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Chronic obstructive pulmonary disease
Serum biomarkers and outcomes in patients with moderate COPD: a substudy of the randomised SUMMIT trial
  1. Bartolome R Celli1,
  2. Julie A Anderson2,
  3. Robert Brook3,
  4. Peter Calverley4,
  5. Nicholas J Cowans5,6,
  6. Courtney Crim7,
  7. Ian Dixon5,6,
  8. Victor Kim8,
  9. Fernando J Martinez9,
  10. Andrea Morris7,
  11. David E Newby10,
  12. Julie Yates7 and
  13. Joergen Vestbo11
  1. 1Pulmonary and Critical Care Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
  2. 2Research & Development, GlaxoSmithKline Plc Stockley Park, Uxbridge, Middlesex, UK
  3. 3Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA
  4. 4Department of Medicine, Clinical Sciences Centre, University of Liverpool, University Hospital Aintree, Liverpool, Liverpool, UK
  5. 5GlaxoSmithKline Plc Stockley Park, Uxbridge, Middlesex, UK
  6. 6Veramed Ltd, Twickenham, UK
  7. 7GlaxoSmithKline Research Triangle Park, Research Triangle Park, North Carolina, USA
  8. 8Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
  9. 9Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine Samuel J Wood Library, New York City, New York, USA
  10. 10British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Edinburgh, UK
  11. 11Division of Infection, Immunity and Respiratory Medicine and Allergy, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  1. Correspondence to Dr Bartolome R Celli; bcelli{at}copdnet.org

Abstract

Rationale Systemic levels of C reactive protein (CRP), surfactant protein D (SPD), fibrinogen, soluble receptor of activated glycogen end-product (sRAGE) and club cell protein 16 (CC-16) have been associated with chronic obstructive pulmonary disease (COPD) outcomes. However, they require validation in different cohorts.

Objectives Relate systemic levels of those proteins to forced expiratory volume in 1 s (FEV1) decline, exacerbations, hospitalisations and mortality in COPD patients (FEV1 of ≥50 and ≤70% predicted) and heightened cardiovascular risk in a substudy of the Study to Understand Mortality and MorbidITy trial.

Methods Participants were randomised to daily inhalations of placebo, vilanterol 25 µg (VI), fluticasone furoate 100 µg (FF) or their combination (VI 25/FF 100) and followed quarterly until 1000 deaths in the overall 16 485 participants occurred. Biomarker blood samples were available from 1673 patients. The FEV1 decline (mL/year), COPD exacerbations, hospitalisations and death were determined. Associations between biomarker levels and outcomes were adjusted by age and gender.

Results Systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen did not relate to baseline FEV1, FEV1 decline, exacerbations or hospitalisations. Fibrinogen and CRP were related to mortality over a median follow-up of 2.3 years. Only the CC-16 changed with study therapy (VI, FF and FF/VI, p<0.01) at 3 months.

Conclusions In COPD, systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen were not associated with FEV1 decline, exacerbations or hospitalisations. These results cast doubts about the clinical usefulness of the systemic levels of these proteins as surrogate markers of these COPD outcomes. The study confirms that CRP and fibrinogen are associated with increased risk of death in patients with COPD.

Trial registration number NCT01313676.

  • chronic obstructive pulmonary disease
  • mortality
  • biomarkers
  • Lung function decline

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: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjresp-2019-000431

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    Footnotes

    • Contributors Study design: BCR, JAA, RB, PC, CC, ID, FJM, DEN, JY and JV. Data collection: JAA, CC, NJC and JY. Database search: N/A. Data analysis/interpretation: BCR, JAA, RB, PC, NJC, CC, ID, VK, FJM, AM, DEN, JY and JV. Writing/reviewing of the manuscript: BCR, JAA, RB, PC, NJC, CC, ID, VK, FJM, AM, DEN, JY and JV. Final approval of the manuscript: all authors.

    • Funding This work was supported by GlaxoSmithKline plc.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval All patients provided written informed consent. The study was approved by local ethics committees and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Members of the Steering Committee Jørgen Vestbo (cochair, UK), Robert Brook (USA), Peter Calverley (UK), Bartolome Celli (USA), Fernando Martinez (USA), David Newby (UK), Courtney Crim, (cochair, GlaxoSmithKline plc, USA), Julie Anderson (GlaxoSmithKline plc, UK) and Julie Yates (GlaxoSmithKline plc, USA). Members of the Independent Data Monitoring Committee Peter Lange (chair, Denmark), Richard Kay (UK), Mark Dransfield (USA) and Sanjay Rajagopalan (USA). Members of the Clinical Endpoint Committee Robert Wise (chair, USA), Dennis Niewoehner (USA), Camilo Gomez (USA), Sheldon Madger (Canada), Martin Denvir (UK) and Pierre Amarenco (France).

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

    • Data availability statement Information on GSK’s data sharing commitments and requesting access to anonymised individual participant data and associated documents can be found at www.clinicalstudydatarequest.com