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-nave 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.
Many asthma patients do not respond to inhaled corticosteroids, the most commonly prescribed anti-inflammatory treatment for asthma. Using invasive bronchoscopy, recent studies have found that this is associated with specific patterns of airway inflammation and also significant differences in the types of bacteria normally present in the lower respiratory tract. This project will determine whether analysis of sputum, a sample more feasible to obtain, can identify microbial predictors of asthma control and responsiveness to inhaled steroids, leading to the development of novel clinical tests and therapeutic strategies to improve asthma care.
| Durack, Juliana; Boushey, Homer A; Huang, Yvonne J (2018) Incorporating the airway microbiome into asthma phenotyping: Moving toward personalized medicine for noneosinophilic asthma. J Allergy Clin Immunol 141:82-83 |
| Begley, Lesa; Madapoosi, Siddharth; Opron, Kristopher et al. (2018) Gut microbiota relationships to lung function and adult asthma phenotype: a pilot study. BMJ Open Respir Res 5:e000324 |
| Durack, Juliana; Huang, Yvonne J; Nariya, Snehal et al. (2018) Bacterial biogeography of adult airways in atopic asthma. Microbiome 6:104 |
| Durack, Juliana; Lynch, Susan V; Nariya, Snehal et al. (2017) Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment. J Allergy Clin Immunol 140:63-75 |
| Huang, Yvonne J (2017) Nasopharyngeal Microbiota: Gatekeepers or Fortune Tellers of Susceptibility to Respiratory Tract Infections? Am J Respir Crit Care Med 196:1504-1505 |
