Randomised controlled trial of inhaled corticosteroids in patients with chronic obstructive pulmonary disease. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease. Short-term treatment with budesonide does not improve hyperresponsiveness to adenosine 5'-monophosphate in COPD. Effect of fluticasone propionate on sputum of patients with chronic bronchitis and emphysema. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. 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. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. The effect of inhaled corticosteroids on bronchoalveolar lavage cells and IL-8 levels in stable COPD patients. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. One-year treatment with mometasone furoate in chronic obstructive pulmonary disease. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. The effect of high-dose inhaled beclomethasone dipropionate in patients with stable COPD. Corticosteroid trials in non-asthmatic chronic airflow obstruction: a comparison of oral prednisolone and inhaled beclomethasone dipropionate. Exhaled nitric oxide and hydrogen peroxide in patients with chronic obstructive pulmonary disease: effects of inhaled beclomethasone. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial. Effects of long-term treatment with corticosteroids in 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. Effects of fluticasone propionate in COPD patients with bronchial hyperresponsiveness. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. 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. Predictive value and utility of oral steroid testing for treatment of COPD in primary care: the COOPT study. The effect of inhaled corticosteroids on the development of emphysema in smokers assessed by annual computed tomography. Inhaled budesonide therapy for patients with stable COPD. 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. Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. A double-blind placebo-controlled study of the effect of inhaled beclomethasone dipropionate for 2 years in patients with nonasthmatic chronic obstructive pulmonary disease. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. The response to inhaled and oral steroids in patients with stable chronic obstructive pulmonary disease. Controlled trial of inhaled fluticasone propionate in moderate to severe COPD. Does addition of inhaled steroid to combined bronchodilator therapy affect health status in patients with COPD? The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Effect of adjunct fluticasone propionate on airway physiology during rest and exercise in COPD. Long term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis. Aerosolized beclomethasone in chronic bronchitis. Improved pulmonary function and diminished airway inflammation. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. 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. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Effects of inhaled HFA beclomethasone on pulmonary function and symptoms in patients with chronic obstructive pulmonary disease.
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.
                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, randomised, 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.
                Randomisation 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.
                Inhaled corticosteroids, even at high doses, were of no physiological or functional benefit in these patients with advanced COPD. Small studies have suggested that inhaled corticosteroids can suppress systemic inflammation in chronic obstructive pulmonary disease (COPD).
                To determine the effect of inhaled corticosteroids with or without long-acting beta(2)-adrenergic agonist on systemic biomarkers of inflammation.
                We conducted a double-blind randomized 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).
                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.
                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. 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. Inhaled corticosteroids are known to reduce respiratory symptoms and airway responsiveness in allergic patients with asthma. The aim of the present randomised, 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 standard 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. 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 randomized 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. 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 clinically 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. Although patients with chronic obstructive pulmonary disease (COPD) should stop smoking, some do not. In a double-blind, placebo-controlled study, we evaluated the effect of the inhaled glucocorticoid budesonide in patients with mild COPD who continued smoking. After a six-month run-in period, we randomly assigned 1277 subjects (mean age, 52 years; mean forced expiratory volume in one second [FEV1], 77 percent of the predicted value; 73 percent men) to twice-daily treatment with 400 microg of budesonide or placebo, inhaled from a dry-powder inhaler, for three years.
                Of the 1277 subjects, 912 (71 percent) completed the study. Among these subjects, the median decline in the FEV1 after the use of a bronchodilator over the three-year period was 140 ml in the budesonide group and 180 ml in the placebo group (P=0.05), or 4.3 percent and 5.3 percent of the predicted value, respectively. During the first six months of the study, the FEV1 improved at the rate of 17 ml per year in the budesonide group, as compared with a decline of 81 ml per year in the placebo group (P<0.001). From nine months to the end of treatment, the FEV1 declined at similar rates in the two groups (P=0.39). Ten percent of the subjects in the budesonide group and 4 percent of those in the placebo group had skin bruising (P<0.001). Newly diagnosed hypertension, bone fractures, postcapsular cataracts, myopathy, and diabetes occurred in less than 5 percent of the subjects, and the diagnoses were equally distributed between the groups.
