Improving asthma prognosis through biomarker discovery and treatable traits From the lab to the clinic

Asthma is in many respects a markedly heterogeneous condition, demonstrating strong variability between patients in terms of clinical presentation as well as pathology. This thesis aimed to expand our knowledge on asthma heterogeneity and to optimise treatment based on more targeted management strategies via an interdisciplinary approach by involving both laboratory and clinical studies. An in vitro study was conducted investigating the effects of short-chain fatty acids on barrier function modulation of human bronchial airway epithelial cells and their restoration after exposure to stimuli. We demonstrated that short-chain fatty acids can enhance barrier function of bronchial airway epithelial cells in a type- and concentration-dependent manner. In a meta-analysis of genome-wide association studies on the influence of genetic variation on exacerbation occurrence in children with asthma despite LABA therapy, we could identify eight suggestively associated genetic variants. In a real-life clinical trial we investigated the extent of exclusion of severe asthma patients from participation in randomised clinical trials investigating targeted biological therapies. The results show an exclusion of 82.4% of severe asthma patients treated in clinical care with biological therapies. Nevertheless, excluded patients demonstrated a similar clinical response to biological therapy after six months of continued use as reported in aforementioned clinical studies. Lastly, an unsupervised, data-driven longitudinal characterisation of different clusters of disease progression in severe asthma was conducted. In this study we could demonstrate that higher FeNO levels at baseline were associated with assignment to a cluster exhibiting respiratory worsening over time.