Rethinking Blood Eosinophils for Assessing Inhaled Corticosteroids Response in COPD

Abstract

BackgroundThe varied treatment response to inhaled corticosteroids (ICS) in COPD and the increased risk of pneumonia necessitate a personalized ICS therapeutic approach. This is informed by blood eosinophil count (BEC), which predicts ICS treatment response. However, BEC appears to change in response to ICS treatment.Research QuestionDoes BEC measured on or off ICS treatment, or the change in BEC during ICS treatment, best predict treatment response to ICS in COPD?Study Design and MethodsFLAME, a 52-week, double-blind randomized controlled trial compared long-acting beta-2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) with LABA/ICS. Corticosteroids were prohibited during a 4-week run-in period. We chose patients previously on ICS, thereby allowing pre-run-in and post-run-in period BEC to represent BEC on and off ICS, respectively. In this post hoc analysis, we revisited outcome data, exploring how the three BEC biomarkers interacted with treatment response to the ICS-containing regimen.ResultsOur study confirms that LABA/LAMA combination is superior, or at least noninferior, to LABA/ICS in curbing exacerbations for most FLAME participants. However, higher BEC off ICS and BEC on ICS and significant BEC suppression during ICS treatment corresponded to superior response to LABA/ICS in terms of exacerbation rate, time to first exacerbation, and time to first pneumonia. In a subgroup, including 9% of participants, BEC changed significantly during ICS treatment (≥ 200 cells/μL), and higher BEC on ICS did not predict ICS treatment response. For these patients, BEC off ICS and BEC change proved more predictive. Excess pneumonia risk associated with ICS appeared to be confined to patients who do not benefit from this treatment. BEC was not predictive of treatment effects on lung function and health status.InterpretationThis exploratory analysis advocates preferentially using BEC off ICS or BEC change during ICS treatment for guiding ICS treatment decisions. BEC measured on ICS is less predictive of treatment response.Trial RegistrationClinicalTrials.gov; No.: NCT01782326; URL: www.clinicaltrials.gov The varied treatment response to inhaled corticosteroids (ICS) in COPD and the increased risk of pneumonia necessitate a personalized ICS therapeutic approach. This is informed by blood eosinophil count (BEC), which predicts ICS treatment response. However, BEC appears to change in response to ICS treatment. Does BEC measured on or off ICS treatment, or the change in BEC during ICS treatment, best predict treatment response to ICS in COPD? FLAME, a 52-week, double-blind randomized controlled trial compared long-acting beta-2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) with LABA/ICS. Corticosteroids were prohibited during a 4-week run-in period. We chose patients previously on ICS, thereby allowing pre-run-in and post-run-in period BEC to represent BEC on and off ICS, respectively. In this post hoc analysis, we revisited outcome data, exploring how the three BEC biomarkers interacted with treatment response to the ICS-containing regimen. Our study confirms that LABA/LAMA combination is superior, or at least noninferior, to LABA/ICS in curbing exacerbations for most FLAME participants. However, higher BEC off ICS and BEC on ICS and significant BEC suppression during ICS treatment corresponded to superior response to LABA/ICS in terms of exacerbation rate, time to first exacerbation, and time to first pneumonia. In a subgroup, including 9% of participants, BEC changed significantly during ICS treatment (≥ 200 cells/μL), and higher BEC on ICS did not predict ICS treatment response. For these patients, BEC off ICS and BEC change proved more predictive. Excess pneumonia risk associated with ICS appeared to be confined to patients who do not benefit from this treatment. BEC was not predictive of treatment effects on lung function and health status. This exploratory analysis advocates preferentially using BEC off ICS or BEC change during ICS treatment for guiding ICS treatment decisions. BEC measured on ICS is less predictive of treatment response. ClinicalTrials.gov; No.: NCT01782326; URL: www.clinicaltrials.gov Take-home PointsStudy Question: (1) Is blood eosinophil count (BEC) measured while patients are not receiving inhaled corticosteroids (ICS)? (2) Is BEC measured while patients are receiving ICS? (3) Is treatment change in BEC (BEC on treatment – BEC off treatment) associated with treatment response to long-acting beta-2 agonist (LABA)/ICS vs LABA/long-acting muscarinic antagonist combinations?Results: Higher BEC off ICS, BEC on ICS, and significant BEC suppression during ICS treatment corresponded to superior response to LABA/ICS in terms of preventing exacerbations and pneumonia. However, in 9% of participants, BEC