Exploring the heterogeneity of asthma exacerbations
Publication Date
December 11, 2024
Creator
Abstract
Asthma is a chronic inflammatory disease of the airways that manifests due to a complex interaction between genetics and the environment. It leads to variable symptoms and airway obstruction.
A decline in lung function can be associated with worsening asthma symptoms that are not alleviated by the asthmatic’s usual medication. This is the basis of asthma exacerbations. Despite our understanding of asthma as a heterogeneous disease process, most exacerbations are therapeutically managed one-dimensionally with oral corticosteroids (OCS)
Aims:
This thesis focuses on asthma exacerbations and will explore them through quantitative and laboratory-based studies.
Methods:
A longitudinal cohort study was conducted to explore the biological heterogeneity of asthma exacerbations. Participants were phenotyped at baseline and then at the point of an exacerbation through a combination of clinical, physiological, and clinically relevant biomarkers of airway inflammation. The cohort was longitudinally followed up over three years. Viruses are the most common cause of asthma exacerbation, and the proportion of exacerbations related to viral aetiology was examined. The heterogeneity of exacerbations was explored by characterising the gene expression at the point of an exacerbation through RNA sequencing.
Results:
Asthma exacerbations were associated with both T2-high and T2-low inflammation. Small airway Disease is a significant contributing factor to asthma exacerbations and has the potential to help distinguish asthma exacerbations that require a course of steroids. Longitudinal assessment suggests that the inflammatory profile of asthma exacerbations is stable. Viral PCR performed on nasal brush samples at baseline and during an exacerbation has identified that 80% of asthma exacerbations that required a course of steroids had a virus present. A virus at exacerbation was associated with worsening peripheral resistance of the smaller airways R5R20 1.30cmH20/L/S (p=0.03). Transcriptomic analysis of nasal epithelial cells was obtained at baseline and the point of an exacerbation and identified enrichment of immune response pathways. Ingenuity Pathway Analysis (IPA) has identified gene modules associated with T1 and T2 inflammation and airway remodelling associated with asthma exacerbations.
Conclusions:
There is evidence of heterogeneity in asthma exacerbations, with T2-high and T2-low exacerbations associated with similar physiological reductions in lung function. Longitudinal follow-up of the APEX cohort has revealed stability within the identified phenotypes.
Item Type
ethesis
Thesis Type
PhD
Supervisors
Subjects (LC)
Associated Schools / Departments
School of Medicine
eprints ID
79814
UoN Repository URI
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Thesis post corrections.pdf
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Full-text
Description
Examined. Thesis post viva correcitons- Ashish Pradhan
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6.2 MB
Format
Adobe PDF
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