The sputum microbiome, airway inflammation, and mortality in chronic obstructive pulmonary disease

J Allergy Clin Immunol. 2021 Jan;147(1):158-167. doi: 10.1016/j.jaci.2020.02.040. Epub 2020 Apr 28.


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 FEV1 (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.

Keywords: COPD; Haemophilus; Microbiome; eosinophil; phenotype.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Disease-Free Survival
  • Female
  • Humans
  • Inflammation
  • Longitudinal Studies
  • Male
  • Microbiota*
  • Proteobacteria / classification*
  • Pulmonary Disease, Chronic Obstructive* / microbiology
  • Pulmonary Disease, Chronic Obstructive* / mortality
  • Sputum / microbiology*
  • Survival Rate