A severe asthma phenotype of excessive airway Haemophilus influenzae relative abundance associated with sputum neutrophilia

Abstract

Abstract Background Severe asthma (SA) encompasses several clinical phenotypes with a heterogeneous airway microbiome. We determined the phenotypes associated with a low α‐diversity microbiome. Methods Metagenomic sequencing was performed on sputum samples from SA participants. A threshold of 2 standard deviations below the mean of α‐diversity of mild‐moderate asthma and healthy control subjects was used to define those with an abnormal abundance threshold as relative dominant species (RDS). Findings Fifty‐one out of 97 SA samples were classified as RDSs with Haemophilus influenzae RDS being most common (n = 16), followed by Actinobacillus unclassified (n = 10), Veillonella unclassified (n = 9), Haemophilus aegyptius (n = 9), Streptococcus pseudopneumoniae (n = 7), Propionibacterium acnes (n = 5), Moraxella catarrhalis (n = 5) and Tropheryma whipplei (n = 5). Haemophilus influenzae RDS had the highest duration of disease, more exacerbations in previous year and greatest number on daily oral corticosteroids. Hierarchical clustering of RDSs revealed a C2 cluster (n = 9) of highest relative abundance of exclusively Haemophilus influenzae RDSs with longer duration of disease and higher sputum neutrophil counts associated with enrichment pathways of MAPK, NF‐κB, TNF, mTOR and necroptosis, compared to the only other cluster, C1, which consisted of 7 Haemophilus influenzae RDSs out of 42. Sputum transcriptomics of C2 cluster compared to C1 RDSs revealed higher expression of neutrophil extracellular trap pathway (NETosis), IL6‐transignalling signature and neutrophil activation. Conclusion We describe a Haemophilus influenzae cluster of the highest relative abundance associated with neutrophilic inflammation and NETosis indicating a host response to the bacteria. This phenotype of severe asthma may respond to specific antibiotics.

Keywords

• α‐diversity
• Haemophilus influenzae
• metagenome
• Moraxella catarrhalis
• neutrophils
• severe asthma