Biological exacerbation clusters demonstrate asthma and chronic obstructive pulmonary disease overlap with distinct mediator and microbiome profiles

Michael A Ghebre, Pee Hwee Pang, Sarah Diver, Dhananjay Desai, Mona Bafadhel, Koirobi Haldar, Tatiana Kebadze, Suzanne Cohen, Paul Newbold, Laura Rapley, Joanne Woods, Paul Rugman, Ian D Pavord, Sebastian L Johnston, Michael Barer, Richard D May, Christopher E Brightling, Michael A Ghebre, Pee Hwee Pang, Sarah Diver, Dhananjay Desai, Mona Bafadhel, Koirobi Haldar, Tatiana Kebadze, Suzanne Cohen, Paul Newbold, Laura Rapley, Joanne Woods, Paul Rugman, Ian D Pavord, Sebastian L Johnston, Michael Barer, Richard D May, Christopher E Brightling

Abstract

Background: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous.

Objective: We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations.

Methods: Patients with severe asthma or moderate-to-severe COPD were recruited prospectively to a single center. Sputum mediators were available in 32 asthmatic patients and 73 patients with COPD assessed at exacerbation. Biologic clusters were determined by using factor and cluster analyses on a panel of sputum mediators. Patterns of clinical parameters, sputum mediators, and microbiome communities were assessed across the identified clusters.

Results: The asthmatic patients and patients with COPD had different clinical characteristics and inflammatory profiles but similar microbial ecology. Three exacerbation biologic clusters were identified. Cluster 1 was COPD predominant, with 27 patients with COPD and 7 asthmatic patients exhibiting increased blood and sputum neutrophil counts, proinflammatory mediators (IL-1β, IL-6, IL-6 receptor, TNF-α, TNF receptors 1 and 2, and vascular endothelial growth factor), and proportions of the bacterial phylum Proteobacteria. Cluster 2 had 10 asthmatic patients and 17 patients with COPD with increased blood and sputum eosinophil counts, type 2 mediators (IL-5, IL-13, CCL13, CCL17, and CCL26), and proportions of the bacterial phylum Bacteroidetes. Cluster 3 had 15 asthmatic patients and 29 patients with COPD with increased type 1 mediators (CXCL10, CXCL11, and IFN-γ) and proportions of the phyla Actinobacteria and Firmicutes.

Conclusions: A biologic clustering approach revealed 3 subgroups of asthma and COPD exacerbations, each with different percentages of patients with overlapping asthma and COPD. The sputum mediator and microbiome profiles were distinct between clusters.

Keywords: Asthma; asthma and chronic obstructive pulmonary disease heterogeneity; chronic obstructive pulmonary disease; factor and cluster analyses; inflammatory profiles; microbiome abundances; phylum and genus levels.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Fig 1
Fig 1
The 3 identified exacerbation biologic clusters presented using the subjects' discriminant scores. Open triangles indicate asthmatic patients, and solid circles indicate patients with COPD. Orange, green, and purple colors represent clusters 1, 2, and 3, respectively.
Fig 2
Fig 2
Alpha diversity at the phylum level (using the Shannon-Weiner index): proportion and patterns of relative abundance of the most abundant phyla and P/F ratio in log format (base 10) across the identified exacerbation biologic clusters.
Fig 3
Fig 3
Alpha diversity at the genus level (using the Shannon-Weiner index): proportion and patterns of relative abundance of the most abundant genera or those known to be important airway pathogens across the identified exacerbation biologic clusters.
Fig E1
Fig E1
Alpha diversity at the phylum level (using the Shannon-Weiner index): relative abundances of the most abundant phyla and P/F ratio in log format (base 10) across asthmatic patients and patients with COPD.
Fig E2
Fig E2
Alpha diversity at the genus level (using the Shannon-Weiner index): relative abundances of the most abundant genera and known major airway pathogens across asthmatic patients and patients with COPD.
Fig E3
Fig E3
Sputum IL-1β, IL-5, and CXCL10 levels in each cluster at stable state and exacerbation.

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