changed significantly on ICS treatment. In this subgroup, higher BEC on ICS did not predict ICS treatment response.Interpretation: Our findings advocate preferentially using BEC off ICS or BEC change during ICS treatment for guiding ICS treatment decisions. Study Question: (1) Is blood eosinophil count (BEC) measured while patients are not receiving inhaled corticosteroids (ICS)? (2) Is BEC measured while patients are receiving ICS? (3) Is treatment change in BEC (BEC on treatment – BEC off treatment) associated with treatment response to long-acting beta-2 agonist (LABA)/ICS vs LABA/long-acting muscarinic antagonist combinations? Results: Higher BEC off ICS, BEC on ICS, and significant BEC suppression during ICS treatment corresponded to superior response to LABA/ICS in terms of preventing exacerbations and pneumonia. However, in 9% of participants, BEC changed significantly on ICS treatment. In this subgroup, higher BEC on ICS did not predict ICS treatment response. Interpretation: Our findings advocate preferentially using BEC off ICS or BEC change during ICS treatment for guiding ICS treatment decisions. COPD, a leading cause of death, disability, and chronic respiratory symptoms, is complex and heterogeneous, thus requiring a precision medicine therapeutic approach.1Agusti A. Bel E. Thomas M. et al.Treatable traits: toward precision medicine of chronic airway diseases.Eur Respir J. 2016; 47: 410-419Crossref PubMed Scopus (732) Google Scholar Only patients with enhanced eosinophilic inflammation in the airways appear to respond to inhaled corticosteroids (ICS).2Singh D. Agusti A. Anzueto A. et al.Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019.Eur Respir J. 2019; 531900164Crossref Scopus (1237) Google Scholar,3Brightling C.E. Monteiro W. Ward R. et al.Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial.Lancet. 2000; 356: 1480-1485Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar Blood eosinophil count (BEC), a practical surrogate marker for airway eosinophilic inflammation,2Singh D. Agusti A. Anzueto A. et al.Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019.Eur Respir J. 2019; 531900164Crossref Scopus (1237) Google Scholar has been shown to predict ICS treatment response in randomized controlled trials (RCTs)4Lipson D.A. Barnhart F. Brealey N. et al.Once-daily single-inhaler triple versus dual therapy in patients with COPD.N Engl J Med. 2018; 378: 1671-1680Crossref PubMed Scopus (833) Google Scholar, 5Rabe K.F. Martinez F.J. Ferguson G.T. et al.Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD.N Engl J Med. 2020; 383: 35-48Crossref PubMed Scopus (351) Google Scholar, 6Papi A. Vestbo J. Fabbri L. et al.Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial.Lancet. 2018; 391: 1076-1084Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 7Bafadhel M. Peterson S. De Blas M.A. et al.Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials.Lancet Respir Med. 2018; 6: 117-126Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 8Siddiqui S.H. Guasconi A. Vestbo J. et al.Blood eosinophils: a biomarker of response to extrafine beclomethasone/formoterol in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2015; 192: 523-525Crossref PubMed Google Scholar; higher BEC at the start of the study is associated with greater benefits for ICS treatment on exacerbations, health status, and pulmonary function.2Singh D. Agusti A. Anzueto A. et al.Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019.Eur Respir J. 2019; 531900164Crossref Scopus (1237) Google Scholar,9Yang I.A. Clarke M.S. Sim E.H. Fong K.M. Inhaled corticosteroids for stable chronic obstructive pulmonary disease.Cochrane Database Syst Rev. 2012; 2012: CD002991Google Scholar Because ICS may cause pneumonia and other side effects, BECs enable a targeted ICS administration strategy in patients with COPD with increased exacerbation risk.9Yang I.A. Clarke M.S. Sim E.H. Fong K.M. Inhaled corticosteroids for stable chronic obstructive pulmonary disease.Cochrane Database Syst Rev. 2012; 2012: CD002991Google Scholar,10Kew K.M. Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.Cochrane Database Syst Rev. 2014; 2014CD010115Google Scholar Systemic corticosteroids suppress BEC in COPD,3Brightling C.E. Monteiro W. Ward R. et al.Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial.Lancet. 2000; 356: 1480-1485Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar,11Siva R. Green R.H. Brightling C.E. et al.Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial.Eur Respir J. 2007; 29: 906-913Crossref PubMed Scopus (377) Google Scholar whereas in asthma it has been demonstrated that ICS can also suppress BEC.12Djukanovic R. Wilson J.W. Britten K.M. et al.Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma.Am Rev Respir Dis. 1992; 145: 669-674Crossref PubMed Google Scholar,13Lim S. Jatakanon A. John M. et al.Effect of inhaled budesonide on lung function and airway inflammation. Assessment by various inflammatory markers in mild asthma.Am J Respir Crit Care Med. 1999; 159: 22-30Crossref PubMed Google Scholar The potential suppression of BEC by ICS in COPD could weaken the correlation between BEC and ICS treatment response. In parallel, BEC is a responsive biomarker because BEC suppression during treatment with corticosteroids has been associated with treatment response.11Siva R. Green R.H. Brightling C.E. et al.Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial.Eur Respir J. 2007; 29: 906-913Crossref PubMed Scopus (377) Google Scholar These suggest three distinct BEC biomarkers for potential prediction of ICS treatment response: BEC measured while patients are receiving ICS (BEC on ICS), BEC off ICS, and BEC change post-ICS administration (BEC on ICS minus BEC off ICS). Our prior post hoc analysis of ISOLDE, a 3-year RCT comparing fluticasone propionate and placebo in COPD, found BEC change to be the superior predictor.14Mathioudakis A.G. Bikov A. Foden P. et al.Change in blood eosinophils following treatment with inhaled corticosteroids may predict long-term clinical response in COPD.Eur Respir J. 2020; 55Crossref Scopus (25) Google Scholar,15Burge P.S. Calverley P.M. Jones P.W. Spencer S. Anderson J.A. Maslen T.K. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.BMJ. 2000; 320: 1297-1303Crossref PubMed Google Scholar Intriguingly, in approximately 20% of patients, ICS treatment onset was associated with a BEC increase, and in these patients ICS administration was associated with a detrimental effect, characterized by a surge in exacerbation rate and accelerated FEV1 decline. Moreover, higher BEC off ICS but lower BEC on ICS was associated with a slower FEV1 decline with ICS treatment. Although ISOLDE was conducted in the 1990s under different care standards and less standardized exacerbation definitions, the analysis nonetheless suggests potential drawbacks in using BEC on ICS for COPD treatment decisions. In this post hoc analysis of the FLAME trial,16Wedzicha J.A. Banerji D. Chapman K.R. et al.Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD.N Engl J Med. 2016; 374: 2222-2234Crossref PubMed Scopus (699) Google Scholar we further evaluate whether BEC off or on ICS is better associated with treatment response to the ICS-containing regimens, primarily focusing on exacerbations. We also investigated the use of BEC change as a novel biomarker of treatment response to ICS. FLAME was chosen for this analysis due to the comprehensive capture of all three BEC biomarkers in a substantial number of participants. This investigator-initiated, post hoc analysis of the FLAME trial was based on a prospectively designed analysis plan submitted to the study sponsor (Novartis) via Study The FLAME and been previously J.A. Banerji D. Chapman K.R. et al.Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD.N Engl J Med. 2016; 374: 2222-2234Crossref PubMed Scopus (699) Google N. Chapman K.R. et al.Blood eosinophils and response to chronic obstructive pulmonary disease treatment. from the FLAME J Respir Crit Care Med. PubMed Scopus Google Scholar In FLAME a double-blind, compared the effects of the long-acting muscarinic antagonist (LAMA) and the long-acting beta-2 agonist with the combination of and fluticasone propionate found the LABA/LAMA combination superior in preventing exacerbations and lung function and health the LABA/ICS J.A. Banerji D. Chapman K.R. et al.Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD.N Engl J Med. 2016; 374: 2222-2234Crossref PubMed Scopus (699) Google Scholar by BEC benefits as superior or to of N. Chapman K.R. et al.Blood eosinophils and response to chronic obstructive pulmonary disease treatment. from the FLAME J Respir Crit Care Med. PubMed Scopus Google Scholar a 4-week run-in period while inhaled corticosteroids were not with BEC measured and the as BEC off ICS. of were on ICS on In this post hoc analysis, we on ICS at who prior to the first BEC (BEC on ICS). We also BEC change (BEC on ICS minus BEC off ICS), a BEC suppression during ICS treatment. We the BEC in the This post hoc analysis investigated the correlation between three BEC biomarkers and treatment response to the ICS-containing regimen. The were the of (1) moderate or severe and (2) severe exacerbations. the rate of all exacerbations, rate of exacerbations to treatment or time to first exacerbation, time to first and change from in in and in Our were for the of at least a 200 BEC change or significant BEC This was by the and the of this analysis was to in BEC that could be by of the Foden P. D. The of COPD blood eosinophil Respir J. 2018; PubMed Scopus Google Scholar We conducted of LABA/LAMA and LABA/ICS in including patients with BEC off ICS (≥ 200 but BEC on ICS 200 and and significant BEC suppression (≥ 200 vs In a analysis, we who