salmeterol/fluticasone propionate combination , respectively . For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study . The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second ( FEV1 ) . Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group . The 2 week change in FEV1 was only partly indicative of a long term response in individual patients . Conclusions : The effects of salmeterol and fluticasone propionate , alone or in combination , on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks The effects of inhaled beclomethasone dipropionate ( BDP ) , 800 micrograms daily , on the long-term course of asthma and chronic obstructive pulmonary disease ( COPD ) were investigated in a prospect i ve , controlled study , over three years . During the first two years , patients were treated with a bronchodilator only ( salbutamol or ipratropium bromide ) . Fifty six patients ( 28 asthma , 28 COPD ) , with an unfavourable course of disease during bronchodilator therapy alone ( an annual decline in forced expiratory volume in one second ( FEV1 ) of > or = 80 ml.yr-1 in combination with at least one exacerbation.yr-1 ) , were selected for additional treatment with inhaled beclomethasone dipropionate ( BDP ) , 800 micrograms daily , during the third year . The FEV1 and provoking concentration of histamine producing a 20 % fall in FEV1 ( PC20-histamine ) were assessed at six-monthly intervals . In asthma , the annual decline in prebronchodilator FEV1 of -158 ml.yr-1 during bronchodilator therapy alone was followed by a significant increase of 562 ml.yr-1 during months 1 - 6 of BDP treatment ( p < 0.0005 ) . During months 7 - 12 of BDP , the FEV1 declined slightly with -31 ml.yr-1 , which was not statistically different from the annual decline before steroid therapy ( p = 0.17 ) . In COPD , the increase of 323 ml.yr-1 during months 1 - 6 of treatment with BDP was different from the annual decline of -156 ml.yr-1 before BDP ( p < 0.05 ) . The PC20-histamine improved by 308 doubling doses during 1 - 12 months of BDP in asthma ( p < 0.05 ) but not in COPD . ( ABSTRACT TRUNCATED AT 250 WORDS Relatively little is known about the influence of inhaled corticosteroids on general well-being ( quality of life ) in patients with asthma or COPD . In a 4-year prospect i ve controlled study , we examined the influence of beclomethasone dipropionate ( BDP ) , 400 micrograms , two times daily , on quality of life in 56 patients with asthma or COPD in comparison with the effects of BDP on symptoms and lung function . During the first 2 years , patients received only bronchodilator therapy with salbutamol or ipratropium bromide . During the third and fourth years , additional treatment with BDP was given . Fifty-six patients ( 28 with asthma , 28 with COPD ) with an annual decline in the forced expiratory volume in 1 s ( FEV1 ) of at least 80 mL/yr in combination with at least two exacerbations per year during bronchodilator therapy alone participated .  Quality of life was assessed at the start and after 2 and 4 years by means of the Inventory of Subjective Health ( ISH ) and the Nottingham Health Profile ( NHP ) . Although BDP significantly improved the course of lung function (FEV1)(p < 0.0001 ) , it did not improve the ISH score or the six dimensions of the NHP neither in asthma nor in COPD . Beclomethasone dipropionate  temporarily decreased respiratory symptoms during months 4 to 6 of BDP treatment in patients with asthma ( p < 0.01 ) and during months 7 to 12 in patients with COPD ( p < 0.05 ) . A weak correlation was found both cross-sectionally and longitudinally between ( change in ) symptoms and quality of life on the one h and , and the ( change in ) FEV1 on the other . It was concluded that BDP did not improve the general well-being of patients with asthma or COPD as measured by these generic health instruments . However , BDP significantly improved the course of lung function and temporarily decreased the severity of symptoms . It seems probable that changes in quality of life would have been better detected by use of a disease-specific health instrument . Such an instrument was not available at the start of the study . Another possible explanation for these observations is that patients soon get used to different levels of lung function and learn to live with their disease . It is advised that disease-specific health instruments are used in future intervention studies and that quality of life is measured frequently during the early phase of the intervention , eg , once every month We compared the effect of inhaled budesonide with placebo on decline in lung function and respiratory symptoms in a three-year study of patients with chronic obstructive pulmonary disease ( COPD ) . We used a parallel-group , r and omized , double-blind , placebo-controlled design , nested in an ongoing epidemiological survey . Patients were non-asthmatic subjects with a decreased ratio between forced expiratory volume in one second ( FEV1 ) and vital capacity ( VC ) ; i.e. , FEV1/VC < or = 0.7 . All included patients had an FEV1 which was irreversible to both inhaled terbutaline and prednisolone .  Two hundred and ninety patients were r and omized to receive either budesonide , 1200 mcg . daily for six months followed by 800 mcg . daily for 30 months , or placebo for 36 months . Patients had a mean age of 59 years and their mean FEV1 was 2.37 liters or 86 % of predicted .  Crude FEV1 declines were 41.8 ml/year in the placebo group and 45.1 ml/year in the budesonide group . Using a regression model in the intention-to-treat population , patients in the placebo group had an FEV1 decline of 49.1 ml/year in contrast to 46.0 ml/year in the budesonide group ; the estimated difference 3.1 ml/year ( 95 % confidence interval--12.8 - 19.0 ) was statistically insignificant , p = 0.70 . No effect of inhaled budesonide was seen on respiratory symptoms or number of exacerbations . These findings question the role of longterm inhaled corticosteroids in the treatment of mild-moderate COPD OBJECTIVE Withdrawal of corticosteroid is associated with a deterioration of health status in COPD . In this study the aim was to determine whether high dose inhaled corticosteroid improves quality of life in patients with COPD . METHODOLOGY In total , 38 male patients with moderate COPD were included in the study . Baseline quality of life scores were determined using a Turkish version of the St George 's Respiratory Question naire ( SGRQ ) . Patients were r and omly divided into two groups . Group 1 consisted of 20 patients who received existing bronchodilator therapy plus inhaled corticosteroid ( 800 micro g budesonide ) for 12 weeks , while 18 patients in group 2 received bronchodilator and placebo . The SGRQ was repeated after the treatment period . RESULTS All patients were male and mean age was 67 + /- 8.2 years .  Symptom , activity , impact , and total scores were assessed and a difference of four units with treatment was considered to be clinical ly significant . Total score and activity score were decreased by six units and eight units , respectively , in the placebo group while symptom and impact scores did not change significantly . Total scores and the three component scores improved significantly in the corticosteroid group compared to the placebo group ( Deltatotal score : -22 in corticosteroid group , -6 in placebo group , P < 0.01 ) . CONCLUSION Inhaled corticosteroid improved quality of life scores in patients with COPD , without significant improvement in airflow obstruction parameters . Since improvement of health status is one of the important aims in COPD treatment , use of inhaled corticosteroids should be considered from this perspective BACKGROUND Inhaled corticosteroids ( ICSs ) and long-acting beta(2)-agonists ( LABAs ) are used to treat moderate to severe chronic obstructive pulmonary disease ( COPD ) . OBJECTIVE To determine whether long-term ICS therapy , with and without LABAs , reduces inflammation and improves pulmonary function in COPD . DESIGN R and omized , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00158847 ) SETTING 2 university medical centers in The Netherl and s. PATIENTS 114 steroid-naive current or former smokers with moderate to severe COPD . MEASUREMENTS Cell counts in bronchial biopsies and sputum ( primary outcome ) ; methacholine responsiveness at baseline , 6 , and 30 months ; and clinical outcomes every 3 months . INTERVENTION R and om assignment by minimization method to receive fluticasone propionate , 500 microg twice daily , for 6 months ( n = 31 ) or 30 months ( n = 26 ) ; fluticasone , 500 microg twice daily , and salmeterol , 50 microg twice daily , for 30 months ( single inhaler ; n = 28 ) ; or placebo twice daily ( n = 29 ) . RESULTS 101 patients were greater than 70 % adherent to therapy . Fluticasone therapy decreased counts of mucosal CD3(+ ) cells ( -55 % [ 95 % CI , -74 % to -22 % ] ; P = 0.004 ) , CD4(+ ) cells ( -78 % [ CI , -88 % to 60 % ] ; P < 0.001 ) , CD8(+ ) cells ( -57 % [ CI , -77 % to -18 % ] ; P = 0.010 ) , and mast cells ( -38 % [ CI , -60 % to -2 % ] ; P = 0.039 ) and reduced hyperresponsiveness ( P = 0.036 ) versus placebo at 6 months , with effects maintained after 30 months . Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium , with accompanying reductions in sputum neutrophil , macrophage , and lymphocyte counts and improvements in FEV(1 ) decline , dyspnea , and quality of life . Reductions in inflammatory cells correlated with clinical improvements . Discontinuing fluticasone therapy at 6 months increased counts of CD3(+ ) cells ( 120 % [ CI , 24 % to 289 % ] ; P = 0.007 ) , mast cells ( 218 % [ CI , 99 % to 407 % ] ; P < 0.001 ) , and plasma cells ( 118 % [ CI , 9 % to 336 % ] ; P = 0.028 ) and worsened clinical outcome . Adding salmeterol improved FEV(1 ) level . LIMITATIONS The study was not design ed to evaluate clinical outcomes . Measurement of primary outcome was not available for 24 % of patients at 30 months . CONCLUSION ICS therapy  decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD . Adding LABAs does not enhance these effects . This r and omized controlled trial examined the benefits of combining an inhaled corticosteroid , fluticasone propionate ( F ) , with an inhaled long-acting beta(2)-agonist , salmeterol ( S ) , to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease ( COPD ) . A total of 691 patients with COPD received the combination of F and S ( FSC ) , S ( 50 mcg ) , F ( 500 mcg ) , or placebo twice daily via the Diskus device for 24 weeks . A significantly greater increase in predose FEV(1 ) at the endpoint was observed after FSC ( 156 ml ) compared with S ( 107 ml , p = 0.012 ) and placebo ( -4 ml , p < 0.0001 ) . A significantly greater increase in 2-hour postdose FEV(1 ) at the endpoint was observed after treatment with FSC ( 261 ml ) compared with F ( 138 ml , p < 0.001 ) and placebo ( 28 ml , p < 0.001 ) . There were greater improvements in the Transition Dyspnea Index with FSC ( 2.1 ) compared with F ( 1.3 , p = 0.033 ) , S ( 0.9 , p < 0.001 ) , and placebo ( 0.4 , p < 0.0001 ) . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and F ) was similar among the treatment groups . We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo The Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) study was a trial that r and omised 752 patients with moderate to severe COPD to fluticasone propionate 1000 mcg/day or placebo for three years . We aim ed to examine the causes of death of the ISOLDE participants after the original three up to 13 years post-r and omisation . Death certificates were obtained either from the NHS Strategic Tracing Service or from the Office of National statistics . Deaths were classified according to the trial protocol . In the sub sample of 375 participants from the seven ISOLDE original centers where complete extended follow-up was conducted , the factors associated with observed higher mortality ( p<0.05 ) were male gender , older age and more severe COPD . Causes of death were ; 107 ( 52 % ) respiratory , 38 ( 18 % ) cardiac , 29 ( 14 % ) lung cancer , 16 ( 8 % ) other cancer and 16 ( 8 % ) other causes . The percentage of respiratory-related deaths increased during the follow-up period ; from 46 % within the three-year trial , to 48 % after 3 - 6 years , 57 % after 6 - 9 years , and 60 % after 9 - 13 years of follow-up ( p for trend<0.05 ) . We conclude that participants ' survival is poor ( only 44 % in the 13 years after the ISOLDE trial ) , and that respiratory-related illnesses were the most frequent causes of death in patients with moderate to severe COPD Chronic obstructive pulmonary disease ( COPD ) is characterised by a chronic inflammatory process in the large and small airways , as well as in the lung parenchyma . Although the role of oral corticosteroids in the management of acute exacerbations of COPD is well documented , its role in stable COPD is not clear . We examined the anti-inflammatory effect of inhaled budesonide on the percentage of neutrophils and on interleukin-8 ( IL-8 ) levels in bronchoalveolar lavage ( BAL ) and their correlation with spirometry and symptom scores .  