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Original article
Biomarkers and clinical outcomes in COPD: a systematic review and meta-analysis
  1. Jilles M Fermont1,2,
  2. Katya L Masconi2,
  3. Magnus T Jensen3,4,
  4. Renata Ferrari5,
  5. Valéria A P Di Lorenzo6,
  6. Jacob M Marott4,
  7. Philipp Schuetz7,
  8. Henrik Watz8,
  9. Benjamin Waschki8,
  10. Hana Müllerova9,
  11. Michael I Polkey10,
  12. Ian B Wilkinson1,
  13. Angela M Wood2
  1. 1 Department of Medicine, Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK
  2. 2 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  3. 3 Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
  4. 4 Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark
  5. 5 Division of Pulmonology, Department of Internal Medicine, Botucatu Medical School, Univ Estadual Paulista, UNESP, Botucatu, Brazil
  6. 6 Department of Physiotherapy, Federal University of Sao Carlos (UFSCar), São Carlos/São Paulo, Brazil
  7. 7 Internal Medicine and Emergency Medicine, Kantonsspital Aarau, Univertsity of Basel, Aarau, Switzerland
  8. 8 LungenClinic Grosshansorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany
  9. 9 Worldwide Epidemiology, GlaxoSmithKline R&D, Uxbridge, UK
  10. 10 Respiratory Muscle Laboratory, Royal Brompton Hospital, London, UK
  1. Correspondence to Mr. Jilles M Fermont, Department of Medicine, Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge CB1 8RN, UK; jmf88{at}


Background Conventional measures to evaluate COPD may fail to capture systemic problems, particularly musculoskeletal weakness and cardiovascular disease. Identifying these manifestations and assessing their association with clinical outcomes (ie, mortality, exacerbation and COPD hospital admission) is of increasing clinical importance.

Objective To assess associations between 6 min walk distance (6MWD), heart rate, fibrinogen, C reactive protein (CRP), white cell count (WCC), interleukins 6 and 8 (IL-6 and IL-8), tumour necrosis factor-alpha, quadriceps maximum voluntary contraction, sniff nasal inspiratory pressure, short physical performance battery, pulse wave velocity, carotid intima-media thickness and augmentation index and clinical outcomes in patients with stable COPD.

Methods We systematically searched electronic databases (August 2018) and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled HRs, following Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Results Shorter 6MWD and elevated heart rate, fibrinogen, CRP and WCC were associated with higher risk of mortality. Pooled HRs were 0.80 (95% CI 0.73 to 0.89) per 50 m longer 6MWD, 1.10 (95% CI 1.02 to 1.18) per 10 bpm higher heart rate, 3.13 (95% CI 2.14 to 4.57) per twofold increase in fibrinogen, 1.17 (95% CI 1.06 to 1.28) per twofold increase in CRP and 2.07 (95% CI 1.29 to 3.31) per twofold increase in WCC. Shorter 6MWD and elevated fibrinogen and CRP were associated with exacerbation, and shorter 6MWD, higher heart rate, CRP and IL-6 were associated with hospitalisation. Few studies examined associations with musculoskeletal measures.

Conclusion Findings suggest 6MWD, heart rate, CRP, fibrinogen and WCC are associated with clinical outcomes in patients with stable COPD. Use of musculoskeletal measures to assess outcomes in patients with COPD requires further investigation.

Trial registration number CRD42016052075.

  • copd epidemiology

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  • Contributors JMF and AMW designed the study. JMF, MTJ, RF, VAPDL, JLM, PS, HW, BW and HM contributed to the data collection. JMF and KLM extracted the data. JMF conducted the analysis and produced the results figures and tables. AMW and KLM provided statistical support. JMF wrote the initial draft of the manuscript. KLM, MIP, IBW and AMW contributed to the writing of the manuscript. All coauthors read and commented on the manuscript.

  • Funding This study was funded by GlaxoSmithKline (RG79358).

  • Disclaimer The views and opinions expressed are those of the authors and do not necessarily reflect those of the University of Cambridge. The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.

  • Competing interests GlaxoSmithKline, a consortium partner, funded JMF. HM is an employee of GSK and own shares and stock options of GSK Plc. MIP received grants from GSK outside the submitted work. IBW received grants from GSK during the conduct of the study and outside the submitted work.

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

  • Data sharing statement Most of the data used in the meta-analysis are publicly available. Where data were unpublished and obtained from the corresponding author, summary statistics can be requested.

  • Patient consent for publication Not required.

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