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Original research
Association between COPD exacerbations and lung function decline during maintenance therapy
  1. Marjan Kerkhof1,
  2. Jaco Voorham1,
  3. Paul Dorinsky2,
  4. Claudia Cabrera3,4,
  5. Patrick Darken5,
  6. Janwillem WH Kocks1,6,
  7. Mohsen Sadatsafavi7,
  8. Don D Sin7,8,
  9. Victoria Carter1,
  10. David B Price1,9
  1. 1Observational and Pragmatic Research Institute, Singapore
  2. 2AstraZeneca, Durham, North Carolina, USA
  3. 3AstraZeneca, Gothenburg, Sweden
  4. 4Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
  5. 5AstraZeneca, 280 Headquarters Plaza, East Tower, Morristown, NJ 07960, USA
  6. 6General Practitioners Research Institute, Groningen, The Netherlands
  7. 7Respiratory Evaluation Sciences Program, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
  8. 8Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada
  9. 9Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
  1. Correspondence to Professor David B Price, Academic Primary Care, University of Aberdeen, Aberdeen AB25 2ZD, UK; dprice{at}


Background Little is known about the impact of exacerbations on COPD progression or whether inhaled corticosteroid (ICS) use and blood eosinophil count (BEC) affect progression. We aimed to assess this in a prospective observational study.

Methods The study population included patients with mild to moderate COPD, aged ≥35 years, with a smoking history, who were followed up for ≥3 years from first to last spirometry recording using two large UK electronic medical record databases: Clinical Practice Research Datalink (CPRD) and Optimum Patient Care Research Database (OPCRD). Multilevel mixed-effects linear regression models were used to determine the relationship between annual exacerbation rate following initiation of therapy (ICS vs non-ICS) and FEV1 decline. Effect modification by blood eosinophils was studied through interaction terms.

Results Of 12178 patients included (mean age 66 years; 48% female), 8981 (74%) received ICS. In patients with BEC ≥350 cells/µL not on ICS, each exacerbation was associated with subsequent acceleration of FEV1 decline of 19.4 mL/year (95% CI 12.0 to 26.7, p<0.0001). This excess decline was reduced by 15.1 mL/year (6.6 to 23.6) to 4.3 mL/year (1.9 to 6.7, p<0.0001) in those with BEC ≥350 cells/µL treated with ICS.

Conclusion Exacerbations are associated with a more rapid loss of lung function among COPD patients with elevated blood eosinophils, defined as ≥350 cells/µL, not treated with ICS. More aggressive prevention of exacerbations using ICS in such patients may prevent excess loss of lung function.

  • COPD exacerbations
  • lung physiology
  • eosinophil biology
  • COPD pharmacology

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, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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  • Contributors DBP and MK led the study design process, and all authors provided input into the research design. MK was responsible for data acquisition and analyses. MS provided statistical advice based on previous work (Zafari et al, CMAJ, 2016). MK developed the first draft of the manuscript. All authors contributed to the interpretation of the data, reviewed and edited drafts of the manuscript, and approved the final draft of the manuscript for submission.

  • Funding This study was funded by AstraZeneca.

  • Competing interests MK, JV, VC and JWHk are employees of the Observational and Pragmatic Research Institute, which conducted this study and which has conducted paid research in respiratory disease on behalf of the following other organisations in the past 5 years: Aerocrine, AKL Research and Development Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, Zentiva (a Sanofi company). DBP has board membership with Aerocrine, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Mundipharma, Napp, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; consultancy agreements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from Aerocrine, AKL Research and Development Ltd, AstraZeneca, Boehringer Ingelheim, British Lung Foundation, Chiesi, Mylan, Mundipharma, Napp, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service, Zentiva (Sanofi Generics); payment for lectures/speaking engagements from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Merck, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Skyepharma, Teva Pharmaceuticals; payment for manuscript preparation from Mundipharma, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from Aerocrine, AstraZeneca, Boehringer Ingelheim, Mundipharma, Napp, Novartis, Teva Pharmaceuticals; funding for patient enrolment or completion of research from Chiesi, Novartis, Teva Pharmaceuticals, Zentiva (Sanofi Generics); stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); and is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, and Health Technology Assessment. CC, PD and PD are employees of AstraZeneca. DDS has received honoraria for speaking engagements from Boehringer Ingelheim (BI), AstraZeneca (AZ) and Novartis. He has received research funding from Merck, BI and AZ for work related to COPD and has sat on advisory boards of AZ, BI and Sanofi. MS has received honoraria for speaking engagements from Boehringer Ingelheim, AstraZeneca and GlaxoSmithKline.

  • Patient consent for publication Not required.

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

  • Data availability statement The dataset supporting the conclusions of this article was derived from the Clinical Practice Research Datalink ( and the Optimum Patient Care Research Database ( The CPRD has broad National Research Ethics Service Committee (NRES) ethics approval for purely observational research using the primary care data and established data linkages. The OPCRD has ethical approval from the National Health Service (NHS) Research Authority to hold and process anonymised research data (Research Ethics Committee reference: 15/EM/0150). This study was approved by the Anonymised Data Ethics Protocols and Transparency (ADEPT) committee – the independent scientific advisory committee for the OPCRD, and the Independent Scientific Advisory Committee (ISAC) for the CPRD. The authors do not have permission to give public access to the study dataset; researchers may request access to CPRD or OPCRD data for their own purposes. Access to CPRD can be made via the CPRD website ( or via the enquiries email Access to OCPRD can be made via the OCPRD website ( or via the enquiries email The study was designed, implemented, and registered in accordance with the criteria of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS19879).

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