Bronchodilator responsiveness as a phenotypic characteristic of established chronic obstructive pulmonary disease
- Paul Albert1,
- Alvar Agusti2,3,
- Lisa Edwards4,
- Ruth Tal-Singer5,
- Julie Yates4,
- Per Bakke6,7,
- Bartolome R Celli8,
- Harvey O Coxson9,
- Courtney Crim4,
- David A Lomas10,
- William MacNee11,
- Bruce Miller5,
- Stephen Rennard12,
- Edwin K Silverman13,14,
- Jørgen Vestbo15,16,
- Emiel Wouters17,
- Peter Calverley1
- 1School of Ageing and Chronic Disease, University Hospital Aintree, Liverpool, UK
- 2Thorax Institute, Hospital Clínic, IDIBAPS, Barcelona, Spain
- 3Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Fundación Caubet-Cimera, Mallorca, Spain
- 4GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, USA
- 5GlaxoSmithKline Research and Development, King of Prussia, Pennsylvania, USA
- 6Institute of Medicine, University of Bergen, Bergen, Norway
- 7Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway
- 8Brigham and Womens Hospital, Boston, Massachusetts, USA
- 9Department of Radiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada
- 10Cambridge Institute for Medical Research, Cambridge, UK
- 11MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
- 12Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- 13Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- 14Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- 15Respiratory Section, Hvidovre Hospital/University of Copenhagen, Copenhagen, Denmark
- 16Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK
- 17Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
- Correspondence to Professor Peter Calverley, School of Ageing and Chronic Disease, University Hospital Aintree, Lower Lane, Liverpool, L9 7AL, UK;
Contributors The authors of this paper developed the study design, agreed the statistical analysis, reviewed the data and contributed to the final manuscript. PA and PMAC wrote the first draft of the paper and LDE conducted the statistical analyses. All authors reviewed and commented on all subsequent drafts, including the final manuscript. All authors vouch for the veracity and completeness of the data and data analysis.
- Received 3 January 2012
- Accepted 18 May 2012
- Published Online First 13 June 2012
Background Bronchodilator responsiveness is a potential phenotypic characteristic of chronic obstructive pulmonary disease (COPD). We studied whether change in lung function after a bronchodilator is abnormal in COPD, whether stable responder subgroups can be identified, and whether these subgroups experience different clinical outcomes.
Methods 1831 patients with COPD, 285 smoking (SC) and 228 non-smoking (NSC) controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort. Spirometric reversibility to 400 μg inhaled salbutamol was assessed on four occasions over 1 year.
Results Forced expiratory volume in 1 s (FEV1) increase after salbutamol was similar in SC (mean 0.14 litres (SD 0.15)) and COPD (0.12 litres (0.15)) and was significantly greater than NSC (0.08 litres (0.14)). Reversibility status varied with repeated testing in parallel with the day-to-day variation in pre-bronchodilator FEV1, which was similar in control subjects and patients with COPD. Absolute FEV1 change decreased by Global initiative for chronic Obstructive Lung Disease (GOLD) stage in patients with COPD (GOLD II, mean 0.16 litres (SD 0.17); III, 0.10 litres (0.13); IV, 0.05 litres (0.08) as did chances of being classified as reversible. CT-defined emphysema was weakly related to the absolute change in FEV1 post salbutamol. Consistently reversible patients (n=227) did not differ in mortality, hospitalisation or exacerbation experience from irreversible patients when allowing for differences in baseline FEV1.
Limitations Reversibility only assessed with salbutamol and defined by FEV1 criteria. The COPD population was older than the control populations.
Conclusions Post-salbutamol FEV1 change is similar in patients with COPD and smoking controls but is influenced by baseline lung function and the presence of emphysema. Bronchodilator reversibility status varies temporally and does not distinguish clinically relevant outcomes, making it an unreliable phenotype.
Clinical trial registration number NCT00292552 (http://ClinicalTrials.gov).
