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.

AP HP Sorbonne Université Unité d'Exploration Fonctionnelle Respiratoire Hôpital Armand Trousseau and Sorbonne Université INSERM U938 Paris France

Children's Hospital and Research Institute Marienhospital Wesel Wesel Germany

Clinical and Experimental Sciences University of Southampton Faculty of Medicine Southampton UK

Concord Hospital Concord Clinical School University of Sydney Department of Respiratory Medicine Sydney Australia

Danish PCD and chILD Centre CF Centre Copenhagen Paediatric Pulmonary Service ERN Accredited Department of Paediatrics and Adolescent Medicine Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of CHROMETA Laboratory for Respiratory Diseases and Thoracic Surgery KU Leuven Leuven Belgium

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of General Pediatrics University Hospital Muenster Muenster Germany

Department of Paediatric Pulmonology University Children's Hospital Ruhr University Bochum Katholisches Klinikum Bochum Bochum Germany

Department of Paediatrics Charles University 2nd Faculty of Medicine University Hospital Motol Prague Czech Republic

Department of Pediatrics Hospital de Santa Maria Centro Hospitalar Universitário Lisboa Norte and Faculty of Medicine University of Lisbon Lisbon Portugal

Department of Respiratory Diseases University Hospitals Leuven Leuven Belgium

Department of Translational Medical Sciences Pediatric Pulmonology Federico 2 University Naples Italy

Division of Paediatric Respiratory Medicine and Allergology Department of Paediatrics Inselspital University Hospital University of Bern Bern Switzerland

Faculty of Medicine Dentistry and Health Sciences Paediatrics University of Melbourne Melbourne Australia

FE Pediatría y Neumología Infantil Unidad de Neumología Infantil y Fibrosis Quística Hospital Clínico de Valencia Valencia Spain

Hacettepe University Faculty of Medicine Department of Pediatric Pulmonology Ankara Turkey

Institute of Social and Preventive Medicine University of Bern Bern Switzerland

Marmara Universitesi Department of Pediatric Pulmonology Istanbul Turkey

Medical School University of Cyprus Nicosia Cyprus

Meyer Children's Hospital IRCCS Florence Italy

MRC Lifecourse Epidemiology Centre University of Southampton Southampton UK

Paediatric Pulmonology Section Department of Paediatrics Hospital Universitari Vall dHebron Barcelona Spain

Primary Ciliary Dyskinesia Centre University Hospital Southampton NHS Foundation Trust Southampton UK

Respiratory and Cystic Fibrosis Unit Academic Pediatric Department Bambino Gesù Children Hospital IRCCS Rome Italy

Royal Brompton and Harefield NHS Foundation Trust Department of Paediatrics Primary Ciliary Dyskinesia Centre London UK

Sorbonne Université Assistance Publique Hôpitaux de Paris Hôpital Trousseau Service de Pneumologie Pédiatrique Paris France

Sorbonne Université Inserm U938 Centre de Recherche Saint Antoine Paris France

These authors contributed equally

Universitat Autònoma de Barcelona Instituto de Salud Carlos 3 Centre for Biomedical Network Research on Rare Diseases Barcelona Spain

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