Article Text

Download PDFPDF

Original article
Airway responsiveness to methacholine and incidence of COPD: an international prospective cohort study
  1. Alessandro Marcon1,
  2. Francesca Locatelli1,
  3. Dirk Keidel2,3,
  4. Anna B Beckmeyer-Borowko2,3,
  5. Isa Cerveri4,
  6. Shyamali C Dharmage5,
  7. Elaine Fuertes6,7,8,
  8. Judith Garcia-Aymerich6,7,8,
  9. Joachim Heinrich9,10,
  10. Medea Imboden2,3,
  11. Christer Janson11,
  12. Ane Johannessen12,
  13. Bénédicte Leynaert13,
  14. Silvia Pascual Erquicia14,
  15. Giancarlo Pesce1,
  16. Emmanuel Schaffner2,3,
  17. Cecilie Svanes12,15,
  18. Isabel Urrutia14,
  19. Deborah Jarvis16,17,
  20. Nicole M Probst-Hensch2,3,
  21. Simone Accordini1
  22. on behalf of the Ageing Lungs in European Cohorts (ALEC) study
    1. 1 Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
    2. 2 Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland
    3. 3 University of Basel, Basel, Switzerland
    4. 4 Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
    5. 5 Allergy and Lung Health Unit, School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia
    6. 6 Institute for Global Health (ISGlobal), Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
    7. 7 Universitat Pompeu Fabra (UPF), Barcelona, Spain
    8. 8 CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
    9. 9 Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital of Ludwig Maximilians University, Munich, Germany
    10. 10 Comprehensive Pneumology Centre Munich, German Centre for Lung Research, Muenchen, Germany
    11. 11 Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden
    12. 12 Department of Global Public Health and Primary Care, Centre for International Health, University of Bergen, Bergen, Norway
    13. 13 Inserm UMR 1152, Pathophysiology and Epidemiology of Respiratory Diseases, University Paris Diderot Paris 7, Paris, France
    14. 14 Respiratory Department, Galdakao Hospital, OSI Barrualde-Galdakao, Biscay, Spain
    15. 15 Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway
    16. 16 MRC-PHE Centre for Environment and Health, Imperial College London, London, UK
    17. 17 Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UK
    1. Correspondence to Dr Alessandro Marcon, Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona 37134, Italy; alessandro.marcon{at}


    Background It has been debated, but not yet established, whether increased airway responsiveness can predict COPD. Recognising this link may help in identifying subjects at risk.

    Objective We studied prospectively whether airway responsiveness is associated with the risk of developing COPD.

    Methods We pooled data from two multicentre cohort studies that collected data from three time points using similar methods (European Community Respiratory Health Survey and Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults). We classified subjects (median age 37 years, 1st–3rd quartiles: 29–44) by their level of airway responsiveness using quintiles of methacholine dose–response slope at the first examination (1991–1994). Then, we excluded subjects with airflow obstruction at the second examination (1999–2003) and analysed incidence of COPD (postbronchodilator FEV1/FVC below the lower limit of normal) at the third examination (2010–2014) as a function of responsiveness, adjusting for sex, age, education, body mass index, history of asthma, smoking, occupational exposures and indicators of airway calibre.

    Results We observed 108 new cases of COPD among 4205 subjects during a median time of 9 years. Compared with the least responsive group (incidence rate 0.6 per 1000/year), adjusted incidence rate ratios for COPD ranged from 1.79 (95% CI 0.52 to 6.13) to 8.91 (95% CI 3.67 to 21.66) for increasing airway responsiveness. Similar dose–response associations were observed between smokers and non-smokers, and stronger associations were found among subjects without a history of asthma or asthma-like symptoms.

    Conclusions Our study suggests that increased airway responsiveness is an independent risk factor for COPD. Further research should clarify whether early treatment in patients with high responsiveness can slow down disease progression.

    • copd epidemiology
    • clinical epidemiology
    • asthma

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

    View Full Text

    Statistics from


    • Contributors AM and SA conceived the study. AM designed the study and drafted the analysis plan and the first version of the manuscript. FL and AM performed the statistical analysis. All the authors contributed in the collection of data in/from the original studies, discussion of the statistical analysis plan and interpretation of study results. All the authors critically reviewed and approved the final version of the manuscript. The corresponding author had full access to all the data and had final responsibility for the decision to submit for publication.

    • Funding The ALEC Study is funded by the European Union’s Horizon 2020 Research and Innovation programme under grant agreement no. 633212. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. The SAPALDIA cohort has been funded since 1991 primarily by the Swiss National Science Foundation (grants no 33CS30-148470/1&2, 33CSCO-134276/1, 33CSCO-108796, 324730_135673, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, PMPDP3_129021/1, PMPDP3_141671/1). Other national funders who supported data collection in the original studies are listed in the supplement.

    • Disclaimer The funders had no role in the writing of the manuscript or the decision to submit it for publication.

    • Competing interests DJ has received support from the European Union, the Medical Research Council and Asthma UK. Other authors have no competing interests to declare.

    • Patient consent Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators The Ageing Lungs in European Cohorts (ALEC) study: The study leader is Deborah Jarvis. The manuscript was done under ALEC Workpackage 4 led by Judith Garcia-Aymerich. Other Workpackage leaders in ALEC are Cecilie Svanes, John Henderson (Department of Community Based Medicine, University of Bristol, Bristol, UK), Nicole Probst-Hensch and Cosetta Minelli (National Heart and Lung Institute, Imperial College London, London, UK). The principal investigators and team members of the original studies are reported in the supplement. The ALEC International Scientific Advisory Board is Marike Boezen (University Medical Center Groningen, University of Groningen, Groningen, The Netherlands), Bernice Elger (Institute for Biomedical Ethics, University of Basel, Basel, Switzerland), Bo Alexander Gleditsch (The Norwegian Asthma and Allergy Association, Norway), Bas Heijmans (Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands), Isabelle Romieu (National Institute of Public Health, Cuernavaca, Mexico; and Emory University, Atlanta, GA, USA) and John Thompson (Department of Health Sciences, University of Leicester, Leicester, UK).

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.