- COPD exacerbations
- pulmonary rehabilitation
- COPD mechanisms
- COPD pharmacology
- cystic fibrosis
- cytokine biology
- exhaled airway markers
- innate immunity
- neutrophil biology
- viral infection
- asthma epidemiology
- COPD epidemiology
- assisted ventilation
- lung physiology
- lung volume reduction surgery
- respiratory muscles
- COPD pathology
- imaging/CT MRI etc
- pulmonary embolism
- alpha1 antitrypsin deficiency
- airway epithelium
- macrophage biology
- tobacco and the lung
- ambulatory oxygen therapy
- long-term oxygen therapy (LTOT)
- short burst oxygen therapy
- sleep apnoea
- chronic obstructive pulmonary disease
- bronchodilator reversibility
Funding The ECLIPSE study is funded by GlaxoSmithKline (http://ClinicalTrials.gov identifier: NCT00292552; GlaxoSmithKline study code SCO104960). The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study is funded by GlaxoSmithKline.
Competing interests PA has received speaker honoraria and travel assistance to attend scientific conferences from GlaxoSmithKline and Pfizer. AA has received travel assistance from GlaxoSmithKline to attend ECLIPSE study meetings and honoraria for speaking at conferences and participating in advisory boards from Almirall, Astra-Zeneca, Boheringer-Ingelheim, Chiesi, Esteve, GlaxoSmithKline, Medimmune, Novartis, Nycomed, Pfizer, Roche and Procter & Gamble. LDE, RT-S, BEM, CC and JY are full-time employees of GlaxoSmithKline and hold stock or stock options in GlaxoSmithKline. PMAC has received fees for serving on advisory boards for GlaxoSmithKline, AstraZeneca, Nycomed, Novartis and Boehringer Ingelheim, for expert testimony for Forest/Nycomed, and has received speaker fees from GlaxoSmithKline and Nycomed; he has received travel assistance from GlaxoSmithKline to attend ECLIPSE study meetings and from Boehringer Ingelheim to attend a scientific conference. HOC has received an honorarium for serving on the steering committee for the ECLIPSE project for GlaxoSmithKline. In addition, HC was the coinvestigator on two multi-centre studies sponsored by GlaxoSmithKline and has received travel expenses to attend meetings related to the project. HC has three contract service agreements with GlaxoSmithKline to quantify the CT scans in subjects with COPD and a service agreement with Spiration Inc to measure changes in lung volume in subjects with severe emphysema. HC was the coinvestigator (D Sin PI) on a Canadian Institutes of Health—Industry (Wyeth) partnership grant. HC has received a fee for speaking at a conference and related travel expenses from AstraZeneca (Australia). HC was the recipient of a GlaxoSmithKline Clinical Scientist Award (06/2010–07/2011). EKS received an honorarium for a talk on COPD genetics, grant support for two studies of COPD genetics, and consulting fees from GlaxoSmithKline. EKS received honoraria for talks and consulting fees from AstraZeneca. SR has received fees for serving on advisory boards, consulting or honoraria from Almirall, APT Pharma, Aradigm, Argenta, AstraZeneca, Boehringer Ingelheim, Chiesi, Dey, Forest, GlaxoSmithKline, HoffmanLaRoche, MedImmune, Mpex, Novartis, Nycomed, Oriel, Otsuka, Pearl, Pfizer, Pharmaxis, Merck and Talecris. DAL has received grant support, honoraria and consultancy fees from GlaxoSmithKline. JV has received fees for serving on advisory boards for GlaxoSmithKline, AstraZeneca, Nycomed and Boehringer Ingelheim, and has received speaker fees from GlaxoSmithKline, AstraZeneca, Pfizer, Boehringer-Ingelheim, Chiesi, Novartis and Nycomed; he has received travel assistance from GlaxoSmithKline to attend ECLIPSE study meetings; his wife has previously worked in pharmaceutical companies, including GlaxoSmithKline and AstraZeneca. WM has received travel assistance from GlaxoSmithKline to attend ECLIPSE study meetings. BC has received consulting fees from Altana, AstraZeneca, Boehringer-Ingelheim and GlaxoSmithKline; speaking fees from Altana, AstraZeneca, Boehringer-Ingelheim and GlaxoSmithKline; and grant support from Boehringer-Ingelheim and GlaxoSmithKline.
Ethics approval Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.