NUOVE PROSPETTIVE NELL'ERA DEI MODULATORI DEL CFTR: APPROCCI EMERGENTI PER IL MONITORAGGIO PRECOCE DELLA MALATTIA POLMONARE IN FIBROSI CISTICA

Background: Improving the early detection and management of cystic fibrosis (CF) lung disease is critical to improving patient outcomes. In addition to traditional methods, non-invasive techniques such as impulse oscillometry (IOS) are gaining traction. The advent of highly effective CFTR modulators, particularly elexacaftor/tezacaftor/ivacaftor (ETI), highlights the need for sensitive markers to monitor treatment effects in broader patient populations. This underscores the importance of exploring innovative tools in CF management. Objectives: The PhD project had two main purposes. First, to identify sensitive tools for early monitoring of lung disease in pediatric CF patients by investigating the efficacy of new functional techniques such as IOS. Second, to identify sensitive outcome measures, such as advanced imaging techniques, to assess the impact of CFTR modulator therapies. Methods: Five observational and prospective studies were performed. One study followed lung function in CF patients aged 2-17 years over 2 years using IOS, spirometry, and chest CT. The other 4 studies evaluated the effects of dual and triple combination CFTR modulators in pediatric and adult patients using MRI and chest CT, lung function tests, and clinical outcomes. Results: In 50 CF patients with preserved lung function, longitudinal analysis of IOS data showed significant changes over time and during exacerbations. However, correlations with spirometry and chest CT scores were weak. CFTR modulator trials have shown promising results: Lumacaftor/ivacaftor (LUM/IVA) therapy showed modest improvements in lung structure and function parameters and quality of life over 36 months. Switching from LUM/IVA to ETI significantly improved lung structural damage, inflammation, lung function, and quality of life at 12 months. Compassionate use of ETI therapy resulted in significant improvements in advanced CF patients over two years, including lung function, structural changes, and other clinical outcomes. ETI therapy in patients with preserved lung function showed consistent improvements in morphologic analysis of chest CT scans, lung function, and clinical outcomes over 72 weeks. Conclusions: Recent advances in CF research emphasize early detection and intervention to mitigate lung disease progression. Studies on IOS suggest its promise in monitoring CF lung function, while research on CFTR modulator therapies, particularly ETI, highlights their profound impact on improving clinical outcomes. Together, these findings are helping to improve the management of cystic fibrosis and hold great promise for improving the quality of life of those affected.