                In patients with mild COPD who continue smoking, the use of inhaled budesonide is associated with a small one-time improvement in lung function but does not appreciably affect the long-term progressive decline. The combination of an inhaled corticosteroid (ICS) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. Budesonide/formoterol dry powder inhaler (DPI) has demonstrated efficacy and tolerability in patients with COPD.
                To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) in patients with COPD.
                This was a 6-month, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicentre study (NCT00206154) of 1704 patients aged > or =40 years with moderate to very severe COPD conducted in 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa. After 2 weeks of treatment based on previous therapy (ICSs and short-acting bronchodilators allowed during the run-in period), patients received one of the following treatments administered twice daily: budesonide/formoterol pMDI 160/4.5 microg x two inhalations (320/9 microg); budesonide/formoterol pMDI 80/4.5 microg x two inhalations (160/9 microg); budesonide pMDI 160 microg x two inhalations (320 microg) plus formoterol DPI 4.5 microg x two inhalations (9 microg); budesonide pMDI 160 microg x two inhalations (320 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo.
                The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV(1)) and 1-hour post-dose FEV(1).
                Budesonide/formoterol 320/9 microg demonstrated significantly greater improvements in pre-dose FEV(1) versus formoterol (p = 0.026; pre-specified primary comparator) and 1-hour post-dose FEV(1) versus budesonide (p < 0.001; pre-specified primary comparator); budesonide/formoterol 160/9 microg demonstrated significantly greater improvements versus budesonide (p < 0.001) for 1-hour post-dose FEV(1) but not versus formoterol for pre-dose FEV(1). Dyspnoea (measured using the Breathlessness Diary) and health-related quality-of-life (HR-QOL) scores (based on the St George's Respiratory Questionnaire total score) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide, formoterol and placebo (p < or = 0.044 for all). Although not powered a priori for comparisons, the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and/or hospitalization was numerically (20-25%) lower with the budesonide-containing treatments (0.710-0.884) versus formoterol (1.098) and placebo (1.110). This result was driven by the exacerbations requiring treatment with oral corticosteroids (79-120 events). The number of exacerbations resulting in hospitalization was very low across treatment groups (11-22); the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 microg (0.158) versus other treatment groups (0.081-0.108) except budesonide/formoterol 160/9 microg (0.139), and for budesonide/formoterol 160/9 microg versus formoterol (0.081) [p < or = 0.05]. All treatments were generally well tolerated. The incidence of individual non-fatal serious adverse events was similar across all treatment groups, except COPD, which was highest in the budesonide/formoterol 320/9 microg group (6.1%) and lowest in the budesonide (3.6%) and formoterol (3.9%) groups, with a range of 4.3-4.6% in the budesonide/formoterol 160/9 microg, budesonide plus formoterol and placebo groups. Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo. There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo.
                Budesonide/formoterol pMDI 320/9 microg demonstrated significantly greater efficacy for pulmonary function on both co-primary endpoints versus the pre-specified comparators (formoterol DPI 9 microg for pre-dose FEV(1) and budesonide pMDI 320 microg for 1-hour post-dose FEV(1)). Budesonide/formoterol pMDI 160/9 microg demonstrated significantly greater efficacy for 1-hour post-dose FEV(1) versus budesonide pMDI 320 microg. Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo. Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo. 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, randomised, 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 microg (delivered dose), budesonide 200 microg (metered dose), formoterol 4.5 microg 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 beta2-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 beta2-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. 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.
                1465 patients with COPD were recruited from outpatient departments in 25 countries. They were treated in a randomised, 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.
                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 clinically 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 clinically significant falls in serum cortisol concentration.
