Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Blood eosinophils as a marker of response to inhaled corticosteroids in COPD Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment Biomarkers to identify sputum eosinophilia in different adult asthma phenotypes Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. The clinical features of the overlap between COPD and asthma Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease Proportional classifications of COPD phenotypes Identification of responders to inhaled corticosteroids in a chronic obstructive pulmonary disease population using cluster analysis Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Can we predict sputum eosinophilia from clinical assessment in patients referred to an adult asthma clinic? Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial Withdrawal of inhaled glucocorticoids and exacerbations of COPD. Blood Eosinophils and Response to Maintenance Chronic Obstructive Pulmonary Disease Treatment. Data from the FLAME Trial
BACKGROUND Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2 ) agonist is more protective than a once-daily longacting β(2 ) agonist alone against exacerbations of chronic obstructive pulmonary disease ( COPD ) is unknown . We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone . METHODS We did two replicate double-blind parallel-group 1 year trials . Both studies began on Sept 25 , 2009 . Study 1 ended on Oct 31 , 2011 , and study 2 on Oct 17 , 2011 . Eligible patients were aged 40 years or older , had a history of COPD , a smoking history of 10 or more pack-years , a ratio of forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity of 0·70 or less after bronchodilators ( and an FEV(1 ) of 70 % or less of predicted ) , and a documented history of one or more moderate or severe disease exacerbations in the year before screening . Patients were r and omly assigned ( 1:1:1:1 ) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg , 100 μg , or 200 μg fluticasone furoate once daily . Our primary endpoint was the yearly rate of moderate and severe exacerbations . The trials were analysed separately and a pooled analysis was also done . These trials are registered with Clinical Trials.gov ( NCT01009463 and NCT01017952 ) . FINDINGS 1622 patients in study 1 and 1633 patients in study 2 were r and omly assigned . In study 1 , no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group ( mean 0·90 events vs 1·05 events per year ; ratio 0·9 [ 95 % CI 0·7 - 1·0 ] ) . Because of the statistical hierarchy used , we could not infer significance for the 50 μg and 100 μg groups . In study 2 , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( p=0·0398 for the 50 μg group , 0·0244 for the 100 μg group , and 0·0004 for the 200 μg group ) . In the pooled analysis , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( 0·0141 for the 50 μg group , < 0·0001 for the 100 μg group , and 0·0003 for the 200 μg group ) . Nasopharyngitis was the most frequently reported adverse event in both studies . Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone . Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group . INTERPRETATION Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD  in patients with a history of exacerbation , but was also associated with an increased pneumonia risk . FUNDING GlaxoSmithKline Identification of a biomarker that predicts response to inhaled corticosteroids ( ICS ) would help evaluate the risk/benefit profile of ICS in chronic obstructive pulmonary disease ( COPD ) and guide treatment . The ISOLDE study r and omised 751 patients ( mean post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) 1.4 L : 50 % predicted normal ) to fluticasone propionate 500 μg twice daily or placebo for 3 years , finding no difference in FEV1 rate of decline between treatments ( p=0.16 ) and a significant reduction in median exacerbation rate with fluticasone propionate versus placebo ( p=0.026 ) . We re-analysed ISOLDE results by baseline blood eosinophil count to investigate whether eosinophil level predicts ICS benefit . Patients with eosinophils < 2 % ( n=456 ) had a similar rate of post-bronchodilator FEV1 decline  with fluticasone propionate as placebo ( –2.9 mL·year−1 ; p=0.688 ) . With eosinophils ≥2 % ( n=214 ) , the rate of decline decreased by 33.9 mL·year−1 with fluticasone propionate versus placebo ( p=0.003 ) . Exacerbation rate reduction on ICS  for fluticasone propionate versus placebo was higher in the eosinophil < 2 % group compared with the ≥2 % group ; time-to-first moderate/severe exacerbation was not different between treatments in either group . A baseline blood eosinophil count of ≥2 % identifies a group of COPD patients with slower rates of decline in FEV1 when treated with ICS : prospect i ve testing of this hypothesis is now warranted . Blood