Background The limits of reproducibility of the lung clearance index (LCI) are higher in children with cystic fibrosis (CF) compared with healthy children, and it is currently unclear what defines a clinically meaningful change.
Methods In a prospective multisite observational study of children with CF and healthy controls (HCs), we measured LCI, FEV1% predicted and symptom scores at quarterly visits over 2 years. Two reviewers performed a detailed review of visits to evaluate the frequency that between visit LCI changes outside ±10%, ±15%, ±20% represented a clinically relevant signal. In the setting of acute respiratory symptoms, we used a generalised estimating equation model, with a logit link function to determine the ability of LCI worsening at different thresholds to predict failure of lung function recovery at follow-up.
Results Clinically relevant LCI changes outside ±10%, ±15% and ±20% were observed at 25.7%, 15.0% and 8.3% of CF visits (n=744), respectively. The proportions of LCI changes categorised as noise, reflecting biological variability, were comparable between CF and HC at the 10% (CF 9.9% vs HC 13.0%), 15% (CF 4.3% vs HC 3.1%) and 20% (CF 2.4% vs HC 1.0%) thresholds. Compared with symptomatic CF visits without a worsening in LCI, events with ≥10% LCI increase were more likely to fail to recover baseline LCI at follow-up.
Conclusion The limits of reproducibility of the LCI in healthy children can be used to detect clinically relevant changes and thus inform clinical care in children with CF.
- Cystic Fibrosis
- Lung Physiology
- Paediatric Lung Disaese
- Respiratory Measurement
Data availability statement
Data are available on reasonable request.
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Contributors LP contributed to conceptualisation of the study design, data collection, data analysis, data interpretation, figures and wrote the manuscript. SS contributed to conceptualisation and design of the study, funding acquisition, data analysis, data interpretation, figures and manuscript review and editing; SDD contributed to funding acquisition, study design, data interpretation and manuscript review and editing. MS, HG, VJW, NS and DS contributed to study design, data interpretation and manuscript review and editing. FR conceptualised, designed and supervised the study and contributed to funding acquisition, data analysis, data interpretation, figures, manuscript review and editing, and is the guarantor of the study.
Funding Funding for the study was obtained from the Cystic Fibrosis Foundation (award no RATJEN16A0), Cystic Fibrosis Canada (Grant ID: 3187) and the Cystic Fibrosis Foundation Therapeutics Development Network National Resource Centre (Center for Pediatric Lung Function). LP is a PhD candidate with the Royal College of Surgeons in Ireland and this research was funded by the National Children's Research Centre, Crumlin (Grant No. D/19/4).
Competing interests SS reports grants from Cystic Fibrosis Canada and US Cystic Fibrosis Foundation, during the conduct of the study. MS reports grants from Vertex Pharmaceutical and Mylene Pharmaceutical, payment for educational module from Vertex Pharamaceutical, outside the submitted work. FR reports grants and personal fees for consultancy from Vertex, Proteostasis, Genentech, Bayer, Novartis and Roche outside the submitted work. The other authors have nothing to disclose.
Provenance and peer review Not commissioned; externally peer reviewed.
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