                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. 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 microg b.i.d.) and oral prednisolone (30 mg o.d.) for 2 weeks. After this time, patients were randomised to b.i.d. inhaled budesonide/formoterol 320/9 microg, budesonide 400 microg, formoterol 9 microg or placebo for 12 months. Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George's Respiratory Questionnaire (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 clinically 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. 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 randomised, 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. Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease (COPD), but their effect on survival is unknown.
                We conducted a randomized, 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.
                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).
                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. (ClinicalTrials.gov number, NCT00268216 [ClinicalTrials.gov].).
                Copyright 2007 Massachusetts Medical Society. Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing.In a 52-week, randomized, double-blind, placebo-controlled study, 911 subjects with moderate-to-severe COPD managed without ICS received MF-DPI 800 microg QD PM, MF-DPI 400 microg BID, or placebo. The change from baseline in postbronchodilator forced expiratory volume in 1 second (FEV1), total COPD symptom scores, and health status as well as the percentage of subjects with a COPD exacerbation were assessed. Adverse events were recorded. Mometasone furoate administered via a dry powder inhaler 800 microg QD PM and 400 microg BID significantly increased postbronchodilator FEV1 from baseline (50 mL and 53 mL, respectively, versus a 19 mL decrease for placebo; P < 0.001). The percentage of subjects exacerbating was significantly lower in the pooled MF-DPI groups than in the placebo group (P = 0.043). Subjects receiving MF-DPI 400 microg BID reported a statistically significant (19%) reduction in COPD symptom scores compared with placebo (P < 0.001). Health status as measured with St. George's Respiratory Questionnaire (SGRQ) improved significantly in all domains (Total, Activity, Impacts, and Symptoms) in the pooled MF-DPI groups versus placebo (P < or = 0.031). MF-DPI treatment was well tolerated.Once-daily MF-DPI improved lung function and health status in subjects with moderate-to-severe COPD and was comparable to BID MF-DPI. 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.
                We used a randomised, double-blind, placebo-controlled design. We enrolled from 13 European countries, New Zealand, 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 randomly 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.
                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 clinically important effect on mean serum cortisol concentration.
                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. 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.
                We used a parallel-group, randomised, 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 randomly 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.
                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.
                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. 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.
                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.
                Thirty patients with stable COPD completed a randomized, 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.
                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.
                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. One hundred and twenty seven adults considered on clinical grounds to have non-asthmatic chronic airflow obstruction entered a randomised, double blind, placebo controlled, crossover trial comparing the physiological response to inhaled beclomethasone dipropionate 500 micrograms thrice daily with oral prednisolone 40 mg a day, both given for two weeks. One hundred and seven patients completed the study. Response was assessed as change in FEV1 and FVC measured on the last treatment day, and as change in mean peak expiratory flow (PEF) over the final seven days of treatment from home PEF recordings performed five times daily. A full response to treatment was defined as an increase in FEV or FVC, or an increase in mean daily PEF over the final seven days of treatment, of at least 20% from baseline values. An improvement in one measurement of at least 15%, or of 10% in any two measurements, was defined as a partial treatment response. Response to placebo showed a significant order effect, suggesting a carry over effect of active treatment of at least three weeks. Response to active treatment was therefore related to initial baseline values, and compared with placebo by considering responses in the first treatment phase only. A full response to oral prednisolone (16/38) was significantly more common than to placebo (3/35). The number of full responses to inhaled beclomethasone (8/34) did not differ significantly from the number responding to oral prednisolone or placebo in the first treatment phase, though full and partial responses to inhaled beclomethasone (12/34) were significantly more common than those to placebo (4/35). When all three treatment phases were considered 44/107 patients showed a full response to one or both forms of corticosteroid treatment, a response to prednisolone (39) occurring more frequently than to inhaled beclomethasone (26). Only 21 of the 44 responders showed a response to both forms of treatment. Inhaled beclomethasone dipropionate 500 micrograms thrice daily was inferior to oral prednisolone 40 mg per day, but better than placebo, in producing improvement in physiological measurements in patients thought to have nonasthmatic chronic airflow obstruction. It was, however, an effective alternative in over half of those showing a response to prednisolone. 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 random, 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. 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.