eosinophil level identifies COPD patients showing a slower rate of lung function decline when treated with ICS BACKGROUND Blood eosinophil counts might predict response to inhaled corticosteroids ( ICS ) in patients with chronic obstructive pulmonary disease ( COPD ) and a history of exacerbations . We used data from the WISDOM trial to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn . METHODS WISDOM was a 12-month , r and omised , parallel-group trial in which patients received 18 μg tiotropium , 100 μg salmeterol , and 1000 μg fluticasone propionate daily for 6 weeks and were then r and omly assigned ( 1:1 ) electronically to receive either continued or reduced ICS over 12 weeks . We did a post-hoc analysis after complete ICS withdrawal ( months 3 - 12 ) to compare rate of exacerbations and time to exacerbation outcomes on the basis of blood eosinophil subgroups of increasing cutoff levels . The WISDOM trial is registered at Clinical Trials.gov , number NCT00975195 . FINDINGS In the 2296 patients receiving treatment after ICS withdrawal  , moderate or severe exacerbation rate  was higher in the ICS-withdrawal group versus the ICS-continuation group in patients with eosinophil counts ( out of total white blood cell count ) of 2 % or greater ( rate ratio 1·22 [ 95 % CI 1·02 - 1·48 ] ) , 4 % or greater ( 1·63 [ 1·19 - 2·24 ] ) , and 5 % or greater ( 1·82 [ 1·20 - 2·76 ] ) . The increase in exacerbation rate became more pronounced as the eosinophil cutoff level rose , with significant treatment-by-subgroup interaction reached for 4 % and 5 % only . Similar results were seen with eosinophil cutoffs of 300 cells per μL and 400 cells per μL , and mutually exclusive subgroups . INTERPRETATION Blood eosinophil counts at screening were related to the exacerbation rate after complete ICS withdrawal in patients with severe to very severe COPD and a history of exacerbations . Our data suggest that counts of 4 % or greater or 300 cells per μL or more might identify a deleterious effect of ICS withdrawal , an effect not seen in most patients with eosinophil counts below these thresholds . FUNDING Boehringer Ingelheim RATIONALE Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination ( salmeterol/fluticasone propionate ) 50/500 microg twice daily and the long-acting bronchodilator ( tiotropium ) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD . METHODS A total of 1,323 patients ( mean age , 64 yr , post-bronchodilator FEV1 , 39 % predicted ) were r and omized in this 2-year , double-blind , double-dummy parallel study . MEASUREMENTS AND MAIN RESULTS Primary endpoint was health care utilization exacerbation rate . Other endpoints included health status measured by St. George 's Respiratory Question naire ( SGRQ ) , mortality , adverse events , and study withdrawal . Probability of withdrawing from the study was 29 % greater with tiotropium than salmeterol/fluticasone propionate ( P = 0.005 ) . The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group ( rate ratio , 0.967 ; 95 % confidence interval [ CI ] , 0.836 - 1.119 ] ; P = 0.656 ) . The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium ( difference 2.1 units ; 95 % CI , 0.1 - 4.0 ; P = 0.038 ) . Mortality was significantly lower in the salmeterol/fluticasone propionate group ; 21 ( 3 % ) of patients in this group died compared with 38 ( 6 % ) in the tiotropium group ( P = 0.032 ) . More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium ( P = 0.008 ) . CONCLUSIONS We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium . More patients failed to complete the study while receiving tiotropium . A small statistically significant beneficial effect was found on health status , with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients . Clinical trial registered with www . clinical trials.gov ( NCT 00361959 ) The role of inhaled corticosteroids in the management of chronic obstructive pulmonary disease ( COPD ) remains controversial . The purpose of this study was to evaluate whether sputum eosinophilia ( defined as eosinophils ≥3 % ) predicts clinical benefit from inhaled corticosteroid treatment in patients with smoking-related clinical ly stable moderate-to-severe COPD . Forty consecutive patients with effort dyspnoea ( mean age 67 yrs ; 52 pack-yr smoking history ; post-bronchodilator forced expiratory volume in one second ( FEV1 ) < 60 % predicted , consistent with moderate-to-severe smoking-related chronic airflow limitation ) were enrolled . Subjects were treated with inhaled placebo followed by inhaled budesonide ( Pulmicort Turbuhaler ® 1,600 µg·day−1 ) , each given for 4 weeks . While the treatment was single-blind ( subject level ) , sputum cell counts before and after treatment interventions were double-blind , thus removing bias . Outcome variables included spirometry , quality -of-life assessment