Background
CF is the most common life-limiting autosomal recessive disease in Caucasian population, and is a complex multisystemic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel which primarily regulates anion transport through cell surface. To date, more than 2000 mutations have been identified 1. Functional failure of CFTR leads to multisystemic dysfunction, involving lungs, gastrointestinal tract, liver and pancreatic gland. Impaired mucociliary clearance and dense secretions primarily result in chronic pulmonary inflammation and infections, irreversible lung architecture modification, respiratory failure and death 2.
In the last decade, LCI started to be used in CF management as an efficacy endpoint in interventional trials thanks to its ability to effectively assess small airways disease both in preschool and middle-age children, when forced expiratory volume in 1 second (FEV1) is generally within normal range and CF lung disease still mild3-5.
LCI is the most commonly reported MBW index in the pediatric literature and it is defined as the number of functional residual capacity lung turnovers required to reduce the alveolar concentration of a tracer-gas to a given fraction of its starting value, historically 1/40 (2.5%). A particular advantage of LCI in pediatric population is feasibility by passive cooperation and minimal coordination across all the pediatric age ranges 6.
Horsley et al. described Lung clearance index as a sensitive, repeatable and practical measure of airways disease also in adults with cystic fibrosis
Despite being the gold standard for the assessment of pulmonary function in CF lung disease, FEV1 measurement through spirometry has been shown to be less sensitive than LCI in detecting early abnormalities and peripheral airways disease in CF 8. LCI is an early marker of ventilation inhomogeneity, reflecting initial airways dysfunction in CF population with normal pulmonary function tests9-10 and is being recognized as a useful surrogate pulmonary outcome measure, especially in the new era of CFTR modulators, where new disease trajectories will require adequate clinical markers to characterize clinical phenotypes and monitor the efficacy of treatments11-14.
LCI is a sensitive and feasible measures index (LCI) with strong intra-test and iter-test repeatability 15.
In CF, pulmonary exacerbations are crucial events which progressively determine a loss of respiratory function, worsening of the quality of life and negatively impact overall survival. According to studies, lung function fails to return to baseline value in up to 25% of CF pulmonary exacerbations, despite a prompt antibiotic treatment16-17. In contrast to studies in which FEV1 was used as primary outcome, consistently showing a positive treatment effect18-21, studies addressing LCI as outcome measure obtained heterogeneous results 22-24. LCI significantly increases in patients with a pulmonary exacerbation, but LCI response to therapy for pulmonary exacerbations is heterogeneous and not completely clear in literature .
Our primary aim was to evaluate LCI index short-term variability in pulmonary exacerbation after antibiotic intravenous therapy. We also aimed to analyze the possible correlations between spirometry and LCI values post therapy course to support treatment variability.