Twenty-six patients with stable COPD were r and omised , in a double-blinded , placebo-controlled trial with either 800 microg of inhaled budesonide or placebo for a 6-month period . The budesonide-treated subjects had significant reductions in IL-8 levels in the BAL after therapy ( mean+/-sem , 1.53+/-0.72 at baseline vs. 0.70+/-0.48 ng/ml at 6 months , P=0.004 ) and a reduction in the mean percentages of neutrophils ( 17.16+/-2.67 % vs. 13.25+/-2.28 % P=0.002 ) . The improvement in sputum production was of borderline ( P=0.058 ) significance but there was no improvement in lung function . In stable patients with COPD , treatment with inhaled budesonide for a period of 6 months has a positive effect on markers of lung inflammation , as assessed by reduction in percentage neutrophils and IL-8 concentration in BAL The objective of this study was to determine the costs and effects of combined bronchodilator and anti-inflammatory therapy . In a 2.5-yr r and omized controlled study , combined beta 2-agonist/corticosteroid therapy ( BA + CS ) and combined beta 2-agonist/anticholinergic therapy ( BA + AC ) were compared with beta 2-agonist/placebo therapy ( BA + PL ) . Included in the study were 274 patients 18 to 60 yr of age with moderately severe obstructive airways disease . The main clinical endpoints were lung function , hyperresponsiveness , restricted activity days , and symptom-free days . The economic endpoints were the costs of health care utilization . Compared with BA + PL , BA + CS led to significant improvements in FEV1 , PC20 , and symptom-free days . BA + AC did not differ from BA + PL in this respect . The respective annual acquisition costs of BA + CS , BA + AC , and BA + PL were 532 US$ , 277 US$ , and 156 US$ . Thus , BA + CS costs 376 US$ more than BA + PL . However , compared with BA + PL therapy , BA + CS led to statistically significant savings in other health care costs of about 175 US$ ( 95 % CI from 46 to 303 US$ ) . Thus , more than half of the additional costs of adding the inhaled corticosteroid are compensated for by a reduction in the costs of other health care services . Overall , inhaled corticosteroids lead to a small but net increase in health care costs of 201 US$ per patient per year . ( ABSTRACT TRUNCATED AT 250 WORDS RATIONALE Combination therapy with corticosteroid and long-acting β(2)-agonists ( LABA ) in a single inhaler is associated with superior effects on airway function and exercise performance in COPD compared with LABA monotherapy . The physiological effects of adding inhaled corticosteroid monotherapy to maintenance bronchodilator therapy ( long-acting anticholinergics and LABA singly or in combination ) in COPD are unknown . METHODS This was a r and omized , double-blind , placebo-controlled , crossover study ( NCT00387036 ) to compare the effects of inhaled fluticasone propionate 500 μg ( FP500 ) twice-daily and placebo ( PLA ) on airway function during rest and exercise , measured during constant work rate cycle exercise at 75 % of maximum incremental cycle work rate , in 17 patients with COPD ( FEV(1 ) ≤ 70 % predicted ) . RESULTS After treatment with FP500 compared to PLA , there were significant increases in post-dose measurements of FEV(1 ) ( + 115 mL , P = 0.006 ) and the FEV(1)/FVC ratio ( + 2.5 % , P = 0.017 ) , along with decreases in plethysmographic residual volume ( -0.32L ; P = 0.031 ) , functional residual capacity ( -0.30L , P = 0.033 ) , and total lung capacity ( -0.30L , P = 0.027 ) but no changes in vital capacity or inspiratory capacity ( IC ) . Post-treatment comparisons demonstrated a significant improvement in endurance time by 188 ± 362 s with FP500 ( P = 0.047 ) with no concomitant increase in dyspnea intensity . End-inspiratory and end-expiratory lung volumes were reduced at rest and throughout exercise with FP500 compared with PLA ( P < 0.05 ) . CONCLUSION Inhaled FP500 monotherapy was associated with consistent and clinical ly important improvements in FEV(1 ) , static lung volumes , dynamic operating lung volumes , and exercise endurance when added to established maintenance long-acting bronchodilator therapy in patients with moderate to severe COPD We analyzed Lung Health Study ( LHS ) data to assess the effect of self-reported lower respiratory illnesses result ing in physician visits ( LRI ) on lung function .  Participants were 5,887 smokers aged 35 - 60 yr , FEV(1)/FVC < 0.70 and FEV(1 ) of 55 - 90 % predicted . Two-thirds were r and omized into an intensive smoking cessation program ( SI ) ; one-third were advised only to stop smoking ( UC ) . For 5 yr participants had annual spirometry and question ing regarding LRI . SI had greater rates of smoking cessation than usual care ( UC ) with fewer LRI ( p = 0.0008 ) . Sustained quitters had fewer LRI than continuing smokers ( p = 0.0003 ) . In the year LRI occurred , FEV(1 ) did not change in sustained quitters , but decreased significantly in smokers ( p = 0.0001 ) with some recovery the following year if no LRI occurred . Over 5 yr , LRI had a significant effect on rate of decline of FEV(1 ) only in smokers . In smokers averaging one LRI/yr over 5 yr there were additional declines in FEV(1 ) of 7 ml /yr ( p = 0.001 ) . Smokers with more than one LRI/yr had greater declines . Chronic bronchitis was associated with increased frequencies of LRI , but did not affect their influence on lung function . Smoking and LRI had an interactive effect on FEV(1 ) in people with mild COPD , and in smokers frequent LRI may influence the long-term course of the disease Inhaled corticosteroids are often used in the treatment of stable chronic obstructive pulmonary disease ( COPD ) , however , studies of these agents have had mixed results . Previous trials have often excluded subjects with bronchodilator response , have failed to evaluate effect on gas exchange , and have usually looked at only post- rather than prebronchodilator forced expiratory volume ( FEV ) . Our objective was to better assess the efficacy of topical corticosteroids in the treatment of COPD . We used a prospect i ve , r and omized , double-blinded , placebo-controlled , crossover study at the Outpatient Department , Department of Veterans Affairs Medical Center . Thirty-six COPD patients with a mean ( ± SD ) FEV1 of 1.10 ± 0.43 L , with or without significant bronchodilator response participated in the study . Subjects received a 3-month course of inhaled fluticasone propionate ( 220 mg/puff ) or identical-appearing placebo by metered-dose inhaler at 2 puffs twice daily , followed by crossover to the alternative inhaler for an additional 3 months . Fluticasone treatment result ed in a higher prebronchodilator FEV1 ( 1.17 ± 0.08 L [ mean ± SEM ] versus 1.07 ± 0.08 L , p = 0.001 ) , a higher PaO2 ( 66.6 ± 1.4 mmHg versus 63.6 ± 1 .6 mmHg , p = 0.002 ) , and a better dyspnea score on the chronic respiratory question naire ( 3.70 ± 0.18 versus 3.47 ± 0.19 , p = 0.03 ) . A trend towards fewer exacerbations  with fluticasone did not quite meet statistical significance ( p = 0.11 ) . Inhaled fluticasone over 3 months improved prebronchodilator airflow obstruction and oxygenation while decreasing dyspnea in moderate to severe COPD . Postbronchodilator FEV1 was not significantly changed Rates of morbidity and mortality due to asthma and chronic obstructive pulmonary disease ( COPD ) have increased during the last two decades [ 1 , 2 ] . These increases might be related to the use of bronchodilator therapy without anti-inflammatory medication [ 3 , 4 ] . Recently , two studies found that regular bronchodilator treatment had adverse effects on the control of asthma [ 5 ] and the progression of asthma and COPD [ 6 ] . In a previous study of 160 patients with asthma or COPD [ 6 ] , we found that continuous treatment with a bronchodilator ( ipratropium bromide , 40 g , or salbutamol , 400 g , four times daily ) was associated with a much higher annual decline in the forced expiratory volume in 1 second ( FEV1 ) compared with treatment on dem and . It is unclear whether an unfavorable course of asthma or COPD during bronchodilator therapy alone can be reversed or decelerated by additional anti-inflammatory therapy with inhaled corticosteroids . We studied 56 of the 160 patients who had an unfavorable disease course during bronchodilator therapy alone ( an annual decline in FEV1 of at least 80 mL/y in combination with at least two exacerbations per year ) . These 56 patients ( 28 with asthma and 28 with COPD ) were also treated with an inhaled corticosteroid ( beclomethasone dipropionate , 800 g daily ) during years 3 and 4 of the study . We assessed whether the worsening of their disease during bronchodilator therapy alone was reversed or decelerated by additional anti-inflammatory treatment with beclomethasone . The outcome measures were dynamic lung function indices ( annual decline in pre- and postbronchodilator FEV1 , peak expiratory flow rate [ PEFR ] , and forced inspiratory volume in 1 second [ FIV1 ] ) , static lung function indices ( residual volume [ RV ] , ratio of residual volume to total lung capacity ( RV/TLC ) , inspiratory vital capacity [ IVC ] ) , nonspecific bronchial responsiveness ( assessed by determining the concentration of histamine that provokes a 20 % decrease in FEV1 [ Pc 20 ] ) , exacerbations , and respiratory symptoms . Methods Patients Patient selection has been previously described [ 6 ] . In short , 29 family physicians in the catchment area of the University of Nijmegen , Nijmegen , the Netherl and s , selected all patients who were 30 years or older and had symptoms of asthma or COPD . Only patients who showed mild-to-moderate airway obstruction ( FEV1 > 50 % of the predicted value [ 7 ] ) or bronchial hyper-responsiveness to histamine ( Pc 20 8 mg/mL ) were included in the study . Patients dependent on inhaled corticosteroids who had chronic heart failure , malignant disorders , or other severe life-threatening diseases were excluded from the study . Of these patients , 160 ( 59 with asthma and 101 with COPD ) completed the bronchodilator trial . During the 2 years of bronchodilator treatment , a rapid decline in FEV1 ( 80 mL/y ) and a relatively high exacerbation rate ( 1/y ) were observed in a subgroup of 56 patients ( 35 % ) . Because of their unfavorable disease course , these patients were selected for additional treatment with inhaled beclomethasone for 2 years . The criteria for diagnosis of asthma or COPD were based on the st and ards of the American Thoracic Society [ 8 ] . Asthma was defined [ 6 , 8 ] by a combination of factors : bronchial hyper-responsiveness to  histamine  ( Pc 20 8 mg/mL ) ; reversible obstruction ( an improvement in FEV1 of more than 15 % of the prebronchodilator value 60 minutes after the administration of both salbutamol , 400 g , and ipratropium bromide , 80 g ) ; dyspnea ; and allergy ( defined as at least one positive result on seven radioallergosorbent tests that assessed sensitivity to pollen from weeds , grasses , and trees ; cats and dogs ; house dust mite ; and Aspergillus fumigatus ) or wheezing . Chronic obstructive pulmonary disease was defined [ 6 , 8 ] by the combination of chronic cough or chronic sputum production for at least 3 months during at least 2 consecutive years ; and continuous bronchus obstruction ( FEV1 85 % of the predicted value ) . The separate features of asthma and COPD overlap ( for instance , some asthmatic patients had chronic cough , and some COPD patients had a Pc 20 8 mg/mL ) , but the definitions based on feature combinations ensured that no patients with asthma also had COPD and vice versa [ 6 ] . The study was approved by the Medical Ethics Committee of the University of Nijmegen . All patients gave informed consent . Study Design and Treatment At the start of the 4-year intervention study , the patients were r and omly assigned to one of two parallel treatment regimens : continuous bronchodilator therapy ( four times daily ) or treatment on dem and ( dry powder inhalations during symptomatic periods ) [ 6 ] . The patients used salbutamol , 400 g , during 1 year and ipratropium bromide , 40 g , during the other year ; both were administered as dry powder inhalations . The sequence of the drugs was determined by r and om allocation . During years 3 and 4 , the 56 patients received 400 g of beclomethasone , two times daily , in combination with 400 g of salbutamol or 40 g of ipratropium bromide , four times daily ( all dry powder inhalations ) . The bronchodilator inhaled during year 2 was also used in years 3 and 4 . During the first 2 years of the study , 27 of the 56 patients received bronchodilator therapy on dem and ( of the 27 , 15 had asthma and 12 had COPD ) . For patients treated on dem and , the mean ( SE ) daily number of dry powder inhalations of salbutamol or ipratropium bromide was 1.2 0.3 in those with asthma and 0.8 0.2 in those with COPD . During years 3 and 4 , 28 patients received salbutamol ( 15 with asthma and 13 with COPD ) and 28 received ipratropium bromide ( 13 with asthma and 15 with COPD ) . Once every 3 months , inhalation technique and compliance with the prescribed medication were checked . Patients were instructed to rinse their mouths after the dry powder inhalations . During the second year of beclomethasone therapy , a single-blind prospect i ve study was done to assess patient compliance with beclomethasone and the additional bronchodilator .  