Sputum metagenomics reveals a multidrug resistant Pseudomonas-dominant severe asthma phenotype in an Asian population.

Background and objective: While the lung microbiome in severe asthma has been studied, work has employed targeted amplicon-based sequencing approaches without functional assessment with none focused on multi-ethnic Asian populations. Here we investigate the clinical relevance of microbial phenotypes of severe asthma in Asians using metagenomics.

Methods: Prospective assessment of clinical, radiological, and immunological measures were performed in a multi-ethnic Asian severe asthma cohort (N = 70) recruited across two centres in Singapore. Sputum was subjected to shotgun metagenomic sequencing and patients followed up for a 2-year period. Metagenomic assessment of sputum microbiomes, resistomes and virulomes were related to clinical outcomes.

Results: The lung microbiome in a multi-ethnic Asian cohort with severe asthma demonstrates an increased abundance of Pseudomonas species. Unsupervised clustering of sputum metagenomes identified two patient clusters: C1 (n = 52) characterized by upper airway commensals and C2 (n = 18) dominated by established respiratory pathogens including M. catarrhalis, S. aureus and most significantly P. aeruginosa. C2 patients demonstrated a significantly increased exacerbation frequency on 2-year follow up and an antimicrobial resistome characterized by multidrug resistance. Virulomes appear indistinguishable between severe asthmatics with or without co-existing bronchiectasis, and C2 patients exhibit increased gene expression related to biofilm formation, effector delivery systems and microbial motility. Independent comparison of the C2 cluster to a non-asthmatic bronchiectasis cohort demonstrates analogous airway microbial virulence patterns.

Conclusion: Sputum metagenomics demonstrates a multidrug-resistant Pseudomonas-dominant severe asthma phenotype in Asians, characterized by poor clinical outcome including increased exacerbations which is independent of co-existing bronchiectasis.