                Patients were treated in a randomised, double blind, parallel group, placebo-controlled trial with either a combination of 50 microg salmeterol and 500 microg FP twice daily (SFC, n = 19, 19 men, mean age 62 years), 500 microg 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.
                CD8+ cells were significantly reduced by SFC compared with placebo (difference -98.05 cells/mm(2); 95% CI -143.14 to -52.9; p<0.001). Such a marked effect was not seen with FP alone (-44.67 cells/mm(2); 95% CI -90.92 to 1.57; p = 0.06). CD68+ macrophages were also reduced by SFC compared with placebo (difference -31.68 cells/mm(2); 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.
                SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone. To determine the effectiveness of treatment with corticosteroids in patients with COPD.
                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, randomized, 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.
                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.
                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. 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. 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.
                The study was a randomised, 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.
                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.
                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 clinically helpful in selecting the small number of patients who may subsequently benefit from this form of therapy. 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).
                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 PC(20) for histamine of <or=8 mg/ml. Patients received either 2 x 500 microg 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.
                In contrast to asthma, indices of BHR were not significantly influenced by treatment with FP. Forced expiratory volume in 1 second (FEV(1)) showed a steep decline in the placebo group but remained stable in patients treated with FP. FEV(1)/FVC, and maximal expiratory flows at 50% and 25% FVC (MEF(50), MEF(25)) 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 resulted in marginal reductions in these indices of inflammation.
                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. Inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD).
                To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD.
                Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847)
                2 university medical centers in The Netherlands.
                114 steroid-naive current or former smokers with moderate to severe COPD.
                Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months.
                Random 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).
                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.
                The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months.
                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. . 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 random 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 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.
                The study included smokers and exsmokers with chronic bronchitis or COPD from primary care, who underwent prednisolone testing (30 mg for 14 days) before randomization in a three-year follow-up randomized 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 Questionnaire), exacerbations, and postbronchodilator forced expiratory volume in one second (FEV(1)), using repeated measurement analysis.
                Two hundred eighty-six patients recruited from 44 primary care practices were randomized. 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 clinically important difference in health status (0.29 points/year, P = 0.05), although a borderline significant effect of inhaled fluticasone was noted. Possible clinically relevant reductions in exacerbation rate (rate ratio 0.67) and FEV(1) decline (39 mL/year) occurred in responders, but did not reach statistical significance.
                Oral steroid testing identifies a limited proportion of COPD patients, but does not reveal any clinically relevant benefit from inhaled steroid treatment on health status. No significant effects on exacerbation rate and lung function decline occurred. 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 randomised to treatment with either an inhaled corticosteroids (ICS), budesonide 400 microg bid, or placebo. COPD was defined as FEV(1) < or = 70% pred, FEV(1)/FVC < or = 60% and no reversibility to beta(2)-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 15th percentile 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 FEV(1) 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 FEV(1) 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. 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. 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.
                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 randomized 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.
                48 subjects were randomized (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.
                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. 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. 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.
                Ten non-allergic subjects with stable disease were investigated; eight completed the randomised, 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.
                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.
                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. To compare the efficacy and safety of the inhaled corticosteroid fluticasone propionate (FP) and the inhaled long-acting beta(2)-agonist salmeterol (SM), when administered together in a single device (Diskus; GlaxoSmithKline, Inc; Research Triangle Park, NC), with that of placebo and the individual agents alone in patients with COPD.
                Randomized, double-blind, multicenter, placebo-controlled study.
                Seventy-six investigative sites in the United States.
                Seven hundred twenty-three patients > or =40 years of age with COPD and a mean baseline FEV(1) of 42% predicted.
                FP (250 microg), SM (50 microg), FP plus SM combined in a single inhaler (FSC), or placebo administered twice daily through the Diskus device for 24 weeks.