were an ICS the the BEC on ICS We to the between treatment and BEC For the rate of exacerbations, we a with a and a time on treatment The of treatment on time to first exacerbation, or was via We the using and the were to evaluate treatment effects on change in pulmonary function and health status, focusing on the between treatment, and BEC We all for status, prior exacerbation prior or COPD and for were significant in were conducted in The post hoc analysis were by FLAME trial between receiving LABA/LAMA and LABA/ICS were between of the in This GOLD – (0) GOLD – GOLD – GOLD – treatment of FEV1 to during the are or GOLD for Chronic Obstructive Lung ICS inhaled long-acting beta-2 long-acting muscarinic in a are or GOLD for Chronic Obstructive Lung ICS inhaled long-acting beta-2 long-acting muscarinic of the at least moderate or severe exacerbation during study BEC off ICS significantly interacted with treatment on the rate of moderate or severe exacerbations for Higher BEC off ICS was to a superior response to LABA/ICS The based on BEC on ICS was to the based on BEC off ICS, but the did not In the for did not due to the in treatment higher BEC off and on ICS were associated with better LABA/ICS response in terms of the time to first moderate or severe exacerbation and BEC off on ICS demonstrated a substantial with treatment on the rate or time to first severe exacerbation, due to a with severe exacerbations The between BEC off ICS and treatment response on the rate of exacerbations of or did not but was an between higher BEC off ICS and treatment response to LABA/ICS on the time to first exacerbation of BEC on ICS was not associated with of these and by exacerbation based on treatment corticosteroids are in and and exacerbations with corticosteroids but not that were with the analysis of moderate or severe exacerbations. BEC off ICS, but not BEC on ICS, was associated with treatment on time to first pneumonia and These were based on a number of pneumonia during the study to the risk of pneumonia FLAME with a BEC off ICS of receiving LABA/ICS was compared with receiving The for with BEC off ICS of were and respectively. BEC off on ICS were predictive of treatment response the change from in pulmonary function or or health BEC change of was for comparing on vs off ICS because it the for blood for in J.A. J. W. of blood using the 2015; Full Text Full Text PDF Scopus Google Scholar on this BEC on ICS was higher in in and in of with BEC off ICS 200 higher (≥ 200 while on ICS. with BEC off ICS 200 BEC on ICS 200 BEC on ICS was significantly lower BEC off ICS BEC change significantly interacted with treatment on the rate of moderate or severe exacerbations rate of exacerbations of time to first moderate or severe exacerbation and time to first pneumonia BEC during ICS treatment was associated with an response to whereas significant BEC suppression an In outcome of moderate or severe the LABA/ICS appeared to be with LABA/LAMA was at We based on BEC change at the of LABA/ICS was superior in the rate of moderate or severe exacerbations with BEC suppression of at least whereas the was the with higher BEC change rate were in other exacerbation and pneumonia. We also the rate of moderate or severe exacerbations using BEC change of to and and that LABA/ICS was the superior treatment in the group, whereas LABA/LAMA was superior in the two to first of pneumonia by treatment vs with BEC change and BEC change The treatment effects between patients with significantly BEC and be BEC blood eosinophil ICS inhaled long-acting beta-2 long-acting muscarinic of LABA/LAMA vs LABA/ICS on the rate of moderate or severe exacerbations in of patients with BEC off vs on ICS. LABA/ICS. BEC blood eosinophil ICS inhaled long-acting beta-2 long-acting muscarinic We the of BEC off vs on ICS by at least 200 BEC suppression was in of these participants, and BEC was in In this subgroup, higher BEC off ICS and BEC suppression ICS response in the rate of moderate or severe exacerbations, time to first moderate or severe exacerbation, and time to first pneumonia. The between treatment response and BEC on ICS was significant for the rate of exacerbations with corticosteroids in this subgroup, lower BEC on ICS appeared to be associated with LABA/ICS In the of BEC off vs on ICS by 200 the of BEC off and on ICS with treatment effects on the rate of moderate or severe exacerbations was to the analysis the of who BEC off ICS 200 with BEC on ICS this was a for a rate of moderate or severe exacerbations LABA/ICS The was with BEC off ICS 200 and BEC on ICS this were in the of the exacerbation and pneumonia BEC change was not predictive of treatment response the change from in pulmonary function or health status. In the of who an ICS prior to BEC on ICS most were not due to the potential were with This post hoc analysis of the FLAME trial has findings to the use of