Rationale The lung clearance index (LCI) is increasingly being used in the clinical surveillance of patients with cystic fibrosis (CF). However, there are limited data on long-term variability and clinically relevant changes in LCI during routine clinical surveillance. Objectives To evaluate long-term variability of LCI and propose a threshold for a clinically relevant change. Methods Children with CF aged 4-18 years performed LCI measurements every three months as part of routine clinical surveillance during 2011-2020 in two centers. The variability of LCI during periods of clinical stability was assessed using mixed-effects models and was used to identify thresholds for clinically relevant changes. Results Repeated LCI measurements of acceptable quality (N= 858) were available in 100 patients with CF. Variability of repeated LCI measurements over time expressed as coefficient of variation (CV%) was 7.4%. The upper limit of normal (ULN) for relative changes in LCI between visits was 19%. Conclusion We report the variability of LCI in children and adolescents with CF during routine clinical surveillance. According to our data, a change in LCI beyond 19% may be considered clinically relevant. These findings will help guide clinical decisions according to LCI changes.

Background: The recently described sensor-crosstalk error in the multiple-breath washout (MBW) device (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) could highly influence clinimetric properties and the current interpretation of MBW results. This study reanalyzes MBW data from clinical routine in the corrected software version Spiroware® 3.3.1 and evaluates the effect on outcomes. Methods: We included nitrogen-MBW data from healthy children and children with CF from previously published trials and ongoing cohort studies. We specifically compared LCI analyzed in Spiroware 3.2.1 and 3.3.1 with regards to i) feasibility, ii) repeatability and iii) validity as outcome parameters in children with CF. Results: (i) All previously collected measurements could be reanalyzed and resulted in unchanged feasibility in Spiroware 3.3.1. (ii) Short- and midterm repeatability of LCI was similar in both software versions. (iii) Clinical validity of LCI remained similar in Spiroware 3.3.1, however, resulted in lower values. Discrimination between health and disease was comparable between both software versions. The increase in LCI over time was less pronounced with 0.16 LCI units/year (95% CI 0.08; 0.24) vs. 0.30 LCI units/year (95% CI 0.21; 0.38) in 3.2.1. Response to intervention in children receiving CFTR-modulator therapy resulted in a comparable improvement in LCI in both Spiroware versions. Conclusion: Our study confirms that clinimetric properties of LCI remain unaffected after correction for the cross-sensitivity error in Spiroware software.