Compliance was measured by counting capsules at the end of a 4-month period . Patients were unaware that their medication was counted after this period . Lung Function , Nonspecific Bronchial Responsiveness , and Reversibility All measurements were carried out by two qualified laboratory assistants during exacerbation-free periods . No bronchodilator was inhaled for at least 8 hours before the pulmonary function tests . At the start and after 24 and 48 months of the study , the inspiratory vital capacity ( IVC ) , residual volume ( RV ) , functional residual capacity ( FRC ) , and total lung capacity ( TLC ) were assessed using the wet Gould spirometer ( Sensormedics , Bilthoven , the Netherl and s ) according to the st and ards of the European Coal and Steel Community [ 7 ] . The FEV1 , bronchial responsiveness to histamine , and the reversibility of airway obstruction were assessed at 6-month intervals using the Microspiro HI-298 ( Chest Corporation , Tokyo , Japan ) [ 9 ] . Moreover , FEV1 and reversibility were also assessed after 1 and 13 months of study [ 6 ] . The best of three forced expiratory maneuvers , with the highest sum of the forced vital capacity ( FVC ) and FEV1 , was used for data analysis . The bronchial responsiveness to histamine was measured according to the method described by Cockcroft and colleagues [ 10 ] . Results were expressed as the concentration of histamine that provoked a 20 % decrease in FEV1 ( Pc 20 ) . After the FEV1 had returned to the baseline value , the bronchodilating response ( reversibility ) was assessed 60 minutes after the administration of both 80 g of ipratropium bromide and 400 g of salbutamol ( metered dose aerosol ) [ 6 ] . The bronchodilating response was expressed as the increase in FEV1 relative to the predicted value of the FEV1 . Peak Expiratory Flow Assessment s Once a week ( on the same day and at the same time ) , peak expiratory flow rate ( PEFR ) was measured with the Assess peak flow meter ( HealthScan Products , Cedar Grove , New Jersey ) [ 11 ] in the morning and in the evening . The highest value of three measurements was included in the analysis . The diurnal PEFR index ( absolute difference between the evening value and the morning value divided by the highest value ) was calculated . Exacerbations Our definition of exacerbation was based on that of Fletcher as modified by Boman and colleagues [ 12 ] . When an exacerbation occurred , a 10-day course of oral prednisone was administered . Patients received 25 mg for 2 days , 20 mg for 2 days , 15 mg for 2 days , and so forth . Symptoms and Adverse Effects Using a scale of 0 to 4 , all patients recorded , on a weekly basis , the presence and severity of symptoms ( cough , phlegm , dyspnea , fatigue , disturbed sleep at night ) . The adverse effects of medication ( dysphonia and oropharyngeal irritation ) were recorded by the patients once every 3 months . Moreover , every 6 months , the presence and severity of oral c and idiasis were assessed using a question naire ( no , light , or severe symptoms ) . Smoking At the start of the study , smoking history was assessed in pack-years . During the study , the average number of cigarettes smoked per day was also recorded in weekly diary entries . Power Calculations Assuming that the clinical ly relevant , decreased annual decline in FEV1 during beclomethasone treatment is 25 mL/y and that the residual st and ard deviation is 50 mL/y , the coefficient of variation is 25/50 or 0.5 . Based on an of 0.05 and a of 0.20 ( power:1 0.2 , or 0.8 ) , the required number of patients for the study would be 51 . Based on an estimated dropout rate of 10 % , the required initial number of study patients would be 56 . Statistical Analysis Data on outcome variables obtained before and during beclomethasone therapy were compared . Differences were tested by repeated- measures analysis of variance , the paired Student t-test for normally distributed variables , and the Wilcoxon paired signed-rank test for non-normally distributed variables . Before the analysis , the Pc 20 values were 2log transformed . The Introduction : Whether smoking-induced lung inflammation subsides after smoking cessation is currently a matter of debate . We used computed tomography ( CT ) to evaluate the effect of smoking cessation on lung density in patients with COPD . Material and methods : Thirty-six patients quit smoking out of 254 current smokers with COPD who were followed with annual CT and lung function tests ( LFT ) for 2–4 years as part of a r and omised placebo-controlled trial of the effect of inhaled budesonide on CT-lung density . Lung density was expressed as the 15th percentile density ( PD15 ) and relative area of emphysema below -910 HU ( RA-910 ) . From the time-trends in the budesonide and placebo groups the expected CT-lung densities at the first visit after smoking cessation were calculated by linear regression and compared to the observed densities . Results : Following smoking cessation RA-910 increased by 2.6 % ( p = 0.003 ) and PD15 decreased by −4.9 HU ( p = 0.0002 ) . Furthermore , changes were larger in the budesonide group than the placebo group ( PD15 : −7.1 vs −2.8 HU . RA-910 3.7 % vs 1.7 % ) . These differences were , however , not statistically significant . The LFT parameters ( FEV1 and diffusion capacity ) were not significantly influenced by smoking cessation . Conclusion : Inflammation partly masks the presence of emphysema on CT and smoking cessation results in a paradoxical fall in lung density , which resembles rapid progression of emphysema . This fall in density is probably due to an anti-inflammatory effect of smoking cessation BACKGROUND Pneumonia is an important complication of COPD and is reported more often in patients receiving inhaled corticosteroids ( ICSs ) . Little is known about the clinical course and factors predisposing to pneumonia in patients with COPD . We investigated patient characteristics and symptoms occurring before pneumonia reports in the Investigating New St and ards for Prophylaxis in Reduction of Exacerbations ( INSPIRE ) study . METHODS This was a 2-year , double-blind , double-dummy parallel study of 1,323 patients r and omized to salmeterol/fluticasone propionate 50/500 μg bid ( SFC ) or tiotropium 18 μg once daily ( Tio ) . Baseline demographics , including serum C-reactive protein ( CRP ) levels , were measured , and daily record cards ( DRCs ) were completed . RESULTS We identified 87 pneumonia reports from adverse event records ( SFC=62 ; Tio=25 ) in 74 patients ( SFC=50 ; Tio=24 ) , compared with 2,255 exacerbations ( SFC=1,185 ; Tio=1,070 ) . Pneumonia was more common in patients with severe dyspnea and in those with a baseline CRP level>10 mg/L. Numbers of de novo pneumonias ( events that were not preceded by symptoms of an exacerbation ) were similar between treatment groups , but pneumonia was more likely after either a treated or untreated unresolved exacerbation in patients receiving ICSs ( SFC=32 ; Tio=7 ) . Similar results were seen when analysis was confined to radiologically confirmed events . CONCLUSIONS Pneumonia is much less frequent than exacerbation in COPD . The excess of events with ICS treatment appears to be associated with protracted symptomatic exacerbations . Earlier identification and treatment of these events to prevent pneumonia merits further investigation . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00361959 ; Study No. : SC040036 ; URL : clinical trials.gov BACKGROUND --The effect of treatment with inhaled corticosteroids in patients with non-asthmatic chronic airflow obstruction is still disputed . Whether any physiological improvements seen are accompanied by changes in bronchial responsiveness and symptoms and quality of life is also still unclear . METHODS --A sequential placebo controlled , blinded parallel group study investigating the effect of three weeks of treatment with inhaled beclomethasone dipropionate ( BDP ) , 750 micrograms or 1500 micrograms twice daily , and oral prednisolone , 40 mg per day , was carried out in 105 patients with severe non-asthmatic chronic airflow obstruction ( mean age 66 years , mean forced expiratory volume in one second ( FEV1 ) 1.05 litres [ 40 % predicted ] , geometric mean PD20 0.52 mumol ) . End points assessed were FEV1 , forced vital capacity ( FVC ) , and peak expiratory flow ( PEF ) , bronchial responsiveness to inhaled histamine , and quality of life as measured by a formal quality of life question naire . RESULTS --Both doses of BDP produced equivalent , small , but significant improvements in FEV1 ( mean 48 ml ) , FVC ( mean 120 ml ) , and PEF ( mean 12.4 l/min ) . The addition of oral prednisolone to the treatment regime in two thirds of the patients did not produce any further improvement in these parameters . Inhaled BDP produced a treatment response in individual patients ( defined as an improvement in FEV1 , FVC , or mean PEF of at least 20 % compared with baseline values ) more commonly than placebo ( 34 % v 15 % ) . The two doses of BDP were equally effective in this respect and again no further benefit of treatment with oral prednisolone was noted . Treatment with BDP for up to six weeks did not affect bronchial responsiveness to histamine . Small but significant improvements were seen in dyspnoea during daily activities , and the feeling of mastery over the disease . CONCLUSIONS --High dose inhaled BDP is an effective treatment for patients with chronic airflow obstruction not caused by asthma . Both objective and subjective measures show improvement . Unlike asthma , no improvement in bronchial responsiveness was detected after six weeks of treatment Abstract Objective : To compare the healthcare costs and effects of budesonide/formoterol in a single inhaler with those of budesonide and formoterol monotherapies , and placebo , in a multinational study in patients with chronic obstructive pulmonary disease ( COPD ) , National Heart , Lung and Blood Institute (NHLBI)/WHO Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stages III or IV . Previous analysis of the clinical data from the study had shown that budesonide/formoterol was associated with better lung function and improved health-related QOL compared with the monocomponents or placebo and lower frequency of exacerbations compared with formoterol and placebo . Method : Patients ( n = 1022 ) were r and omised to twice-daily treatment with two inhalations of budesonide/formoterol ( 160μg/4.5μg ) in a single inhaler , budesonide 200μg , formoterol 4.5μg or placebo for 12 months . Data on medication and healthcare use were combined with Swedish unit cost data to estimate the total annual healthcare cost per patient from the Swedish healthcare payer perspective . Costs were valued in Swedish kronor ( SEK ) [ 2001 values ] and converted to euros ( SEK1 = € 0.11 , 25th April 2003 ) . Results : This evaluation estimated the total annual healthcare costs per patient to be numerically lower for budesonide/formoterol ( € 2518 ) than for budesonide ( € 3194 ) , formoterol ( € 3653 ) or placebo ( € 3213 ) . Cost-effectiveness acceptability curves suggest that budesonide/formoterol may be cost effective compared with formoterol , even if the decision maker is not willing to pay anything for the additional clinical effects , and that budesonide/formoterol  is cost effective  compared with placebo if a decision maker is willing to pay about € 2 per day , per avoided exacerbation . Conclusion : This economic analysis suggests that the clinical benefits of using budesonide/formoterol in a single inhaler are achieved at a numerically lower total healthcare cost  than either monocomponent or placebo . Budesonide/formoterol in patients with severe COPD ( GOLD stages III or IV ) may be cost effective , from the healthcare provider perspective , compared with either monocomponent BACKGROUND Little is known about the long-term efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease ( COPD ) . We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD . METHODS We used a parallel-group , r and omised , double-blind , placebo-controlled design in a singlecentre study , nested in a continuing epidemiological survey ( the Copenhagen City Heart Study ) . Inclusion criteria were as follows : no asthma ; a ratio of forced expiratory volume in 1 s ( FEV1 ) and vital capacity of 0.7 or less ; FEV1 which showed no response ( < 15 % change ) to 1 mg inhaled terbutaline or prednisolone 37.5 mg orally once daily for 10 days . 290 patients were r and omly assigned  budesonide , 800 microg plus 400 microg daily for 6 months followed by 400 microg twice daily for 30 months , or placebo for 36 months . The mean age of the participants was 59 years and the mean FEV1 2.37 L or 86 % of predicted . The main outcome measure was rate of FEV1 decline . Analyses were by intention to treat . FINDINGS The crude rates of FEV1 decline were slightly smaller than expected ( placebo group 41.8 mL per year , budesonide group 45.1 mL per year ) . The estimated rates of decline from the regression model did not differ significantly ( 49.1 mL vs 46.0 mL per year ; difference 3.1 mL per year [ 95 % CI -12.8 to 19.0 ] ; p=0.7 ) . Before the study , the minimum relevant difference was defined as 20 mL per year ; this difference was outside the 95 % CI . No effect of inhaled budesonide was seen on respiratory symptoms . 316 exacerbations occurred during the study period , 155 in the budesonide group and 161 in the placebo group . Treatment was well tolerated . INTERPRETATION Inhaled budesonide was of no clinical benefit in COPD patients recruited from the general population by screening . We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD Systemic inflammation is present in chronic obstructive pulmonary disease ( COPD ) , which has been linked to cardiovascular morbidity and mortality . We determined the effects of oral and inhaled corticosteroids on serum markers of inflammation in patients with stable COPD . We recruited 41 patients with mild to moderate COPD . After 4 weeks during which inhaled corticosteroids were discontinued , patients were assigned to fluticasone ( 500 mcg twice a day ) , oral prednisone ( 30 mg/day ) , or placebo over 2 weeks , followed by 8 weeks of fluticasone at 500 mcg twice a day and another 8 weeks at 1,000 mcg twice a day . Withdrawal of inhaled corticosteroids increased baseline C-reactive protein ( CRP ) levels by 71 % ( 95 % confidence interval [ CI ] , 16 - 152 % ) . Two weeks with inhaled fluticasone reduced CRP levels by 50 % ( 95 % CI , 9 - 73 % ) ; prednisone reduced it by 63 % ( 95 % CI , 29 - 81 % ) . No significant changes were observed with the placebo . An additional 8 weeks of fluticasone were associated with CRP levels that were lower than those at baseline ( a 29 % reduction ; 95 % CI , 7 - 46 % ) . Inhaled and oral corticosteroids are effective in reducing serum CRP levels in patients with COPD and suggest their potential use for improving cardiovascular outcomes in COPD BACKGROUND Osteoporosis is common in patients with COPD , but its prevalence and progression are not well characterized . Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids ( ICSs ) on bone density in this population . Here , we investigated the long-term effects of therapy with fluticasone propionate ( FP ) alone , salmeterol ( SAL ) alone , and a SAL/FP combination ( SFC ) on bone mineral density ( BMD ) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health ( TORCH ) study . METHODS A r and omized , double-blind , parallel-group , placebo-controlled study conducted at 88 US centers involving 658 patients ( a subset of 6,184 international subjects in TORCH ) . Therapy with placebo , SAL ( 50 microg ) , FP ( 500 microg ) , or SFC ( SAL 50 microg/FP 500 microg ) twice daily was administered for 3 years . Baseline and yearly measurements of BMD at the hip and lumbar spine were performed . The incidence of traumatic and nontraumatic bone fractures was recorded . RESULTS At baseline , 18 % of men and 30 % of women had osteoporosis , and 42 % of men and 41 % of women had osteopenia based on BMD assessment s. Forty-three percent of subjects completed all testing . The changes in BMD at the hip and lumbar spine over 3 years were small . No significant differences were observed between treatment arms ( adjusted mean percent change from baseline at hip was -3.1 % for placebo , -1.7 % for SAL , -2.9 % for FP , and -3.2 % for SFC therapy , respectively ; while , the corresponding changes for the lumbar spine were 0 , 1.5 % , -0.3 % , and -0.3 % for placebo , respectively , SAL , FP , and SFC therapy ) . The incidence of fractures was low and was similar for all treatments ( 5.1 % to 6.3 % ) . CONCLUSIONS Osteoporosis is highly prevalent in patients with COPD , irrespective of gender . In the TORCH study , no significant effect on BMD was detected for ICS therapy compared with placebo . TRIAL REGISTRATION Clinical Trials.gov Identifier : NTC00268216 BACKGROUND There is no agreement about the efficacy of systemic corticosteroids in patients with COPD , but corticosteroids often are employed during exacerbations of the disease . The use of systemic or inhaled corticosteroids in patients in stable condition is even more controversial , even though the more severely affected patients seem to respond better . Unfortunately , in this subset of patients , the use of forced expiratory maneuvers frequently fails to detect significant functional response . STUDY OBJECTIVES We evaluated the short-term effects of an inhaled corticosteroid , fluticasone propionate ( FP ) , on FEV(1 ) and on the mechanical properties of patients in stable condition with severe COPD and chronic hypercapnic respiratory failure who were receiving long-term ventilatory support . This allowed us to measure respiratory mechanics ( RM ) passively , thereby avoiding any problems linked with voluntary maneuvers . DESIGN R and omized , placebo-controlled , crossover study . SETTING A respiratory ICU . PATIENTS Twelve hypercapnic COPD patients ( mean [ + /- SD ] PaCO(2 ) , 60+/-11 mm Hg ; mean FEV(1 ) , 13+/-5 % predicted ; and mean FEV(1)/FVC , 31 + /- 7 % ) were enrolled . INTERVENTIONS A daily dose of 2,000 microg FP or placebo was administered via metered-dose inhaler during mechanical ventilation for 5 consecutive days . A washout of 72 h was allowed between regimens . MEASUREMENTS End-expiratory and end-inspiratory airway occlusions were performed to assess static intrinsic positive end-expiratory pressure ( PEEPi , st ) , static compliance of the respiratory system ( Cst , rs ) , maximal respiratory resistance ( Rmax , rs ) , and minimal respiratory resistance ( Rmin , rs ) . The bronchodilator response also was assessed by FEV(1 ) level . RESULTS No significant changes were found in RM after administration of the placebo . By day 6 , FP had induced the following significant decreases : PEEPi , st , 4.3+/-2.4 to 3.1+/-1.7 cm H(2)O ( p<0.01 ) ; Rmax , rs , 19.0+/-6.5 to 14.6+/-6 cm H(2)O/L/s ( p<0.001 ) ; and Rmin , rs , 14.8+/-4.2 to 10.5+/-3.4 cm H(2)O/L/s ( p<0.001 ) . The Cst , rs and the effective additional resistance of the respiratory system did not change significantly , the latter suggesting that the major effect of FP was on the airway caliber ( Rmin , rs ) . FEV(1 ) changes significantly ( p<0.01 ) underestimated the bronchodilator response , as compared with changes in Rmin , rs . CONCLUSIONS We conclude that in patients in stable condition with severe COPD and chronic hypercapnic respiratory failure , a brief trial of FP may induce a bronchodilator response , mainly related to a reduction in airway resistances , that is not detected by the usual pulmonary function tests BACKGROUND : Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease . We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide . METHODS : Ten non-allergic subjects with stable disease were investigated ; eight completed the r and omised , double blind , three period cross over study . Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks , 40 mg oral prednisone a day for eight days , and placebo . After each period cumulative doubling doses of salbutamol , ipratropium , a combination of salbutamol and ipratropium , and placebo were administered on separate days until a plateau in FEV1 was reached . A histamine challenge was then performed . RESULTS : At the end of placebo treatment mean FEV1 was 55.5 % predicted after inhaled placebo , 67.9 % predicted after salbutamol and 64.0 % predicted after ipratropium . Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7 % predicted after treatment with budesonide and by 0.7 % predicted after treatment with prednisone ; the FEV1 with ipratropium  increased by 0.7 % predicted after budesonide and by 4.8 % predicted after prednisone ; none of these changes was significant . After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo , 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium . Compared with the placebo period the PC20 with  salbutamol  was increased by 0.86 doubling concentrations after treatment with budesonide , and by 0.67 doubling concentrations after prednisone ; the PC20 with ipratropium  increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo ; none of these changes was significant . CONCLUSIONS : In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine . Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium In a prospect i ve study , we investigated the long-term compliance to fluticasone propionate ( FP ) by dry powder inhalation ( Rotadisk ® ) in subjects with early signs of asthma and chronic obstructive pulmonary disease ( COPD ) without an established diagnosis . Subjects were selected from a large screening program on early stages of asthma and COPD ( Detection , Intervention , and Monitoring Program of COPD and Asthma [ DIMCA ] program ) in the general practice . Forty-eight adult subjects with “ early signs of COPD ” ( slightly increased forced expiratory volume in 1 sec [ FEV1 ] decline of > 0.04L/year ) and 29 adult subjects with “ early signs of asthma ” ( signs of bronchial hyperresponsiveness or reversibility ) participated in a r and omized placebo-controlled trial with FP ( Flixotide ® 500 jag daily ) versus placebo with a duration of 2 years or 1 year , respectively . Compliance was measured by counting Rotadisks returned . By means of a question naire , participants were asked about perceived effects and /or side effects of the trial drug . The mean overall individual compliance rates of 72 % ( range 7%-102 % ) in the early COPD trial and 71 % ( range 8%-99 % ) in the early asthma trial were maintained throughout the study . Perceived effectiveness ( 12 % of the participants ) or side effects ( 30 % of the participants ) of the trial drug were not related to compliance . The willingness of patients to use the trial drug in daily practice if efficacy would be proved was statistically significantly related to compliance during the trial ( p = 0.017 ) . It was concluded that the compliance rates found were relatively high in patients with symptoms of mild asthma or COPD without an established diagnosis . Conviction of the importance of treatment influenced compliance more positively than perceived ( side ) effects . These results again emphasize the importance of patient education in establishing early treatment with inhaled corticosteroids Treatment of chronic obstructive pulmonary disease ( COPD ) with inhaled and oral corticosteroids is common , although their exact role is unclear . Previous studies suggest these drugs may reduce decline in lung function in this group of patients . We report a study investigating the effect of inhaled beclomethasone diproprionate ( BDP ) on lung function and symptoms in a group of patients with COPD . Treatment was given for 2 years , and the decline in FEV1 in individual patients calculated over this period . Ninety‐eight patients were r and omized for the study , 59 completing 2 years of treatment . Patients withdrawn had more severe airflow obstruction . Decline in FEV1 , measured both prior to and after bronchodilator , was less in patients receiving inhaled BDP , although the differences failed to reach statistical significance except in a subgroup of patients with more severe airflow obstruction . Exacerbation rates were also reduced by inhaled BDP , but again the differences failed to reach conventional levels of statistical significance . The results of this study are consistent with previous published work , but further insight into the long‐term role of corticosteroids in COPD await the publication of large studies which have recently been completed . Although the changes seen in this study and others are numerically small , the rate of decline in FEV1 returned to normal levels expected from age‐related decline , and hence such treatment combined with other strategies may well have a significant role in the long‐term treatment of this condition Background : No consistent data are available regarding the effect of inhaled corticosteroids ( ICS ) in α1-antitrypsin-deficiency (AATD)-related COPD . Recent data report inflammatory effects of the polymers of α1-antitrypsin on the peripheral lung . Objectives : The aim of this study was to assess the effectiveness of an extra-fine ICS , hydrofluoroalkane-134a beclometasone dipropionate ( HFA-BDP ) with a mass median aerodynamic diameter of 1.1 µm , on lung function and exercise tolerance in COPD patients with AATD when added to long-acting bronchodilators ( LABAs ) . Methods : After a 1-week washout , 8 steroid-naïve COPD patients with AATD ( ZZ genotype ) , within a double-blind r and omized cross-over study , were assigned to one of the following 16-week treatments : ( 1 ) HFA-BDP 400 µg b.i.d . , salmeterol 50 µg b.i.d . and oxitropium bromide 200 µg t.i.d . or ( 2 ) placebo , salmeterol 50 µg b.i.d . and oxitropium bromide 200 µg t.i.d ; after a 2-week washout period they received the other treatment . In weeks 1 , 17 , 19 and 35 , patients took a spirometry assessment ( breathing air and heliox ) and a  shuttle walking test ( SWT ) with dyspnea assessed by the modified Borg scale . Results : Significant differences in improvement were found in FEV1 , FVC , IC , distance covered and dyspnea perceived during SWT between the 2 treatments and baseline values ( p < 0.05 ; Friedman ’s test ) . However , further analysis showed that only the LABAs + ICS condition showed significant increases in the FEV1 , FVC , IC , ΔMEF50 % and distance covered during SWT along with a reduction in maximum isostep exertional dyspnea ( p < 0.05 ; Wilcoxon test ) . A greater distance was walked at the end of the SWT with LABA + ICS than LABAs alone ( 301 ± 105 vs. 270 ± 112 m ; p < 0.05 ) . Conclusions : In AATD-related COPD patients ( ZZ genotype ) the addition of extra-fine ICS to LABAs decreases airway narrowing , mostly in the small airways , further reducing dynamic hyperinflation with a marked improvement in exercise tolerance and dyspnea , suggesting that a peripheral inflammatory process contributes to airflow obstruction in these patients Inhaled glucocorticosteroids ( ICS ) are commonly prescribed for chronic obstructive pulmonary disease . No adverse effect on bone mineral density ( BMD ) has been proven . In a r and omized double-blind , placebo-controlled trial at seven centers in North America , we recruited 412 current smokers or recent quitters with mild to moderate chronic obstructive pulmonary disease . They used inhaled triamcinolone acetonide , 600 mcg , or placebo , twice daily . We measured femoral neck and lumbar spine BMD at baseline and after 1 and 3 years , and serum osteocalcin at baseline , 3 months , 1 year , and 3 years . After 3 years , BMD at the femoral neck decreased 1.78 % more with ICS than with placebo ( p < 0.001 ) . More participants in the ICS group experienced 6 % or more loss of femoral neck BMD ( p = 0.002 ) . Lumbar spine BMD increased in the placebo group by 0.98 % but decreased by 0.35 % in the ICS group ( a difference of 1.33 % , p = 0.007 ) . Changes in osteocalcin did not correlate with changes in BMD . Fractures , lost height , or osteoporosis diagnoses were not increased among ICS users compared with placebo users . In summary , the use of inhaled triamcinolone acetonide was associated with loss of BMD at the femoral neck and lumbar spine after 3 years of treatment Inhaled corticosteroids ( ICS ) are effective in the treatment of asthma and markedly reduce the numbers of inflammatory cells in bronchial biopsies . However , the effect of ICS on the inflammatory profile of biopsies in smokers with chronic obstructive pulmonary disease ( COPD ) is unknown . We have performed a double-blind , placebo-controlled , r and omized study to compare fluticasone propionate ( FP ) 500 microg twice daily via a dry powder inhaler and placebo ( P ) over a 3-month period in subjects with COPD .  