and 6-min walk test . Sputum eosinophilia was present in 38 % of subjects . In these , budesonide treatment normalised the eosinophil counts and , in comparison to placebo treatment , result ed in clinical ly significant improvement in the dyspnoea domain of the disease-specific chronic respiratory question naire ( 0.8 versus 0.3 ) and a small but statistically significant improvement in post-bronchodilator spirometry ( FEV1 100 mL versus 0 mL ; p<0.05 ) . In conclusion , sputum eosinophilia predicts short-term clinical benefit from high-dose inhaled corticosteroid treatment in patients with stable moderate-to-severe chronic obstructive pulmonary disease Several biomarkers have been used to assess sputum eosinophilia  in asthma . It has been suggested that the diagnostic accuracy of these biomarkers might differ between asthma phenotypes . We investigated the accuracy of biomarkers in detecting sputum eosinophilia ( ≥3 % ) in different adult asthma phenotypes .  Levels of eosinophils in blood and sputum , exhaled nitric oxide fraction ( FeNO ) and total immunoglobulin (Ig)E  from 336 adult patients , enrolled in three prospect i ve observational clinical trials and recruited at five pulmonology outpatient departments , were analysed . Areas under the receiver operating characteristics curves ( AUC ) for detecting sputum eosinophilia were calculated and compared between severe and mild , obese and nonobese , atopic and nonatopic and (ex-)smoking and never-smoking asthma patients . Sputum eosinophilia was present in 116 patients ( 35 % ) . In the total group the AUC was 0.83 ( 95 % CI 0.78–0.87 ) for blood eosinophils , 0.82 ( 0.77–0.87 ) for FeNO and 0.69 ( 0.63–0.75 ) for total IgE. AUCs were similar for blood eosinophils and FeNO between different phenotypes . Total IgE was less accurate in detecting sputum eosinophilia in atopic and obese patients than in nonatopic and nonobese patients . Blood eosinophils and FeNO had comparable diagnostic accuracy ( superior to total IgE ) in identifying sputum eosinophilia in adult asthma patients , irrespective of asthma phenotype such as severe , nonatopic , obese and smoking-related asthma . FeNO and blood eosinophils can be used to detect sputum eosinophilia in adult asthma patients regardless of phenotype BACKGROUND Treatment with an inhaled corticosteroid ( ICS ) and long-acting bronchodilator is recommended for severe/very severe chronic obstructive pulmonary disease ( COPD ) patients with repeated exacerbations . This r and omized , double-blind , double-dummy , parallel-group , 12-month multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) on COPD exacerbations . METHODS Following a 2-week run-in during which COPD patients aged ≥40 years with an exacerbation history discontinued medications except ICSs , 1219 patients were r and omized 1:1:1 to twice-daily budesonide/formoterol pMDI 320/9 μg , budesonide/formoterol pMDI 160/9 μg , or formoterol dry powder inhaler 9 μg . An exacerbation was defined as COPD worsening requiring oral corticosteroids and /or hospitalization . A post hoc analysis , with antibiotic treatment added to the exacerbation definition , was also performed . RESULTS Budesonide/formoterol 320/9 and 160/9 reduced exacerbation rates ( number per patient-treatment year ) by 34.6 % and 25.9 % , respectively , versus formoterol ( p ≤ 0.002 ) . Budesonide/formoterol 320/9 prolonged time to first exacerbation versus formoterol , corresponding to a 21.2 % reduction in hazard ratio ( 0.788 [ 95 % CI : 0.639 , 0.972 ] ; p = 0.026 ) . Exacerbation rates ( number per patient-treatment year ) including antibiotic treatment ( post hoc analysis ) were reduced by 25.9 % and 18.7 % with budesonide/formoterol 320/9 and 160/9 , respectively , versus formoterol ( p ≤ 0.023 ) . Both budesonide/formoterol doses were well tolerated with safety profiles similar to formoterol . Pneumonia adverse events occurred in 6.4 % , 4.7 % , and 2.7 % of patients in the budesonide/formoterol 320/9 , 160/9 , and formoterol groups . CONCLUSIONS Over 12 months , both budesonide/formoterol doses reduced the exacerbation rate ( defined with or without antibiotic treatment ) versus formoterol . Budesonide/formoterol pMDI is an appropriate treatment for reducing exacerbations in COPD patients with a history of exacerbations . ( NCT00419744 ) RATIONALE Exacerbations of chronic obstructive pulmonary disease ( COPD ) and responses to treatment are heterogeneous . OBJECTIVES Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations . METHODS Subjects with COPD exacerbations were entered into a r and omized biomarker-directed double-blind corticosteroid versus st and ard therapy study . Subjects in the st and ard arm received prednisolone for 2 weeks , whereas in the biomarker-directed arm , prednisolone or matching placebo was given according to the