Abstract
Introduction: Infection is a key component of the pathophysiology of bronchiectasis. Characterisation of the microbiome offers a higher degree of sensitivity and resolution than traditional culture to evaluate the importance of infection in determining the risk of exacerbation and long-term outcomes, including mortality, in bronchiectasis.
Methods: Sputum samples from 281 patients with bronchiectasis included in a longitudinal cohort of patients from two hospitals in the East of Scotland underwent 16S rRNA amplicon sequencing. Sputum supernatant was used to measure neutrophil elastase activity by immunoassay. Patients were enrolled from 2012-2015 and followed up until January 2019 for long term outcomes. Repeat sputum samples were obtained at exacerbation and stable visits during follow-up. Dominant genera was assigned based on a previously published method. Microbiome characteristics were compared to measures of clinical disease severity and long term outcomes.
Results: In both stable bronchiectasis and during exacerbations, a microbiome dominated by Proteobacteria and Firmicutes was observed. Beta diversity analysis indicated that patients' microbiomes were relatively stable over time and showed less variation than that observed between patients. During disease stability, reduced Shannon-Wiener Diversity Index was associated with higher bronchiectasis severity (P<0.0001), more exacerbations (P=0.03) and more severe exacerbations requiring hospitalisations (P=0.02). Patients in whom the dominant genera was Pseudomonas were at increased risk of mortality (Hazard ratio 3.12, 95% CI 1.32-7.38, P=0.009) and had more frequent exacerbations (Incident rate ratio 3.11 95% CI 1.56-6.20, P=0.001) during follow-up. Changes in the microbiome at exacerbation were heterogeneous but exacerbations associated with an increase in pathogenic Proteobacteria from baseline were associated with an increase in sputum neutrophil elastase activity (r=0.30, P=0.0002) suggesting a subset of neutrophilic-bacterial exacerbations accounting for 41.5% of events.
Conclusion: A reduction in microbiome diversity, particularly associated with Pseudomonas or Proteobacteria dominance is associated with greater disease severity, increased frequency and severity of exacerbations, and a higher risk of mortality.
Methods: Sputum samples from 281 patients with bronchiectasis included in a longitudinal cohort of patients from two hospitals in the East of Scotland underwent 16S rRNA amplicon sequencing. Sputum supernatant was used to measure neutrophil elastase activity by immunoassay. Patients were enrolled from 2012-2015 and followed up until January 2019 for long term outcomes. Repeat sputum samples were obtained at exacerbation and stable visits during follow-up. Dominant genera was assigned based on a previously published method. Microbiome characteristics were compared to measures of clinical disease severity and long term outcomes.
Results: In both stable bronchiectasis and during exacerbations, a microbiome dominated by Proteobacteria and Firmicutes was observed. Beta diversity analysis indicated that patients' microbiomes were relatively stable over time and showed less variation than that observed between patients. During disease stability, reduced Shannon-Wiener Diversity Index was associated with higher bronchiectasis severity (P<0.0001), more exacerbations (P=0.03) and more severe exacerbations requiring hospitalisations (P=0.02). Patients in whom the dominant genera was Pseudomonas were at increased risk of mortality (Hazard ratio 3.12, 95% CI 1.32-7.38, P=0.009) and had more frequent exacerbations (Incident rate ratio 3.11 95% CI 1.56-6.20, P=0.001) during follow-up. Changes in the microbiome at exacerbation were heterogeneous but exacerbations associated with an increase in pathogenic Proteobacteria from baseline were associated with an increase in sputum neutrophil elastase activity (r=0.30, P=0.0002) suggesting a subset of neutrophilic-bacterial exacerbations accounting for 41.5% of events.
Conclusion: A reduction in microbiome diversity, particularly associated with Pseudomonas or Proteobacteria dominance is associated with greater disease severity, increased frequency and severity of exacerbations, and a higher risk of mortality.
| Original language | English |
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| Publisher | Preprints with The Lancet |
| DOIs | |
| Publication status | Published - 6 Nov 2019 |