Sputum Microbial Markers of Type 2-Low Asthma

摘要

ABSTRACT Asthma is a heterogeneous disease for which inhaled corticosteroids (ICS) are a cornerstone of treatment by current guidelines. However, up to 45% of patients do not respond to ICS therapy, which is more effective against airway inflammation driven by type 2 immune responses. Moreover, ~50% of asthmatic adults do not demonstrate evidence of significant type 2 airway inflammation. Thus, patients with “Type 2-low” asthma comprise a large subgroup with poorly understood disease etiologies and limited treatment options. Moreover, the consequences of chronic ICS treatment in Type 2-low patients are uncertain and potentially even harmful. Recent bronchoscopy studies have revealed that Type 2-low asthma, even in ICS-naïve patients, is associated with significant alterations in the airway microbiome (“airway dysbiosis”), and patterns of airway dysbiosis are linked to differences in asthma control. These findings have largely relied on invasive studies using bronchoscopy. In contrast, analysis of induced sputum allows for larger numbers of patients to be studied longitudinally, so that relationships between airway dysbiosis, airway immune response patterns, and asthma control can be better understood. In addition, a sputum-based microbial biomarker(s) of asthma phenotype or outcome would allow for identification of particular patients for tailored interventions targeting the microbiome. In Aim 1 we will conduct cross-sectional analyses to identify induced sputum microbiota that are differentially enriched among Type 2-low individuals, stratified by ICS use, whose asthma is or is not well controlled. In Aim 2, a subset of asthmatic subjects in each group will be followed for 12 months, spanning seasonal variations in asthma control, airway microbiome composition, and ICS treatments that are important to consider. We will perform metagenomic sequencing studies to gain comprehensive insights into all microbiota present, the functions they contribute, and relationships between the airway microbiome, concurrent airway immune response patterns and clinical outcomes in Type 2-low patients. We expect to identify novel sputum-based microbial biomarkers of Type 2-low asthma and asthma outcomes in this population that will lead to new therapeutic avenues for this important subgroup.