                Primary efficacy measures were morning predose (ie, trough FEV(1)) for FSC compared with SM and 2-h postdose FEV(1) for FSC compared with FP. Other efficacy measures were as follows: morning peak expiratory flow rate (PEF); transition dyspnea index; chronic respiratory disease questionnaire; chronic bronchitis symptom questionnaire; exacerbations; and other symptomatic measures.
                At Endpoint (ie, the last on-treatment, post-baseline assessment), treatment with FSC significantly (p < or = 0.012) increased the morning predose FEV(1) (165 mL) compared with SM (91 mL) and placebo (1 mL), and significantly (p < or = 0.001) increased the 2-h postdose FEV(1) (281 mL) compared with FP (147 mL) and placebo (58 mL). Improvements in lung function with FSC compared with FP and SM, and with FP and SM compared with placebo, as measured by the average daily morning PEF, was observed within approximately 24 h after the initiation of treatment, indicating an early onset of effect (p < or = 0.034). Compared with placebo, FSC significantly improved dyspnea, quality of life, and symptoms of chronic bronchitis. The incidence of adverse effects (except for an increase in oral candidiasis with FSC and FP) were similar among the treatment groups.
                Treatment with FSC (FP, 250 microg, and SM, 50 microg) twice daily substantially improved morning lung function and sustained these improvements for over a period of 24 weeks compared with FP or SM treatment alone in patients with COPD, with no additional safety concerns for the combination treatment vs that with the individual components. 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 randomized 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. 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.
                Double blind, placebo controlled study.
                Eighteen UK hospitals. Participants: 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV(1)) 50% of predicted normal. Interventions: Inhaled fluticasone propionate 500 microgram twice daily from a metered dose inhaler or identical placebo. Main outcome measures: Efficacy measures: rate of decline in FEV(1) after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events.
                There was no significant difference in the annual rate of decline in FEV(1 )(P=0.16). Mean FEV(1) 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).
                Fluticasone propionate 500 microgram twice daily did not affect the rate of decline in FEV(1) but did produce a small increase in FEV(1). 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. 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.
                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 randomized 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 randomized 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 randomized 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.
                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.
                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. 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 prospective, randomized, 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 micro g/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 resulted 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 questionnaire (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. 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.
                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 Questionnaire (SGRQ). Patients were randomly 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.
                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 clinically 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).
                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. 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, randomized 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. 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.
                This was a randomized, 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).
                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).
                Inhaled FP500 monotherapy was associated with consistent and clinically 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.
                Copyright © 2011 Elsevier Ltd. All rights reserved. The role of inhaled corticosteroids in the long term management of chronic obstructive pulmonary disease (COPD) is still unclear. A meta-analysis of the original data sets of the randomised controlled trials published thus far was therefore performed. The main question was: "Are inhaled corticosteroids able to slow down the decline in lung function (FEV1) in COPD?"
                A Medline search of papers published between 1983 and 1996 was performed and three studies were selected, two of which were published in full and one in abstract form. Patients with "asthmatic features" were excluded from the original data. Ninety five of the original 140 patients treated with inhaled corticosteroids (81 with 1500 micrograms beclomethasone daily, six with 1600 micrograms budesonide daily, and eight with 800 micrograms beclomethasone daily) and 88 patients treated with placebo (of the initial 144 patients) were included in the analysis. The effect on FEV1 was assessed by a multiple repeated measurement technique in which points of time in the study and treatment effects (inhaled corticosteroids compared with placebo) were investigated.
                No baseline differences were observed (mean age 61 years, mean FEV1 45% predicted). The estimated two year difference in prebronchodilator FEV1 was +0.034 l/year (95% confidence interval (CI) 0.005 to 0.063) in the inhaled corticosteroid group compared with placebo. The postbronchodilator FEV1 showed a difference of +0.039 l/year (95% CI -0.006 to 0.084). No beneficial effect was observed on the exacerbation rate. Worsening of the disease was the reason for drop out in four patients in the treatment group compared with nine in the placebo group. In the treatment group six of the 95 subjects dropped out because of an adverse effect which may have been related to the treatment compared with two of the 88 patients in the placebo group.
