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

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.

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).

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.

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.