Personalised Approaches to Managing Adult Respiratory Infections

Personalised approaches are needed to manage patients with heterogenous condition such as bronchiectasis and community acquired pneumonia. Inhaled antibiotics (IAB) are widely prescribed for bronchiectasis patients despite their lack of consistent efficacy in major clinical trials. In this thesis are studies investigating two of the largest IAB trials (ORBIT-3 and ORBIT-4) with the aim of identifying microbiological and inflammatory biomarkers that will predict responders to IAB therapy. Antibodies can be measured as a biomarker of previous infection and could be a precise method of evaluating the prevalence of infection during a pandemic. The rate of natural antibody development to SARS-CoV-2 infection and its protective effect was not known at the start of the COVID-19 pandemic. In this thesis, the MATCH study was conducted to determine these unknown aspects of the early, pre-vaccination era of the COVID-19 pandemic. Severe pneumonia caused by infection with SARS-CoV-2 led to the death of millions of people worldwide. A dysregulated immune response is the hallmark severe pneumonia pathophysiology (including COVID-19 pneumonia). Hence, anti-inflammatory therapies are needed to reduced mortality. Nrf2 is a cytoprotective transcription factor that is strongly expressed in neutrophils and provides the principal inducible defence against oxidative and inflammatory stress. This thesis presents the first trial of an Nrf2 activator in community acquired pneumonia (CAP).