BEC as a biomarker to ICS treatment in In the FLAME LABA/LAMA combination was superior or at least to LABA/ICS in preventing exacerbations in most of the participants, with the previously in the J.A. D. et response to versus in COPD patients by a post-hoc analysis in the FLAME 2019; PubMed Scopus Google Scholar Higher BEC off ICS and BEC on ICS are with a greater risk of exacerbations with ICS treatment. However, in 9% of study participants, BEC changed significantly during ICS treatment, and in these patients, higher BEC on ICS did not predict a response to LABA/ICS. In parallel, we BEC change during ICS treatment, as a as a potential novel the FLAME is in allowing the between BEC change and treatment to be We that suppression of BEC may in which is associated with a greater ICS treatment In of BEC suppression or an in BEC was a of a better response to These the potential of BEC change during ICS treatment as a predictive biomarker of treatment response to ICS in BEC off ICS and BEC change findings that the pneumonia risk associated with ICS is confined to patients who do not benefit from this treatment. demonstrated a of BEC in Foden P. D. The of COPD blood eosinophil Respir J. 2018; PubMed Scopus Google S.H. R. E. of blood eosinophil count in patients with COPD in the PubMed Scopus Google Scholar which is greater at higher has been whether ICS treatment can change We that the change is cells/μL), but change was in 9% change 200 BEC suppression was associated with greater ICS response in different with BEC change to the a LABA/ICS and a treatment trial with higher exacerbation risk with shown a greater benefit for LABA/ICS the in other D.A. Barnhart F. Brealey N. et al.Once-daily single-inhaler triple versus dual therapy in patients with COPD.N Engl J Med. 2018; 378: 1671-1680Crossref PubMed Scopus (833) Google K.F. Martinez F.J. Ferguson G.T. et al.Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD.N Engl J Med. 2020; 383: 35-48Crossref PubMed Scopus (351) Google Scholar the analysis that ICS can suppress BEC in COPD, and that the BEC change can be to predict ICS BEC change suggests that BEC on ICS is not to BEC off ICS. the BEC change that BEC on ICS may patients of this study ICS response prediction higher BEC on ICS lower BEC off ICS to predict ICS but using BEC on ICS in this may predict a ICS response and This can BEC on ICS less of for moderate to severe exacerbations compared with BEC off ICS and less for clinical compared with BEC off ICS of exacerbation, time to first The of could these BECs on ICS been in Our requiring potential for clinical BEC change is a biomarker that appears to and may ICS in with higher BEC on ICS. BEC on and BEC off ICS are not with BEC off ICS to in the prediction et of inhaled corticosteroids in COPD: a Respir J. 2020; 55Crossref Scopus Google Scholar on ICS in COPD using BEC measured on treatment for ICS findings suggest BEC change is a is how to BEC Although BEC change to appeared to is a response this which is to the and a of with 200 change that BEC off and on ICS prediction in this all these the for the patients, ICS be for patients with for Chronic Obstructive Lung with eosinophilic inflammation and exacerbations, in with for Chronic Obstructive Lung a BEC could further clinical with a for in of BEC of exacerbations or of pneumonia may be a more for ICS compared with BEC measured on treatment. BEC measured on ICS treatment and during a trial of ICS could treatment Our analysis also demonstrated a between BEC biomarkers and pneumonia risk patients with COPD receiving ICS. The pneumonia risk was primarily in patients to benefit from ICS. This with to in N. et airway in chronic obstructive pulmonary disease clinical and a J Respir Crit Care Med. PubMed Scopus Google Scholar, A. et between airway and eosinophils in Med. Scopus Google Scholar, S. et and inflammatory a COPD 2020; PubMed Scopus (0) Google Scholar and the to ICS use to We did not a between BEC and treatment on pulmonary function and health This could be due to the period of which not be to evaluate treatment on pulmonary function decline of is not because dual are for on these A.G. Vestbo J. D. for chronic obstructive pulmonary disease: and Med. 2020; Full Text Full Text PDF PubMed Scopus (0) Google Scholar is that the of ICS on BEC may been in this In FLAME, BEC on ICS and bronchodilator were at the run-in in of the of these post hoc study did not ICS for prior to BEC Although the of BEC response to the or of ICS is from the trial suggest effects start P. J. et corticosteroid therapy in patients to with COPD exacerbation a Respir Med. 2019; Full Text Full Text PDF PubMed Google Scholar in analysis, ICS on BEC to BEC on ICS was in the ISOLDE post hoc analysis, that did not a an was between BEC on ICS and treatment response to ICS, the study A.G. Bikov A. 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