Natural variability of lung function in primary ciliary dyskinesia: longitudinal analysis from the PROVALF-PCD cohort.

Abstract

Background The extent to which changes in lung function are due to natural variability in patients with primary ciliary dyskinesia (PCD) is unknown. We aimed to assess intra-individual variability in forced expiratory volume in 1 s (FEV1) derived from spirometry to define the extent to which the observed changes were due to test variability in clinically stable PCD patients. Methods PROVALF-PCD (Prospective Observational Multicentre Study on Variability of Lung Function in Stable PCD Patients) was a large international prospective cohort conducted in 2017-2019. We included patients aged ≥5 years who were clinically stable at two or more consecutive visits and provided spirometry-derived lung function measurements. To calculate the upper limit of normal (ULN), we fitted an unadjusted multilevel mixed-effect model, and to determine the absolute change in FEV1 z-scores, we calculated the coefficient of repeatability (CR). We performed sensitivity analyses by stratifying relative change by age (adults versus children), number of measurements (at least four), and time between measurements (<4 months apart). Results We included 252 participants from 12 countries with confirmed or highly likely PCD. We included 1028 FEV1 measurements from patients in stable state. The ULN for relative change between two measurements of FEV1 was 25%. Test variability remained high in all sensitivity analyses. The CR was 1.88 FEV1 z-score. Conclusions Changes in intra-individual FEV1 >25% between visits in stable PCD patients lie beyond the expected test variability and therefore could be considered physiologically relevant. These findings inform the selection of end-points for pulmonary intervention trials in PCD, as they suggest that FEV1 is not a sensitive test for monitoring lung health in PCD.