blood eosinophil count biomarker . Both study groups received antibiotics . Blood eosinophils were measured in the biomarker-directed and st and ard therapy arms to define biomarker-positive and -negative exacerbations ( blood eosinophil count > and ≤ 2 % , respectively ) . The primary outcome was to determine noninferiority in health status using the chronic respiratory question naire ( CRQ ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and st and ard therapy arms . MEASUREMENTS AND MAIN RESULTS There were 86 and 80 exacerbations in the biomarker-directed and st and ard treatment groups , respectively . In the biomarker-directed group , 49 % of the exacerbations were not treated with  prednisolone . CRQ improvement after treatment in the st and ard and biomarker-directed therapy groups was similar ( 0.8 vs. 1.1 ; mean difference , 0.3 ; 95 % confidence interval , 0.0 - 0.6 ; P = 0.05 ) . There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone ( mean difference , 0.45 ; 95 % confidence interval , 0.01 - 0.90 ; P = 0.04 ) . In biomarker-negative exacerbations , treatment failures occurred in 15 % given prednisolone and 2 % of those given placebo ( P = 0.04 ) . CONCLUSIONS The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations , but larger studies are required Background The coexistence of COPD and asthma is widely recognized but has not been well described . This study characterizes clinical features , spirometry , and chest CT scans of smoking subjects with both COPD and asthma . Methods We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPD Gene Study . Results 119 ( 13 % ) of 915 subjects with COPD reported a history of physician-diagnosed asthma . These subjects were younger ( 61.3 vs 64.7 years old , p = 0.0001 ) with lower lifetime smoking intensity ( 43.7 vs 55.1 pack years , p = 0.0001 ) . More African-Americans reported a history of asthma ( 33.6 % vs 15.6 % , p < 0.0001 ) . Subjects with COPD and asthma demonstrated worse disease-related quality of life , were more likely to have had a severe COPD exacerbation in the past year , and were more likely to experience frequent exacerbations ( OR 3.55 [ 2.19 , 5.75 ] , p < 0.0001 ) . Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT . There were no differences in spirometry or CT measurements of emphysema or airway wall thickness . ConclusionS ubjects with COPD and asthma represent a relevant clinical population , with worse health-related quality of life . They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history . Trial registration Clinical Trials.gov : The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo , budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . In a 12-month , r and omised , double-blind , placebo-controlled , parallel-group study in 812 adults ( mean age 64 yrs , mean forced expiratory volume in one second ( FEV1 ) 36 % predicted normal ) , patients received two inhalations twice daily of either budesonide/formoterol ( Symbicort ® ) 160/4.5 µg ( delivered dose ) , budesonide 200 µg ( metered dose ) , formoterol 4.5 µg or placebo . Severe exacerbations and FEV1 ( primary variables ) , peak expiratory flow ( PEF ) , COPD symptoms , health-related quality of life ( HRQL ) , mild exacerbations , use of reliever β2‐agonist and safety variables were recorded .  Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24 % versus placebo and 23 % versus formoterol . FEV1 increased by 15 % versus placebo and 9 % versus budesonide . Morning PEF improved significantly on day 1 versus placebo and budesonide ; after 1 week , morning PEF was improved versus placebo , budesonide and formoterol . Improvements in morning and evening PEF versus comparators were maintained over 12 months . Budesonide/formoterol decreased all symptom scores and use of reliever β2‐agonists significantly versus placebo and budesonide , and improved HRQL versus placebo . All treatments were well tolerated . These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease Background : Chronic obstructive pulmonary disease ( COPD ) encompasses a group of disorders characterised by the presence of incompletely reversible airflow obstruction with overlapping subsets of different phenotypes including chronic bronchitis , emphysema or asthma . The aim of this study was to determine the proportion of adult subjects aged > 50 years within each phenotypic subgroup of COPD , defined as a post-bronchodilator ratio of forced expiratory volume in 1 s/forced vital capacity ( FEV1/FVC ) < 0.7 , in accordance with current international guidelines . Methods : Adults aged > 50 years derived from a r and om population -based survey  undertook detailed question naires , pulmonary function tests and chest CT scans . The proportion of subjects in each of 16 distinct phenotypes was determined based on combinations of chronic bronchitis , emphysema and asthma , with and without incompletely reversible airflow obstruction defined by a post-bronchodilator FEV1/FVC ratio of 0.7 . Results : A total of 469 subjects completed the investigative modules , 96 of whom ( 20.5 % ) had COPD . Diagrams were constructed to demonstrate the relative proportions of the phenotypic subgroups in subjects with and without COPD . 