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Background: Lung Clearance Index (LCI) is a sensitive measure of lung disease in children with cystic fibrosis (CF). The aim of this study was to determine whether there are modifiable factors that affect the course of lung disease during childhood. Methods: In this prospective two centre cohort study, we continued to follow a cohort (Stanojevic et al., AJRRCM 2017) of children with CF and age-matched healthy controls (HC) into school age (5-10 years). LCI was measured every 3 months for 24 months using Exhalyzer® D multiple breath nitrogen washout equipment. Detailed clinical data were extracted at each study visit, and for the years between the two follow-up periods. Mixed effects linear regression analyses were used. Results: In total 76% of the original preschool cohort (50/72 HC and 64/78 CF) were followed-up at school age. A total of 607 LCI measurements (HC) and 832 measurements (CF) were available for analysis. At the first school age visit, LCI was 2.15 units higher in the CF group compared to the controls (95%CI -2.68; 1.62); LCI was above 7.91 units (68.8%) in 40 children, of which 54% had abnormal LCI during the preschool period. A higher preschool LCI, faster rate of LCI deterioration during preschool years and a greater cumulative number of exacerbations were significant predictors of worse school age LCI. During the school age follow-up, LCI plateaued (slope = 0.07 (95% -0.1; 0.2) with age. Overall, a greater proportion of children received mucolytics and/or modulator treatments during the school age years compared with the preschool years. Conclusions: Early intervention before or during preschool are a critical time period to prevent future lung function impairment. Funded by NHLBI, CFF

The lung clearance index (LCI) measured by the multiple breath washout (MBW) test is sensitive to early lung disease in children with cystic fibrosis. While LCI worsens during the preschool years in cystic fibrosis, there is limited evidence to clarify whether this continues during the early school age years, and whether the trajectory of disease progression as measured by LCI is modifiable.A cohort of children (healthy and cystic fibrosis) previously studied for 12 months as preschoolers were followed during school age (5–10 years). LCI was measured every 3 months for a period of 24 months using the Exhalyzer D MBW nitrogen washout device. Linear mixed effects regression was used to model changes in LCI over time.A total of 582 MBW measurements in 48 healthy subjects and 845 measurements in 64 cystic fibrosis subjects were available. The majority of children with cystic fibrosis had elevated LCI at the first preschool and first school age visits (57.8% (37 out of 64)), whereas all but six had normal forced expiratory volume in 1 s (FEV1) values at the first school age visit. During school age years, the course of disease was stable (−0.02 units·year−1 (95% CI −0.14–0.10). LCI measured during preschool years, as well as the rate of LCI change during this time period, were important determinants of LCI and FEV1, at school age.Preschool LCI was a major determinant of school age LCI; these findings further support that the preschool years are critical for early intervention strategies.