The Clinical Utility of the Lung Clearance Index as a Monitoring Tool in Cystic Fibrosis

Aims: The lung clearance index (LCI) is a lung function test that can detect early cystic fibrosis (CF) lung disease. This PhD aimed to evaluate the clinical utility of the LCI as a monitoring toolin children with CF.

Methods and main findings: The studies included in this thesis are based on two multisite prospective longitudinal studies conducted in children with CF and healthy controls. Study 1 describes for the first time the expected magnitude of change in the lung clearance index (LCI) with different phenotypes of acute respiratory events in school-age children with CF. The LCI was a sensitive measure of lung function worsening with acute respiratory events and detected incomplete recovery at follow-up, even in mild events untreated events.Study 2 explores thresholds that can be used to identify clinically meaningful changes in LCI in children with CF. It demonstrates that the limits of reproducibility of the LCI in healthy children can be used to detect clinically relevant changes in children with CF.Study 2 also shows that an LCI increase (worsening) of ≥10% with acute respiratory events was predictive of failing to recover baseline lung function at follow-up. Studies 3 and 4 explore the role of patient-report outcome measures (PROs) as monitoring tools in children with CFand investigate their relationship with lung function outcomes. Study 3 reports that, in preschool children (2.5-6 years), changes in the parent-proxy Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory score of at least 10-points can be considered clinically meaningful and that its utility to monitor acute respiratory events was improved when combined with LCI. Study 4 shows thatin older children aged 6 to 13 years of age, the parent-proxy CFQ-R was sensitive and predictive of acute respiratory events. The positive and negative predictive value of the PRO was improved when combined with LCI.

Conclusion:This PhD supportsthe routine clinical use of LCI to monitor changes in lung function associated with acute respiratory eventsin children with CF and provides practical guidance on how to interpret visit-to-visit changes in LCI.