18/96 subjects with COPD ( 19 % ) had the classical phenotypes of chronic bronchitis and /or emphysema but no asthma ; asthma was the predominant COPD phenotype , being present in 53/96 ( 55 % ) . When COPD was defined as a post-bronchodilator FEV1/FVC less than the lower limit of normal , there were one-third fewer subjects with COPD and a smaller proportion without a defined emphysema , chronic bronchitis or asthma phenotype . Conclusion : This study provides proportional classifications of the phenotypic subgroups of COPD which can be used as the basis for further research into the pathogenesis and treatment of this heterogeneous disorder Objectives To identify clusters of patients who may benefit from treatment with an inhaled corticosteroid (ICS)/long-acting β2 agonist ( LABA ) versus LABA  alone , in terms of exacerbation reduction , and to vali date previously identified clusters of patients with chronic obstructive pulmonary disease ( COPD ) ( based on diuretic use and reversibility ) . Design Post hoc supervised cluster analysis using a modified recursive partitioning algorithm of two 1-year r and omised , controlled trials of fluticasone furoate (FF)/vilanterol ( VI ) versus VI alone , with the primary end points of the annual rate of moderate-to-severe exacerbations . Setting Global . Participants 3255 patients with COPD ( intent-to-treat population s ) with a history of exacerbations in the past year . Interventions FF/VI 50/25 µg , 100/25 µg or 200/25 µg , or VI 25 µg ; all one time per day . Outcome measures Mean annual COPD exacerbation rate to identify clusters of patients who benefit from adding an ICS ( FF ) to VI bronchodilator therapy . Results Three clusters were identified , including two groups that benefit from FF/VI versus VI : patients with blood eosinophils > 2.4 % ( RR=0.68 , 95 % CI 0.58 to 0.79 ) , or blood eosinophils ≤2.4 % and smoking history ≤46 pack-years , experienced a reduced rate of exacerbations with FF/VI versus VI ( RR=0.78 , 95 % CI 0.63 to 0.96 ) , whereas those with blood eosinophils ≤2.4 % and smoking history > 46 pack-years were identified as non-responders ( RR=1.22 , 95 % CI 0.94 to 1.58 ) . Clusters of patients previously identified in the fluticasone propionate/salmeterol ( SAL ) versus SAL trials of similar design were not vali date d ; all clusters of patients tended to benefit from FF/VI versus VI alone irrespective of diuretic use and reversibility . Conclusions In patients with COPD with a history of exacerbations , those with greater blood eosinophils or a lower smoking history may benefit more from ICS/LABA versus LABA alone as measured by a reduced rate of exacerbations . In terms of eosinophils , this finding is consistent with findings from other studies ; however , the validity of the 2.4 % cut-off and the impact of smoking history require further investigation . Trial registration numbers NCT01009463 ; NCT01017952 ; Post- results BACKGROUND Some patients with chronic obstructive pulmonary disease ( COPD ) respond to corticosteroid therapy . Whether these patients have different airway pathology from other COPD patients is unclear . We tested the hypothesis that response to prednisolone is related to the presence of eosinophilic airway inflammation . METHODS We did a r and omised , double-blind , crossover trial . Patients who had COPD treated with bronchodilators only were assigned placebo and 30 mg prednisolone daily for 2 weeks each , in a r and om order , separated by a 4-week washout period . Before and after each treatment period , we assessed patients with spirometry , symptom scores , the chronic respiratory disease question naire ( CRQ ) , incremental shuttle walk test , and induced sputum .  Analysis was done by intention to treat . FINDINGS 83 patients were recruited , of whom 67 were r and omised . The geometric mean sputum eosinophil count fell significantly after prednisolone ( from 2.4 % to 0.4 % ; mean difference six-fold [ 95 % CI 3.1 - 11.4 ] ) but not after placebo . Other sputum cell counts did not change . After stratification into tertiles by baseline eosinophil count , postbronchodilator forced expiratory volume in 1 s ( FEV1 ) and total scores on the CRQ improved progressively after prednisolone from the lowest to the highest eosinophilic tertile , compared with placebo . The mean change in postbronchodilator FEV1 , total CRQ score , and shuttle walk distance with prednisolone compared with placebo in the