human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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. 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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. 
    Output:
    