Jerome Bouquet1, David E Tabor2, Jonathan S Silver3, Varsha Nair2, Andrey Tovchigrechko4, M Pamela Griffin3, Mark T Esser5, Bret R Sellman5, Hong Jin2. 1. Clinical Pharmacology & Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, South San Francisco, USA. jerome.bouquet@astrazeneca.com. 2. Clinical Pharmacology & Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, South San Francisco, USA. 3. Respiratory Inflammation and Autoimmunity, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, USA. 4. Data Science and AI, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, USA. 5. Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, USA.
Abstract
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by frequent exacerbation phenotypes independent of disease stage. Increasing evidence shows that the microbiota plays a role in disease progression and severity, but long-term and international multicenter assessment of the variations in viral and bacterial communities as drivers of exacerbations are lacking. METHODS: Two-hundred severe COPD patients from Europe and North America were followed longitudinally for 3 years. We performed nucleic acid detection for 20 respiratory viruses and 16S ribosomal RNA gene sequencing to evaluate the bacterial microbiota in 1179 sputum samples collected at stable, acute exacerbation and follow-up visits. RESULTS: Similar viral and bacterial taxa were found in patients from the USA compared to Bulgaria and Czech Republic but their microbiome diversity was significantly different (P < 0.001) and did not impact exacerbation rates. Virus infection was strongly associated with exacerbation events (P < 5E-20). Human rhinovirus (13.1%), coronavirus (5.1%) and influenza virus (3.6%) constitute the top viral pathogens in triggering exacerbation. Moraxella and Haemophilus were 5-fold and 1.6-fold more likely to be the dominating microbiota during an exacerbation event. Presence of Proteobacteria such as Pseudomonas or Staphylococcus amongst others, were associated with exacerbation events (OR > 0.17; P < 0.02) but more strongly associated with exacerbation frequency (OR > 0.39; P < 4E-10), as confirmed by longitudinal variations and biotyping of the bacterial microbiota, and suggesting a role of the microbiota in sensitizing the lung. CONCLUSIONS: This study highlights bacterial taxa in lung sensitization and viral triggers in COPD exacerbations. It provides a global overview of the diverse targets for drug development and explores new microbiome analysis methods to guide future patient management applications.
BACKGROUND:Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by frequent exacerbation phenotypes independent of disease stage. Increasing evidence shows that the microbiota plays a role in disease progression and severity, but long-term and international multicenter assessment of the variations in viral and bacterial communities as drivers of exacerbations are lacking. METHODS: Two-hundred severe COPDpatients from Europe and North America were followed longitudinally for 3 years. We performed nucleic acid detection for 20 respiratory viruses and 16S ribosomal RNA gene sequencing to evaluate the bacterial microbiota in 1179 sputum samples collected at stable, acute exacerbation and follow-up visits. RESULTS: Similar viral and bacterial taxa were found in patients from the USA compared to Bulgaria and Czech Republic but their microbiome diversity was significantly different (P < 0.001) and did not impact exacerbation rates. Virus infection was strongly associated with exacerbation events (P < 5E-20). Human rhinovirus (13.1%), coronavirus (5.1%) and influenza virus (3.6%) constitute the top viral pathogens in triggering exacerbation. Moraxella and Haemophilus were 5-fold and 1.6-fold more likely to be the dominating microbiota during an exacerbation event. Presence of Proteobacteria such as Pseudomonas or Staphylococcus amongst others, were associated with exacerbation events (OR > 0.17; P < 0.02) but more strongly associated with exacerbation frequency (OR > 0.39; P < 4E-10), as confirmed by longitudinal variations and biotyping of the bacterial microbiota, and suggesting a role of the microbiota in sensitizing the lung. CONCLUSIONS: This study highlights bacterial taxa in lung sensitization and viral triggers in COPD exacerbations. It provides a global overview of the diverse targets for drug development and explores new microbiome analysis methods to guide future patient management applications.
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