highest tertile was 0.19 L ( 0.06 - 0.32 ) , 0.62 ( 0.31 - 0.93 ) , and 20 m ( 5 - 35 ) , respectively . INTERPRETATION Our findings suggest that eosinophilic airway inflammation contributes to airflow obstruction and symptoms in some patients with COPD and that the short-term effects of prednisolone are due to modification of this feature of the inflammatory response . The possibility that sputum eosinophilia identifies a subgroup of patients who particularly respond to long-term treatment with inhaled corticosteroids should be investigated OBJECTIVES COPD exacerbations are associated with significant morbidity and mortality . This r and omized , double-blind , parallel-group , multicenter study evaluated the effect of fluticasone propionate/salmeterol 250/50 and salmeterol 50 microg twice daily on moderate to severe exacerbations . METHODS Patients received st and ardized treatment with fluticasone propionate/salmeterol 250/50 during a 1-month run-in , followed by r and omization to fluticasone propionate/salmeterol 250/50 or salmeterol for 12 months . Moderate to severe exacerbations were defined as worsening symptoms of COPD requiring treatment with oral corticosteroids , antibiotics , or hospitalization . RESULTS In 782 patients with COPD ( mean FEV(1)=0.94+/-0.36 L , 33 % predicted normal ) , treatment with fluticasone propionate/salmeterol 250/50 significantly reduced ( 1 ) the annual rate of moderate to severe exacerbations by 30.5 % compared with salmeterol ( 1.06 and 1.53 per subject per year , respectively , p<0.001 ) , ( 2 ) the risk of time to first exacerbation by 25 % ( hazard ratio=0.750 , p=0.003 ) and ( 3 ) the annual rate of exacerbations requiring oral corticosteroids by 40 % ( p<0.001 ) . Clinical improvements observed during run-in treatment with fluticasone propionate/salmeterol 250/50 were better maintained over 12 months with fluticasone propionate/salmeterol 250/50 than salmeterol .  Adverse events were reported for a similar percentage of subjects across groups . A higher reporting of pneumonia was observed with fluticasone propionate/salmeterol 250/50 than salmeterol ( 7 % vs. 4 % ) . CONCLUSIONS We conclude that fluticasone propionate/salmeterol 250/50 is more effective than salmeterol at reducing the rate of moderate to severe exacerbations over 1 year . The benefits of this reduction relative to the risk of a higher incidence of reported pneumonia should be considered . This study supports the use of fluticasone propionate/salmeterol 250/50 for the reduction of COPD exacerbations in patients with COPD BACKGROUND The short-term benefits of inhaled corticosteroids for patients with chronic obstructive pulmonary disease ( COPD ) are greater in patients with evidence of eosinophilic airway inflammation . We investigated whether blood eosinophil count is a useful biomarker of the long-term effect of the inhaled corticosteroid fluticasone furoate on exacerbation frequency . METHODS We did a post-hoc analysis of data from two replicate , r and omised , double-blind trials of 12 months ' duration ( Sept 25 , 2009 to Oct 21 , 2011 and Oct 17 , 2011 ) in which once a day vilanterol 25 μg was compared with 25 μg vilanterol plus 50 μg , 100 μg , or 200 μg fluticasone furoate in patients with moderate-to-severe COPD and a history of one or more exacerbation in the previous year . We compared exacerbation rates according to two baseline eosinophil cell count strata ( < 2 % and ≥2 % ) , and according to four baseline percentage groupings . We also assessed lung function and incidence of pneumonia per strata in treatment groups . FINDINGS We included 3177 patients in the analyses , with 2083 patients ( 66 % ) having an eosinophil count of 2 % or higher at study entry . Across all doses of inhaled corticosteroids , fluticasone furoate and vilanterol  reduced exacerbations by 29 % compared with vilanterol alone ( mean 0·91 vs 1·28 exacerbations per patient per year ; p<0·0001 ) in patients with eosinophil counts of 2 % or higher , and by 10 % ( 0·79 vs 0·89 ; p=0·2827 ) in patients with eosinophil counts lower than 2 % . Reductions in exacerbations  with fluticasone furoate and vilanterol , compared with vilanterol alone , were 24 % in patients with baseline eosinophil counts of ≥2-<4 % , 32 % for those with counts of 4-<6 % , and 42 % for those with eosinophil counts of ≥6 % . In patients treated with vilanterol alone , exacerbation rates increased progressively with increasing eosinophil count percentage category . Improvement in trough forced expiratory volume in 1 s ( FEV1 ) and the increased risk of pneumonia  with fluticasone furoate and vilanterol compared with vilanterol alone were not associated with eosinophil count . INTERPRETATION Blood eosinophil count is a promising biomarker of response to inhaled corticosteroids in patients with COPD . Blood eosinophil