Microbial-immune interactions in severe asthma: Insights into pathogen dominance and treatment approaches

Study identifies treatable microbiome features in severe asthma, revealing potential for precision antibiotic therapies.

Study: Species-level, metagenomic and proteomic analysis of microbe-immune interactions in severe asthma. Image Credit: Olga Rolenko / Shutterstock.com

A recent study published in Allergy assesses the airway microbiome and host immune-inflammatory responses to identify treatable aspects of severe asthma.

Asthma and the airway microbiome

Asthma is characterized by reversible airway constriction. In severe asthma, it is important to identify treatable features that distinguish subsets of this condition. For example, in the type-2 high subset, both sputum and blood eosinophils are high, with most patients responding well to corticosteroids and anti-interleukin 5 (IL-5) agents.

Conversely, the type-2 low subtype, which affects 30-50% of individuals with severe asthma, is associated with a poor response to approved biologics or systemic corticosteroids. The type-2 low subtype includes both neutrophilic and paucigranulocytic asthma, the latter of which is also referred to as non-neutrophilic or eosinophilic asthma.

The lack of response to treatments in the type-2 low subtype may be due to bacterial infection and/or neutrophilic infiltration of the airways due to immunologic responses. This may also explain the observed efficacy of long-term macrolide antibiotics like azithromycin in this subset of patients.  

Previous studies have identified Hemophilus and Moraxella as the most common microorganisms present in the airway microbiome, particularly the lower airway. Low commensal abundance, neutrophilic inflammation, and adverse outcomes often accompany H. influenzae infection.

About the study

The researchers of the current study were interested in determining whether the dominance of microorganisms in the airway microbiome could function as a treatable trait in severe asthma. They hypothesized that this shift would only be observed the lower airway and, as a result, contribute to treatment-refractory neutrophilic inflammation caused by type-1 cytokine release.

Sputum and nasal lavage samples were obtained from patients with severe asthma from the Oxford and Wessex cohorts. DNA extracted from these samples was examined by long read metagenomic sequencing, following which species-level genetic data was integrated with clinical and airway proteomics parameters.  

Different immune responses

Participants in both cohorts had similar demographic, lung function, and inhaled corticosteroid use data. Oral corticosteroids were more common in the Wessex cohort, as these individuals were recruited before biologics were frequently used.

Neutrophilic asthma was identified in 25.5% of patients with severe asthma, whereas 39% had paucigranulocytic asthma. Current smokers comprised 33% of the study cohort, with less than ten mean pack years smoked.

Only severe asthma patients were included in the Oxford cohort. A high baseline blood eosinophil count was observed in these individuals, with eosinophilic sputum reported in 36.7%.

In both cohorts, disease control was often poor in patients with severe asthma.

Differing microbial profile in severe asthma

In the Wessex cohort, the sputum microbiome was similar between healthy individuals and those with mild asthma. However, among 81 patients with severe asthma, over 23% of the microbiomes exhibited dominance of one respiratory pathogen during clinical stability.

H. influenzae, M. catarrhalis , S. pneumoniae, and P. aeruginosa were the dominant species in ten, four, four, and one sample, respectively. Single-pathogen dominance by H. influenzae, M. catarrhalis, S. pneumoniae, and T. whipplei is associated with neutrophilic asthma, along with Firmicutes depletion, a known marker for poor outcomes.

Eosinophilic asthma patients were more likely to exhibit higher M. catarrhalis, S. intermedius and V. parvula abundance with lower abundance of H. influenzae and S. pneumoniae. Paucigranulocytic asthma was associated with lower abundances of M. catarrhalis, H. influenzae, and T. whipplei.

Neutrophilic asthma was associated with higher levels of type 1 cytokines and proteases. H. influenzae dominance predicted higher eosinophil cationic protein, elastase, and IL-10 levels, thus suggesting disruption of normal immunologic response, pathogen persistence, and airway remodeling.

Rothia mucilaginosa is a facultative anerobe that can thrive at lower oxygen levels in mucus-plugged airways. Increased abundance of this microorganism was observed in microbiomes without single-pathogen dominance.

Rothia mucilaginosa abundance was also associated with IL-6 levels and inversely correlated with fibroblast growth factor (FGF) levels. FGFs drive airway remodeling through smooth muscle and vascular hyperplasia, which is reduced by antibiotic treatment.

Using Bayesian analysis, H. influenzae and M. catarrhalis were independently but strongly associated with type-1 airway inflammation.

Not ‘one airway, one disease’

The upper airway microbiome and cytokine profile differed significantly from that of the lower airway.

Assuming that nasal lavage and sputum samples represent these two locations, respectively, the upper airway is enriched for S. epidermidis and S. aureus, whereas the lower airway is enriched for Firmicutes, mostly Streptococcus species. Nasal lavage specimens exhibited higher abundance of D. pigrum, M. catarrhalis and E. coli as compared to H. influenzae and H. parainfluenzae.

Azithromycin is effective for the treatment of both neutrophilic and non-neutrophilic phenotypes of severe asthma, which may be attributed to the dominance of H. influenzae, M. catarrhalis, and S. pneumoniae. However, targeted therapy after confirming this trait is important considering widespread resistance to this antibiotic.

Conclusions

The current study is the first to examine airway microbiome profiles at the species level in a large sample of individuals with severe asthma. Single-pathogen dominance was observed in 20-30% of these patients, the most common of which was H. influenzae, along with neutrophilic infiltration and type-1 inflammation.

The ‘one airway, one disease’ concept does not apply to the airway microbiome in severe asthma.”

The study findings also demonstrate the feasibility of Nanopore sequencing to identify pathogen dominance in ordinary medical practice. Future applications of this technology could guide the precise antibiotic management of patients with severe asthma and other airway diseases.