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Sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the COPDMAP study
  1. Zhang Wang1,
  2. Richa Singh2,
  3. Bruce E Miller3,
  4. Ruth Tal-Singer3,
  5. Stephanie Van Horn4,
  6. Lynn Tomsho4,
  7. Alexander Mackay2,
  8. James P Allinson2,
  9. Adam J Webb5,
  10. Anthony J Brookes5,
  11. Leena M George6,
  12. Bethan Barker6,
  13. Umme Kolsum7,
  14. Louise E Donnelly2,
  15. Kylie Belchamber2,
  16. Peter J Barnes2,
  17. Dave Singh7,
  18. Christopher E Brightling6,
  19. Gavin C Donaldson2,
  20. Jadwiga A Wedzicha2,
  21. James R Brown1
  22. on behalf of COPDMAP
  1. 1Computational Biology, Target Sciences, Research and Development (R&D), GlaxoSmithKline, Collegeville, Pennsylvania, USA
  2. 2National Heart and Lung Institute, Imperial College London, London, UK
  3. 3Respiratory Therapy Area Unit, R&D, GlaxoSmithKline, King of Prussia, Pennsylvania, USA
  4. 4Target and Platform Validation, Target Sciences,, GlaxoSmithKline, Collegeville, Pennsylvania, USA
  5. 5Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
  6. 6Institute for Lung Health, University of Leicester, Leicester, UK
  7. 7Centre for Respiratory Medicine and Allergy, University of Manchester and University Hospital of South Manchester, Manchester, UK
  1. Correspondence to Dr James R Brown, Computational Biology, Target Sciences, Research and Development (R&D), GlaxoSmithKline (GSK), Collegeville, PA 19426, USA; james.r.brown{at}gsk.com

Abstract

Background Recent studies suggest that lung microbiome dysbiosis, the disease associated disruption of the lung microbial community, might play a key role in chronic obstructive pulmonary disease (COPD) exacerbations. However, characterising temporal variability of the microbiome from large longitudinal COPD cohorts is needed to better understand this phenomenon.

Methods We performed a 16S ribosomal RNA survey of microbiome on 716 sputum samples collected longitudinally at baseline and exacerbations from 281 subjects with COPD at three UK clinical centres as part of the COPDMAP consortium.

Results The microbiome composition was similar among centres and between stable and exacerbations except for a small significant decrease of Veillonella at exacerbations. The abundance of Moraxella was negatively associated with bacterial alpha diversity. Microbiomes were distinct between exacerbations associated with bacteria versus eosinophilic airway inflammation. Dysbiosis at exacerbations, measured as significant within subject deviation of microbial composition relative to baseline, was present in 41% of exacerbations. Dysbiosis was associated with increased exacerbation severity indicated by a greater fall in forced expiratory volume in one second, forced vital capacity and a greater increase in CAT score, particularly in exacerbations with concurrent eosinophilic inflammation. There was a significant difference of temporal variability of microbial alpha and beta diversity among centres. The variation of beta diversity significantly decreased in those subjects with frequent historical exacerbations.

Conclusions Microbial dysbiosis is a feature of some exacerbations and its presence, especially in concert with eosinophilic inflammation, is associated with more severe exacerbations indicated by a greater fall in lung function.

Trial registration number Results, NCT01620645.

  • copd pathology
  • copd exacerbations
  • bacterial infection

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Footnotes

  • ZW and RS contributed equally.

  • Contributors ZW, RS, BEM, RT-S, LED, KB, PJB, DS, CEB, GCD, JAW and JRB contributed to the study conception and design. AM, JPA, AJW, AJB, LMG, BB, UK, LED, KB, DS, CEB, GCD and JAW coordinated the collection of sputum samples and clinical data. SVH and LT performed microbiome DNA purification and sequencing. ZW performed microbiome computational analyses. AJB performed other statistical analysis. ZW wrote the initial draft of the manuscript with additional content provided by RS, RT-S, PJB, CEB and JRB and critical revisions from all authors. All authors read and approved the final version of the manuscript.

  • Funding COPD MAP (MRC/ABPIInflammation and Immunology Initiative) was funded by the Medical Research Council (UK), Additional supportfor this study was provided by GSKand the Leicester NIHR BRC, University of Leicester, Leicester,UK. This article presentsindependent research funded by the National Institute for Health Research(NIHR).

  • Disclaimer The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

  • Competing interests ZW, BEM, RT-S, SVH, LT and JRB were employees and shareholders in GlaxoSmithKline PLC at the time of this study. Other authors have no competing interest to declare.

  • Ethics approval Imperial College London, University of Leicester and University of Manchester Research Ethics Committee.

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

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