count could potentially be used to stratify patients for different exacerbation rate reduction strategies . FUNDING GlaxoSmithKline ( study ID 201595 ) A reliable predictor of benefit from corticosteroid treatment in patients with chronic airflow limitation is needed . In a single-blind , sequential crossover trial of placebo and prednisone ( 30 mg/day ) treatment , with each given for 2 wk , we investigated whether an increased proportion of sputum eosinophils ( > = 3 % ) predicts a beneficial effect of prednisone in smokers with severe obstructive bronchitis . Patients were seen before and after each treatment . Clinical measurements were made blind to the laboratory findings and vice-versa . Eighteen of 20 patients completed the study . Eight had sputum eosinophilia and similar clinical and physiologic characteristics to those of 10 patients without a finding of sputum eosinophilia . Only in patients with sputum eosinophilia did prednisone , as compared with placebo , produce a statistically significant and clinical ly important mean effect on effort dyspnea of 0.8 ( 95 % confidence interval [ CI ] : 0.3 to 1.2 ) , p = 0.008 , and in quality of life of 1.96 ( 95 % CI : 0.5 to 3.3 ) , p = 0.01 , associated with a small improvement in FEV1 of 0.11 L ( 95 % CI : - 0.04 to 0.23 L ) , p = 0.05 . In these patients , prednisone also produced a significant decline in the median sputum eosinophil percentage , from 9.7 % to 0.5 % ( p = 0.002 ) , eosinophil cationic protein ( ECP ) , from 6 , 000 microgram/L to 1,140 microgram/L ( p < 0.001 ) , and fibrinogen , from 25 . 3 mg/L to 5.4 mg/L ( p < 0.001 ) . These findings indicate that in smokers with severe airflow limitation , sputum eosinophilia predicts a beneficial effect of prednisone treatment . Improvement in FEV1 , after prednisone treatment in this population , is small , and may not be appreciated in clinical practice BACKGROUND There is overwhelming evidence that asthma guidelines aim ed at reducing airway inflammation are superior to those based on clinical symptoms alone . This involves targeting eosinophilic inflammation with inhaled corticosteroids . AIM Because induced sputum is not readily available , our study set out to investigate whether the collective or singular use of routine asthma investigations can predict sputum eosinophilia . METHODS Eighty patients underwent skin prick testing , blood tests ( IgE , full blood count ) , spirometry , exhaled fraction nitric oxide ( FeNO ) , PD15 to hypertonic saline , and induced sputum testing at first assessment .  A predictive model for sputum eosinophilia ( defined as ≥3 % eosinophils ) was sought using routinely available tests . RESULTS Fifty-four subjects underwent both induced sputum and FeNO testing . Seventeen ( 30 % ) revealed eosinophilic inflammation , nine ( 16 % ) neutrophilic , four ( 7 % ) mixed granulocytic and 26 ( 46 % ) paucigranulocytic . Positive predictors for sputum eosinophilia included low forced expiratory volume in 1 s ( FEV(1))% predicted , raised serum eosinophil , positive smoking history , Polynesian ethnicity and negative asthma family history . There was a non-statistically significant trend for FeNO predicting sputum eosinophilia . The best combination of predictors was low FEV(1)% predicted , raised serum eosinophil , positive smoking history and negative family history of asthma . CONCLUSION This study demonstrates that the serum eosinophil count and FEV(1 ) combined with aspects of a clinical history may provide a simple and practical alternative to assessment of airway ( sputum ) eosinophilia in the clinical setting . A full blood count can be performed at a substantially lesser cost and with greater accessibility than induced sputum . We feel the time has come for the clinical utility of the serum eosinophil count to be revisited Abstract Objectives : To determine the effect of long term inhaled corticosteroids on lung function , exacerbations , and health status in patients with moderate to severe chronic obstructive pulmonary disease . Design : Double blind , placebo controlled study . Setting : Eighteen UK hospitals . Participants : 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second ( FEV1 ) 50 % of predicted normal . Interventions : Inhaled fluticasone propionate 500 μg twice daily from a metered dose inhaler or identical placebo . Main outcome measures : Efficacy measures : rate of decline in FEV1 after the bronchodilator and in health status , frequency of exacerbations , respiratory withdrawals . Safety measures : morning serum cortisol concentration , incidence of adverse events . Results : There was no significant difference in the annual rate of decline in FEV1 ( P=0.16 ) . Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo ( P<0.001 ) . Median exacerbation rate was reduced by 25 % from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate ( P=0.026 ) . Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate ( P=0.0043 ) . Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group ( 25 % v 19 % , P=0.034 ) . Conclusions : Fluticasone propionate 500 μg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1 . Patients on fluticasone propionate  had fewer exacerbations and a slower decline in health status . These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease BACKGROUND Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease ( COPD ) . However , the benefit of inhaled glucocorticoids in addition to two long-acting bronchodilators has not been fully explored . METHODS In this 12-month , double-blind , parallel-group study , 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium ( at a dose of 18 μg once daily ) , salmeterol ( 50 μg twice daily ) , and the inhaled glucocorticoid fluticasone propionate ( 500 μg twice daily ) during a 6-week run-in period . Patients were then r and omly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period . The primary end point was the time to the first moderate or severe COPD exacerbation . Spirometric findings , health status , and dyspnea were also monitored . RESULTS As compared with continued glucocorticoid use , glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95 % confidence interval ( CI ) with respect to the first moderate or severe COPD exacerbation ( hazard ratio , 1.06 ; 95 % CI , 0.94 to 1.19 ) . At week 18 , when glucocorticoid withdrawal was complete , the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group ( P<0.001 ) ; a similar between-group difference ( 43 ml ) was seen at week 52 ( P=0.001 ) . No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group . CONCLUSIONS In patients with severe COPD  receiving tiotropium plus salmeterol , the risk of moderate or severe exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy . However , there was a greater decrease in lung function during the final step of glucocorticoid withdrawal . ( Funded by Boehringer Ingelheim Pharma ; WISDOM Clinical Trials.gov number , NCT00975195 . ) Rationale : Post hoc analyses suggest that blood eosinophils have potential as a predictive biomarker of inhaled corticosteroid efficacy in the management of chronic obstructive pulmonary disease ( COPD ) . Objectives : We prospect ively investigated the value of blood eosinophils as a predictor of responsiveness to an inhaled corticosteroid/long‐acting & bgr;2‐agonist combination versus a long‐acting & bgr;2‐agonist/long‐acting muscarinic antagonist combination for exacerbation prevention . Methods : We conducted prespecified analyses of data from the FLAME ( Effect of Indacaterol Glycopyronium vs Fluticasone Salmeterol on COPD Exacerbations ) study , which compared once‐daily long‐acting & bgr;2‐agonist/long‐acting muscarinic antagonist indacaterol/glycopyrronium 110/50 & mgr;g with twice‐daily long‐acting & bgr;2‐agonist/inhaled corticosteroid salmeterol/fluticasone combination 50/500 & mgr;g in patients with one or more exacerbations in the preceding year . Subsequent post hoc analyses were conducted to address further cutoffs and endpoints . Measurements and Main Results : We compared treatment efficacy according to blood eosinophil percentage ( < 2 % and ≥2 % , <3 % and ≥3 % , and < 5 % and ≥5 % ) and absolute blood eosinophil count ( < 150 cells/&mgr;l , 150 to < 300 cells/&mgr;l , and ≥300 cells/&mgr;l ) . Indacaterol/glycopyrronium was significantly superior to salmeterol/fluticasone for the prevention of exacerbations ( all severities , or moderate or severe ) in the < 2 % , ≥2 % , < 3 % , < 5 % , and < 150 cells/&mgr;l subgroups , and at no cutoff was salmeterol/fluticasone superior to indacaterol/glycopyrronium . Furthermore , the rate of moderate or severe exacerbations did not increase with increasing blood eosinophils . The incidence of pneumonia was higher in patients receiving salmeterol/fluticasone than indacaterol/glycopyrronium in both the < 2 % and ≥2 % subgroups . Conclusions : Our prospect i ve analyses indicate that indacaterol/glycopyrronium provides superior or similar benefits over salmeterol/fluticasone regardless of blood eosinophil levels in patients with COPD . Clinical trial registered with www . clinical trials.gov ( NCT01782326 )
Background COPD is a highly heterogeneous disease .
Potential biomarkers to identify patients with COPD who will derive the greatest benefit from inhaled corticosteroid ( ICS ) treatment are needed .
Blood eosinophil count can serve as a predictive biomarker for the efficacy of ICS treatment .
The aim of this systematic review and meta- analysis was to assess whether a blood eosinophil count of ≥2 % in patients undergoing ICS therapy was associated with a greater reduction in COPD exacerbation rate and pneumonia incidence .