Exhaled volatile organic compounds as biomarkers for airway biology in severe asthma

Abstract

Breathomics, the measurement of exhaled volatile organic compounds (VOCs), is an exciting new biomarker medium for airways disease. The greatest unmet need for biomarkers in severe asthma is in T2 low disease and so, in this thesis, I sought to identify a T2 low phenotype and assess whether breathomics could be used as a biomarker for this patient group.
A cohort of severe asthma patients was recruited and clinically characterised in parallel to sputum induction and exhaled breath collection. Though the T2 high phenotype was easy to recognise, T2 low disease was poorly defined by inflammatory cell counts alone. Measures of inflammatory cell activation provided were insufficient to describe new phenotypes.
16s rRNA sequencing of sputum samples identified a cohort of T2 low patients, characterised by airway colonisation with Haemophilus, sputum neutrophilia and ongoing disease burden. However, none of the clinically available biomarkers were able to identify this cohort of patents.
The exhaled VOC samples from this severe asthma cohort demonstrate a clear structure to the exhaled VOC matrix, however, sensitivity to underlying airway inflammation was weak. Repeated breath sampling identified heterogeneity in the stability of VOCs during an otherwise clinically stable state. Exclusion of VOCs with a high degree of within-subject variability resulted in less model overfitting and AUC an of 0.643 for predicting sputum eosinophilia (>2%). 2-pentanone, was identified as having the strongest feature importance. This ketone is thought to be generated in the airway epithelium.
Applying this newly established analytical framework, a model was built to predict the cluster of patients with heavy Haemophilus colonisation, potentially amenable to Azithromycin therapy. A model built on non-erratic VOCs predicting Haemophilus with an AUC of 0.857. Decane was identified as a possible biomarker, however further validation is required.
The findings from this thesis demonstrate sensitivity of exhaled VOCs to the airway biology of severe asthma patients but require validation.

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Identifiers

ORCID for John Holloway: orcid.org/0000-0001-9998-0464

ORCID for Paul Skipp: orcid.org/0000-0002-2995-2959

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