Fiberoptic bronchoscopy and bronchial biopsy was carried out at baseline and after the 3 months of treatment . Thirty-one subjects completed the trial and 30 paired biopsies were available for analysis . Compared with P ( n = 14 ) , subjects on inhaled FP ( n = 16 ) had no significant reductions in the primary endpoints : CD8 + , CD68 + cells , or neutrophils , considered to be of importance in COPD . However , there was a reduction in the CD8:CD4 ratio in the epithelium and of the numbers of subepithelial mast cells in the FP group . CD4 + cells were significantly raised in the P group in both subepithelium and epithelium . Symptoms significantly improved , and there were significantly fewer exacerbations in subjects on FP , compared to subjects on P. The data indicate that inhaled fluticasone does affect selected aspects of airway inflammation in COPD , and this may explain , in part , the decrease in exacerbations seen in long-term studies with fluticasone propionate There is controversy about the role of inhaled corticosteroids in chronic obstructive pulmonary disease ( COPD ) . Although they appear to have little impact on airways obstruction or its progression , their use may reduce the frequency and /or severity of exacerbations in a subset of patients . We undertook the following study to determine the impact of inhaled corticosteroid on two noninvasive markers of airways inflammation . We assigned 20 stable nonsmoking patients with COPD in r and om , double-blind crossover fashion to two 2-wk treatment periods with inhaled beclomethasone 500 microg twice daily or matching placebo , followed by a 2-wk washout period . We measured exhaled nitric oxide ( ENO ) , breath condensate H(2)O(2 ) , and flow volume spirometry at weekly intervals . Median baseline ENO was 26.2 ( 19.3 to 54.8 ) ppb and fell significantly following 1 and 2 wk of beclomethasone ( -10.6 ppb , p = 0.002 , and -6.3 ppb , p = 0.013 , respectively ) but was unchanged by placebo inhalation . Breath condensate H(2)O(2 ) levels did not change significantly with inhaled beclomethasone or placebo . Although there were no significant changes in FEV(1 ) with BDP therapy , there was a moderate inverse correlation between changes in ENO and changes in FEV(1 ) ( r -0.50 ) . We conclude that inhaled beclomethasone reduces ENO levels in stable nonsmoking patients with COPD , a finding compatible with an antiinflammatory mechanism of action RATIONALE Small studies have suggested that inhaled corticosteroids can suppress systemic inflammation in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To determine the effect of inhaled corticosteroids with or without long-acting beta(2)-adrenergic agonist on systemic biomarkers of inflammation . METHODS We conducted a double-blind r and omized placebo-controlled trial across 11 centers ( n = 289 patients with FEV(1 ) of 47.8 + /- 16.2 % of predicted ) to compare the effects of inhaled fluticasone alone or in combination with salmeterol against placebo on circulating biomarkers of systemic inflammation over 4 weeks . The primary endpoint was C-reactive protein ( CRP ) level . Secondary molecules of interest were IL-6 and surfactant protein D ( SP-D ) . MEASUREMENTS AND MAIN RESULTS Neither fluticasone nor the combination of fluticasone/salmeterol had a significant effect on CRP or IL-6 levels . There was , however , a significant reduction in SP-D levels with fluticasone and fluticasone/salmeterol compared with placebo ( P = 0.002 ) . Health status also improved significantly in both the fluticasone and fluticasone/salmeterol groups compared with placebo , driven mostly by improvements in the symptom scores . Changes in the circulating SP-D levels were related to changes in health status scores . FEV(1 ) improved significantly only in the fluticasone/salmeterol group compared with placebo . CONCLUSIONS ICS in conjunction with long-acting beta(2)-adrenergic agonist do not reduce CRP or IL-6 levels in serum of patients with COPD over 4 weeks . They do , however , significantly reduce serum SP-D levels . These data suggest that these drugs reduce lung-specific but not generalized biomarkers of systemic inflammation in COPD One hundred and twenty one patients considered on clinical grounds to have non-asthmatic chronic airflow obstruction completed a double blind , crossover trial comparing oral prednisolone 40 mg per day with inhaled beclomethasone dipropionate 500 micrograms thrice daily , each given for 14 days , with a 14 day washout period between treatments . The time course of response was analysed for the 57 occasions where there was a significant increase in mean daily peak expiratory flow ( PEF ) over the treatment period . Mean daily PEF was still rising at day 14 on 12 occasions . After withdrawal of treatment mean daily PEF remained above pretreatments levels for more than two weeks in half the responses analysed . The peak response occurred earlier with inhaled beclomethasone ( median 9.5 ( range 3 - 14 ) days ) than with oral prednisolone ( median 12 ( range 1 - 14 ) days ) , though both treatments produced a response that was sustained for a similar period . The results suggest that a trial of treatment with corticosteroids in this group of patients should last more than 14 days , and that in a study with a crossover design the washout period should be longer than two weeks BACKGROUND Increased oxidative stress and bronchial inflammation are important mechanisms in the pathophysiology of COPD . AIM To investigate whether treatment with the inhaled corticosteroid fluticasone propionate ( FP ) or the anti-oxidative agent N-acetylcysteine ( NAC ) are effective in primary care patients . METHODS The study was a 3-year placebo-controlled  r and omised controlled trial preceded by a 3-month washout and 2-week prednisolone pre-treatment . Patients were (ex-)smokers with chronic bronchitis or COPD . Interventions were inhaled FP 500microg b.i.d . , oral NAC 600 mg o.d . , or placebo .  Exacerbation rate and quality of life measured with the Chronic Respiratory Question naire ( CRQ ) were the primary outcomes , FEV(1 ) decline and respiratory symptoms secondary outcomes . RESULTS 286 patients recruited from 44 general practice s were r and omised . Exacerbation rate was 1.35 times higher for NAC ( p=0.054 ) and 1.30 times higher for FP ( p=0.095 ) compared with placebo  . CRQ total scores did not differ between NAC ( p=0.306 ) or FP ( p=0.581 ) treatment compared to  placebo  . Annual postbronchodilator FEV(1 ) decline was 64mL [ SD 5.4 ] for NAC [ p=0.569 versus placebo ] , 59mL [ SD 5.7 ] for FP [ p=0.935 ] , and 60mL [ SD 5.4 ] for placebo . CONCLUSION No beneficial treatment effects for either high-dosed inhaled fluticasone propionate or oral N-acetylcysteine were observed in our study population of patients with COPD or chronic bronchitis OBJECTIVE To define the relationship between skin bruising ( as well as other cutaneous manifestations ) and inhaled corticosteroid ( ICS ) therapy vs placebo in subjects with COPD who were participating in a clinical trial . To explore the relationship between easy skin bruising and other systemic effects of ICS therapy , including adrenal suppression and loss of bone mineral density ( BMD ) . DESIGN Double-blind , r and omized , placebo-controlled clinical trial of triamcinolone acetonide ( 1200 microg daily ) vs placebo in participants with mild-to-moderate COPD . SETTING Lung Health Study II , a clinical trial to assess the effect of ICS compared to placebo in 1,116 participants in 10 centers over > 3.5 to 4.5 years . PARTICIPANTS A total of 1,116 smokers or recent ex-smokers with mild-to-moderate COPD ( age range , 40 to 69 years ; mean age , 56.3 years ; 37.2 % female ) . MEASUREMENTS AND RESULTS Every 6 months , a structured question naire was administered to elicit reports of any bruising and /or skin rashes , slow healing of cuts or sores , or other skin changes . Compliance with inhaler use was assessed by canister weighing . A significantly higher proportion of ICS than placebo participants who complied with using their inhaler reported easy bruising ( 11.2 % vs 3.5 % , respectively ) and the slow healing of skin cuts or sores ( 2.4 % vs 0.5 % , respectively ) . Older men in the ICS group with good inhaler compliance appeared to be at the greatest risk of bruising . In those participants undergoing serial measurements of adrenal function and BMD , no association was noted between skin bruising and either the suppression of adrenal function or the loss of BMD as systemic complications of ICS use . CONCLUSION These findings indicate that moderate-to-high doses of ICSs result in an increased incidence of easy bruising and impairment in skin healing in middle-aged to elderly persons with COPD . No association was noted between skin bruising and other markers of systemic toxicity from the use of ICSs There is a need for study ing the effects of long-term inhaled corticosteroid therapy on bone mineral density ( BMD ) and vertebral fracture rates in patients with mild chronic obstructive pulmonary disease ( COPD ) . Patients ( n=912 , mean age 52 yrs ) with mild COPD ( mean forced expiratory volume in one second ( FEV1 ) 77 % of predicted ; mean FEV1/slow vital capacity ratio 62 % ) were r and omized to receive budesonide 400 µg , or placebo twice daily via Turbuhaler ® . BMD was measured at the L2–L4 vertebrae and the femoral neck , trochanter and Ward 's triangle by dual-energy X-ray absorptiometry at baseline and after 6 , 12 , 24 and 36 months ( n=161 ) . Radiographs of the thoracic and lumbar spine were obtained at the beginning and end of treatment ( n=653 ) . Previous fractures were present at baseline in 43 budesonide-treated patients ( 13.4 % ) and 38 placebo-treated patients ( 11.5 % ) . New fractures occurred in five budesonide-treated patients , compared with three in the placebo group ( p=0.50 ) . There were no significant changes in BMD at any site in budesonide-treated patients , compared with the placebo group , during the course of the study . Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin . In the present study , involving a large group of patients with chronic obstructive pulmonary disease , long-term treatment with budesonide 800 µg·day−1 via Turbuhaler ® had no clinical ly significant effects on bone mineral density or fracture rates BACKGROUND --In the day to day care of obstructive airways diseases ( asthma and chronic obstructive pulmonary disease ) important decisions such as disease classification and choice of therapy are based on assessment of the bronchodilator response . However , surprisingly little is known of the long term course of the bronchodilator response in patients with obstructive airways disease . METHODS -- Data from a multicentre trial were used in which 274 patients aged 18 - 60 years with airways obstruction were selected with PC20 < 8 mg/ml and FEV1 < 95 % CI of predicted . FEV1 was measured before and 20 minutes after 1000 micrograms terbutaline and 40 minutes after an additional 80 micrograms ipratropium bromide . Data were analysed from 185 patients who were followed up for 21 months ( five measurements ) . Four different expressions of bronchodilator response ( BDR ) were examined for change under long term therapy , long term variability , and prognostic value in predicting response to inhaled corticosteroids . RESULTS --There was a significant reduction in BDR of 117 ml after three months of treatment with a beta 2 agonist plus a corticosteroid ( BA + CS ) , but not after bronchodilators only . Significant reductions with BA + CS were also found in BDR as a percentage of initial FEV1 , and in BDR as a percentage of predicted FEV1 . Bronchodilator tests were quite variable ( SD 186 ml or 11 % of initial value ) and less than half of the patients could consistently be classified as " irreversible " with recommended cutoff levels . The bronchodilator response at the start of the study proved to be a poor predictor of improvement in FEV1 under BA + CS treatment ( correct prediction 60 % ) . CONCLUSIONS --Bronchodilator responses decrease substantially with inhaled corticosteroid therapy , and within subject variability is considerable both in asthma and chronic obstructive pulmonary disease . Dichotomous decisions on whether patients are " irreversible " according to any single bronchodilator measurement should therefore be made with great caution . The bronchodilator response can not be used accurately as a predictor of response to inhaled corticosteroids in obstructive airways disease BACKGROUND Early treatment with inhaled corticosteroids may prevent progression of irreversible obstruction in COPD , especially in patients with bronchial hyperresponsiveness . We investigated the clinical effects of early introduction of inhaled steroids in subjects showing early signs and symptoms of COPD without a prior clinical diagnosis . METHODS Study subjects were detected in a general population screening and monitoring program . Those with a moderately accelerated annual FEV1 decline and persistent respiratory symptoms were invited to participate in a 2-year r and omized controlled trial comparing fluticasone propionate DPI 250 microg b.i.d . with placebo .  