                This meta-analysis in patients with clearly defined moderately severe COPD showed a beneficial course of FEV1 during two years of treatment with relatively high daily dosages of 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, randomized 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) An association between the sputum eosinophil count and the response to a 2 week course of prednisolone has previously been reported in patients with chronic obstructive pulmonary disease (COPD). Whether the response to inhaled corticosteroids is related to the presence of eosinophilic inflammation is unclear.
                A randomised, double blind, crossover trial of placebo and mometasone furoate (800 microg/day), each given for 6 weeks with a 4 week washout period, was performed in subjects with COPD treated with bronchodilator therapy only. Spirometric tests, symptom scores, chronic respiratory disease questionnaire (CRQ), and induced sputum were performed before and after each treatment phase.
                Ninety five patients were recruited of which 60 were randomised. Overall there were no treatment associated changes in forced expiratory volume in 1 second (FEV(1)), total CRQ, or sputum characteristics. After stratification into tertiles by baseline eosinophil count, the net improvement in post-bronchodilator FEV(1) increased with mometasone compared with placebo progressively from the least to the most eosinophilic tertile. The mean change in post-bronchodilator FEV(1) with mometasone compared with placebo in the highest tertile was 0.11 l (95% CI 0.03 to 0.19). This improvement was not associated with a fall in the sputum eosinophil count.
                An increased sputum eosinophil count is related to an improvement in post-bronchodilator FEV(1) following treatment with inhaled mometasone in COPD, but the improvement is not associated with a reduction in the sputum eosinophil count. 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.
                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, randomized 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 substudy 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.
                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).
                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 randomized 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 outpatients 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. This randomized 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 candidiasis 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. Chronic obstructive pulmonary disease is characterized by progressive airflow limitation and pulmonary inflammation. Inhaled corticosteroids (ICS) have been shown to be effective in the reduction of the number of exacerbations and the rate of deterioration in health status in patients with more advanced chronic obstructive pulmonary disease (COPD). Therefore current international guidelines recommend ICS for patients with severe COPD (FEV1 < 50%) with at least one exacerbation within the last year. We determined the short-term effect of the inhaled corticosteroid beclomethasone in HFA 134 formulation (Ventolair) on Health related Quality of Life (HRQOL), pulmonary function and the release of the cytokines Interleukin-10 (IL-10), Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF), Interferon-gamma (IFN-gamma) and Macrophage Inflammatory Protein-1alpha (MIP-1alpha) from peripheral blood monocytes of patients with COPD (n = 11) in a 12 week double blind cross over placebo-controlled study. Baseline lung function and the St. George Respiratory Questionnaire (SGRQ) were performed at the start and the end of each treatment phase. Monocytes were separated from blood at the end of each treatment phase. The treatment with Ventolair) resulted in an increase of PEF from 4.92 to 5.53 l/s and a decrease of RV% TLC (% predicted) values from 144.52 to 131.36. Inhaled HFA beclomethasone did not affect the cytokine release of IL-10, IFN-gamma, GM-CSF and MIP-1alpha. All cytokines were measured using commercially available Enzyme Linked Immun Sorbent Assay (ELISA) kits. The symptom score of the St. George Respiratory Questionnaire significantly decreased from 55.12 to 47.77 units in the active period compared to the placebo period after the treatment with HFA beclomethasone. The present study shows that a short-term treatment with inhaled steroid beclomethasone in fine particle HFA formulation decreases the hyperinflation and improves the PEF and the COPD symptoms.
Patients and clinicians should balance the potential benefits of inhaled steroids in COPD (reduced rate of exacerbations, reduced rate of decline in quality of life and possibly reduced rate of decline in FEV1) against the potential side effects (oropharyngeal candidiasis and hoarseness, and risk of pneumonia).