S24 Proteomics reveals distinct drivers of cystic fibrosis lung function and quality of life outcomes: post-hoc analysis of the AZTEC-CF study

<h3>Introduction</h3> Lung function and quality of life are key outcomes in most interventional clinical trials conducted in people living with cystic fibrosis. However, the precise pathophysiological mechanisms leading to treatment related improvements in these outcomes are incompletely understood. In this post-hoc analysis of the Aztreonam Lysine for Treatment of Exacerbations of CF (AZTEC-CF) study we investigated proteomic changes in response to treatment and how these changes related to the clinical trial outcomes. <h3>Methods</h3> Paired sputum samples collected pre and post 14 days of antibiotics for the treatment of an acute pulmonary exacerbation were included. After homogenisation and digestion, samples were analysed by nanoLC-MS/MS. Identification and quantification was performed in ThermoProteomeDiscover v2.5 and ProgenesisQIP v4.2 respectively. DESeq2 was used to calculate log-fold change for individual proteins and relationships between protein change and changes in lung function (% predicted FEV1) and quality of life (Respiratory Domain CFQ-R) were evaluated. <h3>Results</h3> Paired samples from 13 patients, (samples n=26) were included for analysis. In this group, after 14 days treatment, average lung function improvement was +11.6% absolute improvement in% predicted FEV1, improvement in Respiratory Domain CFQ-R score was +11.1 points. For lung function, 20 of the top 30 (66%) differential proteins were bacterial derived. 22 proteins were significantly correlated with changes in lung function, 4 of which were bacterial. For quality of life, 0 of the top 30 (0%) differential proteins were bacterial, 78 proteins were significantly correlated with changes in quality of life, all host-derived and completely distinct from those associated with lung function. Bacterial proteins were therefore significantly less likely to be associated with quality of life than lung function (Chi2 8.5, p=0.003). <h3>Conclusion</h3> These results suggest changes in two key CF clinical trial outcomes (lung function and quality of life) may be underpinned by different pathophysiological mechanisms. Understanding these divergent mechanisms is vital to underpin optimal clinical trial design in CF in the modulator era.