Pre- and post-bronchodilator ( BD ) FEV1 , PC20 histamine , functional status ( COOP/WONCA charts ) and occurrence of exacerbations were periodically assessed . Subjects recorded respiratory symptoms . Post-BD FEV1 decline served as the main outcome . Multivariable repeated measurements analysis techniques were applied . RESULTS 48 subjects were r and omized ( 24 fluticasone , 24 placebo ) . After 3 months , the post-BD FEV1 had increased with 125 ml ( SE = 68 , P = 0.075 ) and the pre-BD FEV1 with 174 ml ( SE 90 , P = 0.059 ) in the fluticasone relative to the placebo group . The subsequent post-BD and pre-BD FEV1 decline were not beneficially modified by fluticasone treatment . There were no statistically significant differences in respiratory symptoms , functional status , or exacerbations favoring fluticasone . Subgroup analysis indicated that the presence of bronchial hyperresponsiveness modified the initial FEV1 response on fluticasone , but not the subsequent annual FEV1 decline . CONCLUSION Early initiation of inhaled steroid treatment does not seem to affect the progressive deterioration of lung function or other respiratory health outcomes in subjects with early signs and symptoms of COPD . In subjects at risk for , or in an early stage of COPD , long-term inhaled steroid treatment should not be based on a single spirometric evaluation after 3 months We have compared the effects of three-month periods of treatment with an inhaled corticosteroid , budesonide 600 micrograms twice daily and with placebo on bronchial responses to inhaled histamine and to bronchodilators in a double-blind crossover trial in 14 middle-aged male smokers ( mean age , 59.6 years ) with mild airways obstruction ( mean FEV1 2.42 L , 80 percent predicted [ range , 48 to 110 percent ] ) . Responsiveness to inhaled histamine was assessed monthly by the provocative concentration ( mg/ml ) reducing FEV1 by 20 percent ( PC20 ) . Bronchodilator response to a combination of inhaled salbutamol ( 5 mg ) and ipratropium ( 0.5 mg ) was assessed before and after three months ' treatment . Compliance with treatment was checked by weighing aerosol canisters , and by measuring plasma budesonide and metabolites . There was no significant change in FEV1 ( budesonide mean 2.38 L [ SEM 0.17 ] vs placebo 2.40 L [ 0.17 ] ) , vital capacity ( budesonide mean 3.69 L [ 0.17 ] vs placebo 3.81 L [ 0.17 ] ) or in bronchodilator responsiveness ( mean increase over baseline FEV1 , budesonide 11.6 [ 2.7 ] percent vs placebo 10.5 [ 3.2 ] percent ) . There was a small overall reduction in bronchoconstrictor responsiveness over the period of the trial , but there was no effect of 12 weeks of budesonide treatment compared with 12 weeks of placebo treatment ( mean log PC20 during budesonide 0.595 [ SEM 0.063 ] , placebo 0.591 [ SEM 0.055 ] ) . Following the three-month crossover trial , six men continued for nine more months to receive budesonide in a single-blind trial and the results were compared with those in six men who took no active treatment for the subsequent nine months . No improvements in baseline spirometry , home peak flow measurements , bronchoconstrictor or bronchodilator responsiveness were observed after 12 months of budesonide treatment . Thus , a regimen of budesonide treatment that consistently attenuates bronchial responsiveness in asthmatic subjects had no effect in these men ; larger and longer trials will be required to establish whether a subgroup of smokers shows a favorable response The prevalence of chronic obstructive pulmonary disease ( COPD ) in women is increasing worldwide . Women may have greater susceptibility to COPD progression than men , and differences in efficacy and safety of respiratory medications by gender are largely unexplored . We aim ed to determine whether the response to treatment in women with COPD differed from men in a large , 1-year double-blind trial ( ' TRISTAN ' ) . In a sensitivity analysis , we compared 539 male and 180 female COPD patients , who were r and omized to the saLmeterol/fluticasone combination 50/500mcg bid or placebo for 12 months .  Combination therapy  improved pre-treatment FEV1 significantly more than placebo in women by 152 ml ( 95 % confidence interval 95 - 208 ) and in men by 127 ml ( 94 - 159 ) . Similarly , a reduction in COPD exacerbation rates of 31 % in women ( 9 - 48 % ) and of 23 % in men ( 8 - 35 % ) was observed . Combination therapy  reduced COPD exacerbations requiring treatment with oral corticosteroids by 36 % in women and by 41 % in men . Finally , combination treatment produced a better improvement in health status than placebo with a decrease in the SGRQ scores in women by -2.3 ( -4.6 - 0.1 ) and in men by -2.1 ( -3.5 to -0.8 ) . No gender interaction was found for any outcome . Treatments were well tolerated with no difference in the frequency of adverse events in women and men . In this trial , therapy with the salmeterol/fluticasone combination produced significant improvements compared to placebo on all main endpoints and the magnitude of these improvements was similar for both men and women In a two-stage detection program , subjects with signs of obstructive airway disease were selected from a r and om sample of the general population . Subjects ( n = 82 ) were r and omly assigned to either fluticasone propionate 250 microg twice a day or placebo twice a day via pMDI in a 1-yr , double-blind trial if they met criteria for persistent airway obstruction , increased bronchial hyperresponsiveness , or a rapid decline in FEV(1 ) . Main outcome measures were postbronchodilator FEV(1 ) , quality -adjusted life years ( QALYs ) , and direct medical cost . Secondary measures were prebronchodilator FEV(1 ) , PC(20 ) , health-related quality of life ( CRQ ) , symptom-free weeks , episode-free weeks , exacerbations , and indirect cost . Subgroup analysis was based on reversibility of obstruction . Analysis revealed a significant gain in postbronchodilator FEV(1 ) ( 98 ml/yr ; p = 0.01 ) in favor of fluticasone . Only subjects with reversible obstruction showed an improvement in PC(20 ) ( 1.4 doubling dose ; p = 0.03 ) . Early treatment result ed in 2.7 QALYs gained per 100 treated subjects ( p = 0.17 ) and in a clinical ly relevant improvement in dyspnea ( CRQ ; p < 0.03 ) . The incremental cost effectiveness ratios were US$ 13,016/QALY for early treatment and US$ 33,921/QALY for the combination of detection and treatment . The incremental cost for one additional subject with a clinical ly relevant difference in dyspnea was US$ 1,674 . In conclusion , early intervention with fluticasone result ed in significant health gains at relatively low financial cost BACKGROUND Chronic obstructive airway disease ( COAD ) is associated with hyperplasia and hypertrophy of the mucus producing gl and s. The beneficial effect of inhaled drug may be due to improved mucociliary function . The present study was done to evaluate the effect of salbutamol , ipratropium bromide and beclomethasone dipropionate inhalation on mucociliary clearance in patients with COAD . METHODS Ten patients of COAD were taken up , two patients however did not complete the study .  Salbutamol , ipratropium bromide , beclomethasone dipropionate and placebo inhalation were given r and omly to each patient on four separate days . Radioaerosol inhalation lung cine-scintigraphy  after inhalation of the different drugs was followed up to two hours and than after 24 hours . RESULTS There was no significant visually noticeable increased mucociliary clearance on any of the days . Two patients showed definite steep slope in the time activity curves with salbutamol as compared to other drugs or placebo . All the quantitative indices analysed at the end of one hour and two hours for the three drugs were comparable to placebo . CONCLUSIONS A single dose of inhaled salbutamol , ipratropium bromide and beclomethasone dipropionate has no appreciable effect on mucociliary clearance in patients with COAD BACKGROUND The institution of inhaled corticosteroids is generally advocated for effective treatment of patients with asthma . It is yet unknown what is the best time to start inhaled corticosteroid therapy and especially whether delayed introduction is harmful . PHASE 1 : In a previous study in patients with asthma and COPD , we found that 2.5 years of treatment with a beta 2-agonist plus inhaled corticosteroid ( BA + CS ) was more effective in improving the FEV1 and the provocative concentration of histamine causing a 20 % reduction in FEV1 ( PC20 ) than treatment with a beta 2-agonist plus anticholinergic ( BA + AC ) or placebo ( BA + PL ) . PHASE 2 : We extended this study with 6 months to investigate whether delayed introduction of inhaled CS therapy ( 800 micrograms beclomethasone dipropionate ) in the groups previously not treated with inhaled CS ( BA + /- AC ) could also improve FEV1 and PC20 to the same degree . A distinction was made between patients with predominantly asthma ( high baseline reversibility , delta FEV1 > or = 9 % of predicted ) , and predominantly COPD ( low baseline reversibility , delta FEV1 < 9 % of predicted ) . RESULTS Improvement of FEV1 percent predicted by inhaled CS  was comparable both in the asthmatics between phase 1 ( 13.8 % predicted ) and phase 2 ( 8.5 % predicted ; p = 0.31 ) as well as in the patients with COPD ( 2.5 % and 1.5 % predicted , respectively ) . PC20 , however , increased significantly more in the asthmatics in phase 1 ( 1.77 doubling concentration [ DC ] ) than in phase 2 ( 0.79 DC ; p = 0.03 ) . Improvement of PC20 in the patients with COPD was not significantly higher in phase 1 ( 0.74 DC ) than in phase 2 ( 0.00 DC ; p = 0.19 ) . CONCLUSIONS Our study indicates that although delayed introduction of inhaled CS in asthmatics leads to similar improvements in FEV1 , improvements in PC20 are significantly less . These findings in patients with longer-existing asthma concur with other findings in newly detected asthma . We suggest that institution of inhaled CS therapy should not be postponed in asthmatics with documented airways obstruction and reversibility It remains unclear whether inhaled corticosteroids can produce the maximum benefits of corticosteroids  in patients with chronic obstructive pulmonary disease ( COPD ) . To assess the additive effects of 30 mg/day prednisolone to high-dose , inhaled beclomethasone dipropionate ( BDP ) , we conducted a r and omised double-blind , placebo-controlled cross-over trial . The study population consisted of 21 men with stable COPD . The mean age of the patients was 69.1 + /- 6.8 years , and FEV(1)was 0.86 + /- 0.28 l. Seventeen out of the 21 patients ( 81 % ) were considered susceptible to steroids in a previous trial ( FEV(1)increased at least 15 % from baseline after receiving 14 days of 30 mg/day prednisolone ) . All of the patients had been on 1600 microg/day BDP for more than 3 months .  Spirometry was performed before the entry , and at the end of 3-week placebo and prednisolone periods . The peak expiratory flow ( PEF ) , symptoms , and Guyatt 's Chronic Respiratory Disease Question naire ( CRQ ) as a disease specific health-related quality of life over the last seven days of each period were also evaluated . Although a marginal increase in PEF was found during the prednisolone period , no significant differences in FEV(1 ) , FVC , symptoms or CRQ scores were observed between the two treatment periods . We conclude that the therapeutic effects of steroid therapy may be achieved by the long-term use of high-dose , inhaled corticosteroid in some patients with stable COPD We have studied the relationship between emphysema and airways collapse , and response to corticosteroids in patients with chronic airflow obstruction . One hundred and seven patients completed a placebo-controlled trial comparing 2 wks treatment with oral prednisolone 40 mg.day-1 to inhaled beclomethasone dipropionate 500 micrograms t.d.s . Response to corticosteroids was defined on the basis of changes in forced expiratory volume in one second ( FEV1 ) , and /or forced vital capacity ( FVC ) , and /or mean peak expiratory flow ( PEF ) after treatment . Patients were categorized as those with physiologically defined emphysema ( carbon monoxide transfer coefficient ( KCO ) less than 70 % predicted and total lung capacity greater than 120 % predicted ) , and those with pressure dependent airways collapse on the flow-volume loop ( ratio of inspiratory to expiratory flow at 50 % vital capacity [ I : E50 ] greater than 10 ) . The response to placebo showed a significant order effect , probably due to a carry-over effect of active treatment of at least 3 wks . Hence , the efficacy of active treatment over placebo in the subgroups defined was assessed by analysis of data generated from the first treatment phase of the trial . The presence or absence of physiologically defined emphysema did not affect the response to  oral prednisolone . Inhaled beclomethasone dipropionate  , however , was less effective in the emphysema group . Pressure dependent airways collapse did not affect the response to either prednisolone or beclomethasone . However , when data from all three treatment phases were analysed there was no significant difference in the response to either drug in any of the subgroups defined . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND The pathology of chronic obstructive pulmonary disease ( COPD ) includes both obstructive and inflammatory components . OBJECTIVE The aim of this study was to confirm the findings of a previous study that compared the efficacy of a combination of 2 short-acting bronchodilators with the use of an inhaled corticosteroid and a long-acting beta-agonist in the treatment of COPD . METHODS We conducted an 8-week , multicenter , r and omized , double-blind , double-dummy , parallel-group study of subjects with moderate to severe COPD to compare fluticasone propionate/salmeterol 250/50 microg BID ( FSC ) with ipratropium/albuterol 36/206 microg QID ( IB/ALB ) . The primary efficacy measure was morning preadministration forced expiratory volume in 1 second ( FEV(1 ) ) . Secondary measures were morning peak expiratory flow ( PEF ) , 6-hour FEV(1 ) AUC , percentage of symptom-free nights , Transition Dyspnea Index ( TDI ) score , and overall daytime symptom score . Additional measures included sleep symptoms , supplemental albuterol use , and nighttime awakenings due to respiratory symptoms . Safety evaluations were based on clinical adverse events and COPD exacerbations . RESULTS Baseline characteristics were similar between the FSC ( n = 180 ) and IB/ALB ( n = 181 ) groups , including mean age ( 63.7 and 65.4 years , respectively ) , mean body weight ( 81 and 79 kg , respectively ) , screening pulmonary function ( mean [ SD ] , 43.7 % [ 14.2 % ] and 41.6 % [ 13.4 % ] of predicted FEV(1 ) ) , race ( 82 % and 91 % white ) , and sex ( 64 % and 62 % male ) . FSC result ed in greater improvements in morning preadministration FEV(1 ) , morning PEF , and 6-hour FEV(1 ) AUC ( all , P < 0.001 ) , TDI score ( P = 0.026 ) , overall daytime symptom score ( P = 0.024 ) , percentage of symptom-free nights ( P = 0.010 ) , nighttime awakenings due to respiratory symptoms ( P = 0.002 ) , sleep symptom score ( P = 0.003 ) , and percentage of days and nights without rescue albuterol use compared with IB/ALB ( P = 0.021 and P < 0.001 , respectively ) . Compared with day 1 , the FEV(1 ) AUC at week 8 increased by 0.38 L-h with FSC and decreased by 0.18 L-h with IB/ALB ( P < 0.001 between groups ) . The type and incidence of adverse events were similar between the 2 groups . One or more adverse event was reported for 81 ( 45 % ) and 85 ( 47 % ) subjects in the FSC and IB/ALB groups , respectively . CONCLUSION In this 8-week study , subjects with moderate to severe COPD experienced greater improvements in lung function and symptom measures with FSC than with IB/ALB The