The Sputum Microbiome, Airway Inflammation and Mortality in Chronic Obstructive Pulmonary Disease

TY - JOUR

T1 - The Sputum Microbiome, Airway Inflammation and Mortality in Chronic Obstructive Pulmonary Disease

AU - Dicker, Alison J.

AU - Huang, Jeffrey T. J.

AU - Lonergan, Mike

AU - Keir, Holly R.

AU - Fong, Christopher J.

AU - Tan, Brandon

AU - Cassidy, Andrew J.

AU - Finch, Simon

AU - Mullerova, Hana

AU - Miller, Bruce E.

AU - Tal-Singer, Ruth

AU - Chalmers, James D.

N1 - Funding Information: We acknowledge Mr Alun Barton at the Biomarker and Drug Analysis Core Laboratory (University of Dundee) for technical assistance and Dr Robert Dickson for his helpful comments on the article. Publisher Copyright: © 2020 American Academy of Allergy, Asthma & Immunology

PY - 2021/1

Y1 - 2021/1

N2 - Background: The sputum microbiome has a potential role in disease phenotyping and risk stratification in chronic obstructive pulmonary disease (COPD), but few large longitudinal cohort studies exist. Objective: Our aim was to investigate the COPD sputum microbiome and its association with inflammatory phenotypes and mortality.Methods: 16S ribosomal RNA gene sequencing was performed on sputum from 253 clinically stable COPD patients (4-year median follow-up). Samples were classified as Proteobacteria or Firmicutes (phylum level) and Haemophilus or Streptococcus (genus level) dominant. Alpha diversity was measured by using Shannon-Wiener diversity and Berger-Parker dominance indices. Survival was modeled by using Cox proportional hazards regression. A subset of 78 patients had label-free liquid chromatography with tandem mass spectrometry performed, with partial least square discriminant analysis integrating clinical, microbiome, and proteomics data.Results: Proteobacteria dominance and lower diversity was associated with more severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease classification system (P =.0015), more frequent exacerbations (P =.0042), blood eosinophil level less than or equal to 100 cells/μL (P <.0001), and lower FEV 1 (P =.026). Blood eosinophil counts showed a positive relationship with percent of Firmicutes and Streptococcus and a negative association with percent Proteobacteria and Haemophilus. Proteobacteria dominance was associated with increased mortality compared with Firmicutes-dominated or balanced microbiome profiles (hazard ratio = 2.58; 95% CI = 1.43-4.66; P =.0017 and hazard ratio = 7.47; 95% CI = 1.02-54.86; P =.048, respectively). Integrated omics analysis showed significant associations between Proteobacteria dominance and the neutrophil activation pathway in sputum.Conclusion: The sputum microbiome is associated with clinical and inflammatory phenotypes in COPD. Reduced microbiome diversity, associated with Proteobacteria (predominantly Haemophilus) dominance, is associated with neutrophil-associated protein profiles and an increased risk of mortality.

AB - Background: The sputum microbiome has a potential role in disease phenotyping and risk stratification in chronic obstructive pulmonary disease (COPD), but few large longitudinal cohort studies exist. Objective: Our aim was to investigate the COPD sputum microbiome and its association with inflammatory phenotypes and mortality.Methods: 16S ribosomal RNA gene sequencing was performed on sputum from 253 clinically stable COPD patients (4-year median follow-up). Samples were classified as Proteobacteria or Firmicutes (phylum level) and Haemophilus or Streptococcus (genus level) dominant. Alpha diversity was measured by using Shannon-Wiener diversity and Berger-Parker dominance indices. Survival was modeled by using Cox proportional hazards regression. A subset of 78 patients had label-free liquid chromatography with tandem mass spectrometry performed, with partial least square discriminant analysis integrating clinical, microbiome, and proteomics data.Results: Proteobacteria dominance and lower diversity was associated with more severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease classification system (P =.0015), more frequent exacerbations (P =.0042), blood eosinophil level less than or equal to 100 cells/μL (P <.0001), and lower FEV 1 (P =.026). Blood eosinophil counts showed a positive relationship with percent of Firmicutes and Streptococcus and a negative association with percent Proteobacteria and Haemophilus. Proteobacteria dominance was associated with increased mortality compared with Firmicutes-dominated or balanced microbiome profiles (hazard ratio = 2.58; 95% CI = 1.43-4.66; P =.0017 and hazard ratio = 7.47; 95% CI = 1.02-54.86; P =.048, respectively). Integrated omics analysis showed significant associations between Proteobacteria dominance and the neutrophil activation pathway in sputum.Conclusion: The sputum microbiome is associated with clinical and inflammatory phenotypes in COPD. Reduced microbiome diversity, associated with Proteobacteria (predominantly Haemophilus) dominance, is associated with neutrophil-associated protein profiles and an increased risk of mortality.

KW - COPD

KW - Haemophilus

KW - Microbiome

KW - eosinophil

KW - phenotype

UR - https://www.scopus.com/pages/publications/85086942824

U2 - 10.1016/j.jaci.2020.02.040

DO - 10.1016/j.jaci.2020.02.040

M3 - Article

C2 - 32353489

SN - 0091-6749

VL - 147

SP - 158

EP - 167

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 1

ER -