European Respiratory Society 's study on chronic obstructive pulmonary disease ( EUROSCOP ) is a multicentre study performed initially in 12 countries to assess the effect of 3 years ' treatment with inhaled corticosteroids on lung function decline in smokers with chronic obstructive pulmonary disease ( COPD ) . It aim ed at recruiting 50 subjects in 50 European centres . This study discusses the most successful , countrywise , recruitment strategies , an important issue since many multicentre European studies may follow in the future . The total number of recruited subjects was 2147 in 39 participating centres . In total , at least 25,000 screening spirometries were performed , and about 80,000 hospital records were checked . The most effective way of recruiting subjects was to screen subjects by spirometry after mass media campaigns ( eight out of nine countries ) . Others used workplace screenings and different types of population survey , and only a few centres successfully recruited participants by hospital records . Inclusion criteria were slightly changed upon low initial accrual rate . Initial surveys in one country , where 2405 subjects were screened by spirometry  , gave an important indication for the change of the inclusion criteria . Extension of the upper age limit from 60 to 65 yr considerably improved recruitment , as did a change of the upper limit of FEV1 from below 80 % predicted normal to below 100 % predicted normal , while maintaining the FEV1/VC ratio below 70 % . A tremendous effort is needed to recruit individuals with pre clinical COPD , but this is certainly feasible with adequate strategies adjusted to each country BACKGROUND Airways inflammation is a feature of chronic obstructive pulmonary disease ( COPD ) , but the role of corticosteroids in the management of clinical ly stable patients has yet to be established . A r and omised controlled study was carried out to investigate the effect of high dose inhaled beclomethasone dipropionate ( BDP ) administered for two months to patients with stable , smoking related COPD . Sputum induction was used to evaluate bronchial inflammation response . METHODS 34 patients ( 20 men and 14 women ) were examined on three separate occasions . At the initial clinical assessment ( visit 0 ) , spirometry and blood gas analysis were performed . On visit 1 ( within one week of visit 0 ) sputum induction was performed and each patient was r and omised to receive either BDP 500 μg three times daily ( treated group ) or nothing ( control group ) . After two months ( visit 2 ) , all patients underwent repeat clinical assessment , spirometry , and sputum induction . RESULTS There were no differences in sputum cell counts between the groups at baseline . After two months of treatment , induced sputum sample s from patients in the treated group showed a reduction in both neutrophils ( −27 % ) and total cells ( −42 % ) with respect to baseline , while the control group did not ( neutrophils + 9 % , total cells + 7 % ) . Macrophages increased in the treated group but not in the control group . The mean final value of sputum neutrophils was 52 % in the treated group and 73.3 % in the control group ( 95 % confidence interval ( CI ) −27.2 to −15.4 ) . The mean final value of sputum macrophages was 35.8 % in treated group and 19.3 % in control group ( 95 % CI 10.3 to 22.8 ) . The differences between the treated and control groups for neutrophils ( −21.3 % ) , macrophages ( + 16.5 % ) , and total cells ( −65 % ) were significant . Spirometry and blood gas data did not change from baseline in either patient group . CONCLUSIONS A two month course of treatment with high dose inhaled BDP reduces significantly neutrophil cell counts in patients with clinical ly stable , smoking related COPD . Further studies on the effectiveness of inhaled steroids in COPD are needed to confirm the clinical importance of this observation BACKGROUND The benefits of inhaled corticosteroids in the management of COPD are less apparent than they are in asthma therapy , and the potential for adverse systemic effects of high-dose inhaled corticosteroids has been recognized recently . It is therefore essential to know the maximal obtainable benefits in order to assess the risk/benefit ratio of this treatment . PURPOSE The aim of this study was to investigate the maximal obtainable benefits of high-dose inhaled corticosteroids , 3 mg/d of beclomethasone dipropionate ( BDP ) , when used in combination with adequate doses of regular bronchodilators in patients with stable COPD . STUDY DESIGN Thirty patients with stable COPD completed a r and omized , double-blind , placebo-controlled cross-over trial with either 3 mg/d of BDP or with a matching placebo using a metered-dose inhaler with a spacer device for 4 weeks during each treatment period . All of the patients continued to inhale both 400 microg of salbutamol qid and 80 microg of ipratropium bromide qid . RESULTS The mean prebronchodilator FEV1 was 0.97+/-0.35 L during the placebo period and 1.08+/-0.38 L during the BDP period ( p < 0.001 ) . While on BDP , five patients demonstrated a response in their FEV1 of more than 8.5 % of the predicted value , which was above the range that covered 95 % of the distribution of the placebo response . The mean absolute improvement in the FEV1 in these 5 objective responders was 0.34+/-0.10 L , compared to 0.06+/-0.09 L in the 25 objective nonresponders . Symptom scores for wheezing and dyspnea were significantly better with BDP than with placebo .  Hoarseness and sore throat were associated more with BDP treatment . CONCLUSION Although a considerable minority of patients benefited substantially from this treatment , the overall outcome does not seem to justify the widespread use of this treatment in the light of increasing recognition of the potential adverse systemic effects of high-dose inhaled corticosteroids Systemic corticosteroids have been recommended as a therapeutic option in patients with moderate to severe COPD . In an early stage of the disease , i.e. chronic bronchitis with mild or no airflow obstruction , a trial with inhaled steroids could reveal potential benefits , particularly in terms of a modulation of airway inflammation . We therefore investigated the effect of inhaled fluticasone ( 1000 microg day(-1 ) ) on markers of airway inflammation in 19 patients with chronic bronchitis ( mean+/-SEM FEV1 , 83.4+/-3.0 % predicted ; FEV1/VC , 67.5+/-2.4 % ) in a double-blind , cross-over , placebo-controlled manner . Visits were performed before and after two 4-week treatment periods . separated by a 4-week washout period . Lung function , the concentration of exhaled nitric oxide , differential cell counts in induced sputum and the number of cells positive for iNOS , as well as the levels of LDH , ECP , neutrophil elastase and IL-8 in sputum supernatants were determined . Although the total cell number decreased significantly after fluticasone ( geometric mean 12.3 vs. 7.7 x 10(6)/ml ; P<0.05 ) it was not significantly different from the change observed after placebo ( 14.2 vs. 10.6 x 10(6)/ml ; n.s . ) . None of the other parameters showed statistically significant changes after fluticasone or placebo and the results did not depend on the presence of airway hyperresponsiveness . We conclude that in patients with chronic bronchitis short-term treatment with inhaled corticosterids did not improve lung function or inflammatory parameters to an extent which was statistically significant as compared to spontaneous variability AIMS The aims of this investigation were to evaluate the efficacy of regular inhaled beclomethasone in the control of symptoms and lung function with non-asthmatic smoking related obstructive pulmonary disease and to evaluate the relationship between clinical responses to a short course of oral prednisone and longer term outcomes using inhaled steroid . METHODS The study was a r and omised , double blind , placebo controlled , crossover investigation in 18 patients . The active treatment was inhaled beclomethasone 1000 micrograms given twice daily for three months by metered dose inhaler . At the end of each treatment period , patients received oral prednisone 30 mg/day for ten days . The two treatment phases were separated by a one month washout interval . Peak flow rates , symptom scores and " rescue " bronchodilator use were recorded twice daily . Lung function ( FEV1 , FVC and lung volumes ) and bronchial hyperresponsiveness ( PC20 methacholine ) were measured at monthly visits . The number of exacerbations requiring intervention therapy were also recorded . RESULTS There were no consistent benefits attributable to beclomethasone .  Lung function was not significantly better as a result of active treatment . Sputum production improved but other symptom scores were similar during active and placebo therapy . Three patients exhibited an increase in FEV1 of 15 % or more during active treatment but did not do so when oral prednisone was administered immediately after the period of placebo treatment . A further three patients showed an improvement in FEV1 of 15 % or more with oral prednisone but failed to improve during treatment with inhaled beclomethasone . The predictive value of the " trial of steroid " was 0 % and 81.3 % for positive and negative outcomes respectively . CONCLUSIONS Our results indicate that in non-asthmatic chronic obstructive pulmonary disease inhaled corticosteroid fails to achieve significant improvements in either lung function or symptoms . The response to a " trial of steroid " using oral prednisone is not clinical ly helpful in selecting the small number of patients who may subsequently benefit from this form of therapy BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment .  All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) Chronic obstructive pulmonary disease ( COPD ) is a common disease in industrialised countries and responsible for a considerable morbidity and mortality . Cigarette smoking is the most important aetiological factor . The EUROSCOP trial aims at investigating the hypothesis that airway inflammation plays an important pathogenic role in the development of chronic obstructive airway disease in smokers . In cigarette smokers with poorly reversible airflow obstruction , the effect over 3 yrs of an inhaled glucocorticosteroid , budesonide 400 micrograms b.i.d . , on the decline of lung function , measured as postbronchodilator forced expiratory volume in one second ( FEV1 ) , will be compared with that of placebo . The trial has been design ed to detect a difference in yearly decline of at least 30 ml.year-1 . The study is a parallel group , r and omised , double-blind , multicentre study . Patients will be recruited from 47 centres in 12 countries in Europe . It will start with a run-in consisting of two 3 month periods . During the first 3 months , the patients will be offered a smoking cessation programme . All patients who have not stopped smoking during this period will enter the second half of the run-in where compliance with the dosage regimen will be tested . After these two periods , patients will be r and omised to receive either inhaled budesonide , 400 micrograms b.i.d . , or placebo for a period of 3 yrs The objective was to evaluate the effect of inhaled corticosteroids on disease progression in smokers with moderate to severe chronic obstructive pulmonary disease ( COPD ) , as assessed by annual computed tomography ( CT ) using lung density ( LD ) measurements . Two hundred and fifty-four current smokers with COPD were r and omised to treatment with either an inhaled corticosteroids ( ICS ) , budesonide 400 μ g bid , or placebo . COPD was defined as FEV1 ≤ 70 % pred , FEV1/FVC ≤ 60 % and no reversibility to β2-agonists and oral corticosteroids . The patients were followed for 2–4 years with biannual spirometry and annual CT and comprehensive lung function tests ( LFT ) . CT images were analysed using Pulmo-CMS software . LD was derived from a pixel-density histogram of the whole lung as the 15thpercentile density ( PD15 ) and the relative area of emphysema at a threshold of −910 Hounsfield units ( RA-910 ) , and both were volume-adjusted to predicted total lung capacity . At baseline , mean age was 64 years and 64 years ; mean number of pack-years was 56 and 56 ;  mean FEV1 was 1.53 L ( 51 % pred ) and 1.53 L ( 53 % pred ) ; mean PD15 was 103 g/L and 104 g/L ; and mean RA-910 was 14 % and 13 % , respectively , for the budesonide and placebo groups . The annual fall in PD15 was −1.12 g/L in the budesonide group and −1.81 g/L in the placebo group ( p = 0.09 ) ; the annual increase in RA–910 was 0.4 % in the budesonide group and 1.1 % in the placebo group ( p = 0.02 ) . There was no difference in annual decline in FEV1 between ICS ( −54 mL ) and placebo ( −56 mL ) ( p = 0.89 ) . Long-term budesonide inhalation shows a non-significant trend towards reducing the progression of emphysema as determined by the CT-derived 15th percentile lung density from annual CT scans in current smokers with moderate to severe COPD BACKGROUND Chronic obstructive pulmonary disease ( COPD ) results from a progressive decline in lung function , which is thought to be the consequence of airway inflammation . We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline . METHODS We enrolled 1116 persons with COPD whose forced expiratory volume in one second ( FEV1 ) was 30 to 90 percent of the predicted value in a 10-center , placebo-controlled , r and omized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily . The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator . The secondary outcome measures included respiratory symptoms , use of health care services , and airway reactivity . In a sub study of 412 participants , we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment . RESULTS The mean duration of follow-up was 40 months . The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group ( 44.2+/-2.9 vs. 47.0+/-3.0 ml per year , P= 0.50 ) . Members of the triamcinolone group had fewer respiratory symptoms during the course of the study ( 21.1 per 100 person-years vs. 28.2 per 100 person-years , P=0.005 ) and had fewer visits to a physician because of a respiratory illness ( 1.2 per 100 person-years vs. 2.1 per 100 person-years , P=0.03 ) . Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months ( P=0.02 for both comparisons ) . After three years , the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group ( P < or = 0.007 ) . CONCLUSIONS Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD , but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems . These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density The aim of this study was evaluate the predictive value of a 2 week course of prednisolone on the effect of 6 months treatment with inhaled budesonide in patients with stable chronic obstructive pulmonary disease ( COPD ) . Forty patients with stable COPD entered the study , and received prednisolone ( 37.5 mg o.d . ) for 2 weeks . They were subsequently divided into steroid-irreversible and steroid-irreversible , using 15 % of baseline as a dividing point . In each group patients were r and omized to receive budesonide 400 micrograms b.i.d . or placebo for 6 months . During treatment with prednisolone , three patients dropped out because of side effects . Of the remaining 37 , only two patients ( 5 % ) were reversible with prednisolone forced expiratory volume in 1s [ ( FEV1 ) > 15 % of baseline ] , and among the steroid-irreversible , 26 patients were evaluated after 6 months treatment with either placebo or budesonide . No significant differences in spirometry values , symptoms , or number of exacerbations were found between these two groups . Reversibility with prednisolone is rarely seen in COPD . In out patients with stable COPD and no signs of asthma or atopy  , 2 weeks treatment with prednisolone seems to be of no value in choosing subsequent long-term therapy Withdrawal of inhaled corticosteroids is known to worsen disease control in bronchial asthma but similar data are lacking in chronic obstructive pulmonary disease ( COPD ) . We hypothesized that clinical exacerbations requiring treatment would occur more often in patients whose inhaled corticosteroids were stopped than in other patients not treated with these agents . We studied 272 patients in mean age 65 ( SD 0.8 ) years , mean FEV1 42.8 ( SD 12.6)% predicted , entering the run-in phase of the Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) trial . All had been clinical ly stable for at least 6 weeks and there were no differences in the degree of bronchodilator reversibility , baseline lung function or pack-years of smoking  between the 160 patients receiving inhaled corticosteroids and those not so treated .  Inhaled corticosteroids were withdrawn in the first week of the study and during the remaining 7 weeks of the study 38 % of those previously treated with these drugs had an exacerbation compared to 6 % of the chronically untreated group . Patients receiving inhaled corticosteroids reported a longer duration of symptoms but neither this or any other recorded variable predicted the risk of exacerbation . These data suggest that abrupt withdrawal of inhaled corticosteroids should be monitored carefully even in patients with apparently irreversible COPD Background : Although both inhaled and oral corticosteroids have anti-inflammatory effects causing improvement in clinical symptoms and spirometry in the treatment of asthma , the role of corticosteroids in the management of chronic obstructive pulmonary disease ( COPD ) is controversial . Objective : To evaluate the effects of inhaled corticosteroids on sputum neutrophilia in clinical ly stable COPD patients . Methods : In total , 18 patients were enrolled in the study . During 2 months , 9 patients in group A inhaled fluticasone propionate ( FP ) 500 μg 3 times daily . In group B 9 patients received placebo . All of the patients continued to inhale both salbutamol and ipratropium bromide . In 9 patients , sustained-released theophylline was also administered . Blood sample s , spirometric tests , blood gas analyses , and either spontaneous or induced sputum cultures were evaluated on entry into the study , after a 2 months of treatment and following the 6-week washout period . Results : After the 2-month FP treatment , no significant changes in the number of peripheral blood neutrophils , blood gas and spirometry data were observed in both groups . In group A , the total cell number and the number of neutrophils decreased from a mean of 3.4 ± 1.3 × 106 cells/g and 0.6 ± 0.3 × 106 neutrophils/g on entry into study to 1.9 ± 0.6 × 106 cells/g and 0.02 ± 0.01 × 106 neutrophils/g after 8-week treatment with FP , returning to 3.3 ± 1.1 × 106 cells/g and 0.5 ± 0.3 × 106 neutrophils/g following the washout period . The percentages of neutrophils were 55.6 and 77.9 % in groups A and B after 2 months of FP treatment . There was no significant change in group B values during the study . Conclusion : These data suggest that neutrophilic inflammation in sputum may be decreased by inhaled corticosteroids in clinical ly stable COPD patients BACKGROUND The morbidity from obstructive airways disease ( asthma and chronic obstructive pulmonary disease ) is considerable , and the mortality rate is rising in several countries . It has been hypothesized that long-term improvement in prognosis might result from vigorous bronchodilator or antiinflammatory therapy . METHODS In a multicenter trial we compared three inhalation regimens in which a beta 2-agonist ( terbutaline , 2000 micrograms daily ) was combined with a corticosteroid ( beclomethasone , 800 micrograms daily ) , an anticholinergic bronchodilator ( ipratropium bromide , 160 micrograms daily ) , or placebo .  Patients with airways hyperresponsiveness and obstruction who were 18 to 60 years old were followed for 2 1/2 years . RESULTS Of the 274 patients enrolled , 56 percent had allergies . The mean forced expiratory volume in one second ( FEV1 ) was 64 percent of the predicted value . The mean PC20 ( the concentration of inhaled histamine causing a 20 percent decrease in FEV1 , a measure of hyperresponsiveness ) was 0.26 mg per milliliter . Withdrawal from the study , due mainly to pulmonary symptoms , was less frequent in the corticosteroid group ( 12 of 91 patients ) than in the anticholinergic-drug group ( 45 of 92 patients ) or the placebo group ( 44 of 91 patients ; P < 0.001 ) . The mean FEV1 ( + /- SE ) increased by 10.3 + /- 1.3 percent of the predicted value in the corticosteroid group within three months and remained stable thereafter , whereas it did not change in the other two groups ( P < 0.001 ) . The PC20 increased by 2.0 doubling concentrations in the corticosteroid group but did not change in the other groups ( P < 0.001 ) . In the corticosteroid group , patients who did not smoke , who had allergies , or who were less than 40 years old benefited more from their treatment than did those who smoked , did not have allergies , or were over 40 , but all subgroups of the corticosteroid group had improvement as compared with the anticholinergic-drug or placebo group . CONCLUSIONS The addition of an inhaled corticosteroid -- but not an inhaled anticholinergic agent -- to maintenance treatment with a beta 2-agonist ( terbutaline ) substantially reduced morbidity , hyperresponsiveness , and airways obstruction in patients with a spectrum of obstructive airways disease Inhaled corticosteroid therapy has proven efficacy for asthmatics , but the benefit for patients with chronic obstructive pulmonary disease ( COPD ) is less well supported . We hypothesized that withdrawal of inhaled steroids in elderly patients with severe irreversible airway obstruction would not lead to a deterioration in respiratory function . We design ed a prospect i ve , double-blind , r and omized , placebo-controlled , crossover study to follow spirometry , quality of life question naire , six-minute ( 6-min ) walk test , and sputum markers of inflammation during a 6-wk placebo treatment period and a 6-wk treatment period with beclomethasone dipropionate ( BDP ) , 336 microg/d . There were 24 men receiving BDP who entered the study ; 15 completed the study . Their mean age was 66.9 + /- 1.9 yr , and mean FEV(1 ) was 1.61 + /- 0.1 L ( 47 % of predicted ) . There was a significant decrease in the mean FEV(1 ) while using the placebo inhaler ( 1.70 L versus 1.60 L , baseline versus placebo : 95 % CI , 0.002 to 0.195 ; p < 0.05 ) . There was a decrease in the mean percentage change in FEV(1 ) for the study subjects during the placebo treatment period as compared with the BDP treatment period ( -6.28 versus 5.03 % , placebo versus BDP : 95 % CI , -23.38 to 0.76 ; p = 0.06 ) . Six-minute walk test results and sputum analysis for cell count and differential were not significantly different during placebo and BDP treatment periods . Borg scale assessment of dyspnea after exercise was increased while using the placebo inhaler as compared with baseline , and decreased during the BDP treatment period . Chronic Respiratory Disease Question naire ( CRQ ) scores revealed no significant difference between placebo and BDP . This study has demonstrated that in elderly patients with severe irreversible airway obstruction , withdrawal of inhaled corticosteroid therapy leads to a deterioration in ventilatory function and increased exercise-induced dyspnea Aerosolized steroids may be implicated in the increased incidence of chest infections . To evaluate such a possibility , we utilized a double-blind study to investigate the acute effect of inhaled beclomethasone dipropionate on mucociliary clearance in 10 patients with chronic obstructive lung disease ( 5 receiving the drug and 5 placebo ) . Mucociliary clearance was measured by inhalation of a 99mTc-labelled albumin aerosol . The result ing radioactivity was recorded externally by a large-field gamma camera and dedicated computer for 3 consecutive hours without patient repositioning . After 1-hour baseline recording , the subjects inhaled from a commercial pressurized canister either beclomethasone dipropionate ( 250 micrograms ) or vehicle alone . The recording was then continued for 2 more hours . No statistically significant difference was found in clearance rates throughout the entire period of observation between patients receiving beclomethasone and controls . The data suggest that mechanisms other than mucociliary function impairment are responsible for the increased incidence of chest infections which may accompany steroid treatment by the inhalatory route Abstract Objectives : To determine the effect of long term inhaled corticosteroids on lung function , exacerbations , and health status in patients with moderate to severe chronic obstructive pulmonary disease . Design : Double blind , placebo controlled study . Setting : Eighteen UK hospitals . Participants : 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second ( FEV1 ) 50 % of predicted normal . Interventions : Inhaled fluticasone propionate 500 μg twice daily from a metered dose inhaler or identical placebo . Main outcome measures : Efficacy measures : rate of decline in FEV1 after the bronchodilator and in health status , frequency of exacerbations , respiratory withdrawals . Safety measures : morning serum cortisol concentration , incidence of adverse events . Results : There was no significant difference in the annual rate of decline in FEV1 ( P=0.16 ) . Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo ( P<0.001 ) . Median exacerbation rate was reduced by 25 % from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate ( P=0.026 ) . Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate ( P=0.0043 ) . Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group ( 25 % v 19 % , P=0.034 ) . Conclusions : Fluticasone propionate 500 μg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1 . Patients on fluticasone propionate  had fewer exacerbations and a slower decline in health status . These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease BACKGROUND A key feature of chronic obstructive pulmonary disease ( COPD ) is an accelerated rate of decline in forced expiratory volume in 1 second ( FEV(1 ) ) , but data on the variability and determinants of this change in patients who have established disease are scarce . METHODS We analyzed the changes in FEV(1 ) after administration of a bronchodilator over a 3-year period in 2163 patients . A r and om-coefficient model was used to evaluate possible predictors of both FEV(1 ) levels and their changes over time . RESULTS The mean ( ±SE ) rate of change in FEV(1 ) was a decline of 33±2 ml per year , with significant variation among the patients studied . The between-patient st and ard deviation for the rate of decline was 59 ml per year . Over the 3-year study period , 38 % of patients had an estimated decline in FEV(1 ) of more than 40 ml per year , 31 % had a decline of 21 to 40 ml per year , 23 % had a change in FEV(1 ) that ranged from a decrease of 20 ml per year to an increase of 20 ml per year , and 8 % had an increase of more than 20 ml per year . The mean rate of decline in FEV(1 ) was 21±4 ml per year greater in current smokers than in current nonsmokers , 13±4 ml per year greater in patients with emphysema than in those without emphysema , and 17±4 ml per year greater in patients with bronchodilator reversibility than in those without reversibility . CONCLUSIONS The rate of change in FEV(1 ) among patients with COPD is highly variable , with increased rates of decline among current smokers , patients with bronchodilator reversibility , and patients with emphysema
BACKGROUND The role of inhaled corticosteroids ( ICS ) in chronic obstructive pulmonary disease ( COPD ) has been the subject of much controversy .
Major international guidelines recommend selective use of ICS .
Recently published meta-analyses have reported conflicting findings on the effects of inhaled steroid therapy in COPD .
OBJECTIVES To determine the efficacy and safety of inhaled corticosteroids in stable patients with COPD , in terms of objective and subjective outcomes .