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

Kewei Zhang^{1

2}, Avni Kant^{1

2}, Mieke Boon^{3

4}, Melissa Borrelli⁵, Carolina Constant⁶, Silvia Castillo Corullon⁷, Renato Cutrera⁸, Stefanie Dillenhöfer⁹, Sanem Eryılmaz Polat¹⁰, Ela Eralp¹¹, Nathalie Feyaerts^{3

4}, Amanda Harris^{1

2}, Claire Hogg¹², Cordula Koerner-Rettberg^{9

13}, Panayiotis Kouis¹⁴, Enrico Lombardi¹⁵, Natalie Lorent^{3

4}, June K Marthin^{16

17}, Vendula Martinu¹⁸, Antonio Moreno-Galdo^{19

20}, Lucy Morgan²¹, Kim Nielsen^{16

17}, Heymut Omran²², Ugur Ozcelik¹⁰, Petr Pohunek¹⁸, Phil Robinson²³, Sandra Rovira-Amigo^{19

20}, Francesca Santamaria⁵, Anne Schlegtendal⁹, Aline Tamalet^{24

25}, Guillaume Thouvenin^{24

25}, Dilber Ademhan Tural¹⁰, Nicola Ullmann⁸, Woolf T Walker^{1

2}, Panayiotis Yiallouros¹⁴, Camille Pearse²⁶, Bettina Frauchiger²⁷, Claudia E Kuehni^{27

28}, Nicole Beydon²⁹, Philipp Latzin²⁷, Jane S Lucas^{1

2

30}, Bruna Rubbo^{1

2

30}

Affiliations

¹ Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK.
² Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
³ Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.
⁴ Department of CHROMETA, Laboratory for Respiratory Diseases and Thoracic Surgery, KU Leuven, Leuven, Belgium.
⁵ Department of Translational Medical Sciences, Pediatric Pulmonology, Federico II University, Naples, Italy.
⁶ Department of Pediatrics, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte and Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁷ FE Pediatría y Neumología Infantil, Unidad de Neumología Infantil y Fibrosis Quística, Hospital Clínico de Valencia, Valencia, Spain.
⁸ Respiratory and Cystic Fibrosis Unit, Academic Pediatric Department, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
⁹ Department of Paediatric Pulmonology, University Children's Hospital, Ruhr University Bochum, Katholisches Klinikum Bochum, Bochum, Germany.
¹⁰ Hacettepe University Faculty of Medicine, Department of Pediatric Pulmonology, Ankara, Turkey.
¹¹ Marmara Universitesi, Department of Pediatric Pulmonology, Istanbul, Turkey.
¹² Royal Brompton and Harefield NHS Foundation Trust, Department of Paediatrics, Primary Ciliary Dyskinesia Centre, London, UK.
¹³ Children's Hospital and Research Institute, Marienhospital Wesel, Wesel, Germany.
¹⁴ Medical School, University of Cyprus, Nicosia, Cyprus.
¹⁵ Meyer Children's Hospital IRCCS, Florence, Italy.
¹⁶ 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.
¹⁷ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Department of Paediatrics, Charles University, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic.
¹⁹ Paediatric Pulmonology Section, Department of Paediatrics, Hospital Universitari Vall dHebron, Barcelona, Spain.
²⁰ Universitat Autònoma de Barcelona, Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
²¹ Concord Hospital, Concord Clinical School, University of Sydney, Department of Respiratory Medicine, Sydney, Australia.
²² Department of General Pediatrics, University Hospital Muenster, Muenster, Germany.
²³ Faculty of Medicine Dentistry and Health Sciences, Paediatrics, University of Melbourne, Melbourne, Australia.
²⁴ Sorbonne Université, Inserm U938, Centre de Recherche Saint-Antoine, Paris, France.
²⁵ Sorbonne Université, Assistance Publique - Hôpitaux de Paris, Hôpital Trousseau, Service de Pneumologie Pédiatrique, Paris, France.
²⁶ MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK.
²⁷ Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, University Hospital, University of Bern, Bern, Switzerland.
²⁸ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
²⁹ AP-HP, Sorbonne Université, Unité d'Exploration Fonctionnelle Respiratoire, Hôpital Armand-Trousseau, and Sorbonne Université, INSERM U938, Paris, France.
³⁰ These authors contributed equally.

PMID: 40551797
PMCID: PMC12183702
DOI: 10.1183/23120541.01115-2024

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

Kewei Zhang et al. ERJ Open Res. 2025.

. 2025 Jun 23;11(3):01115-2024.

doi: 10.1183/23120541.01115-2024. eCollection 2025 May.

Authors

Affiliations

¹ Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK.
² Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
³ Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.
⁴ Department of CHROMETA, Laboratory for Respiratory Diseases and Thoracic Surgery, KU Leuven, Leuven, Belgium.
⁵ Department of Translational Medical Sciences, Pediatric Pulmonology, Federico II University, Naples, Italy.
⁶ Department of Pediatrics, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte and Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁷ FE Pediatría y Neumología Infantil, Unidad de Neumología Infantil y Fibrosis Quística, Hospital Clínico de Valencia, Valencia, Spain.
⁸ Respiratory and Cystic Fibrosis Unit, Academic Pediatric Department, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
⁹ Department of Paediatric Pulmonology, University Children's Hospital, Ruhr University Bochum, Katholisches Klinikum Bochum, Bochum, Germany.
¹⁰ Hacettepe University Faculty of Medicine, Department of Pediatric Pulmonology, Ankara, Turkey.
¹¹ Marmara Universitesi, Department of Pediatric Pulmonology, Istanbul, Turkey.
¹² Royal Brompton and Harefield NHS Foundation Trust, Department of Paediatrics, Primary Ciliary Dyskinesia Centre, London, UK.
¹³ Children's Hospital and Research Institute, Marienhospital Wesel, Wesel, Germany.
¹⁴ Medical School, University of Cyprus, Nicosia, Cyprus.
¹⁵ Meyer Children's Hospital IRCCS, Florence, Italy.
¹⁶ 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.
¹⁷ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Department of Paediatrics, Charles University, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic.
¹⁹ Paediatric Pulmonology Section, Department of Paediatrics, Hospital Universitari Vall dHebron, Barcelona, Spain.
²⁰ Universitat Autònoma de Barcelona, Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
²¹ Concord Hospital, Concord Clinical School, University of Sydney, Department of Respiratory Medicine, Sydney, Australia.
²² Department of General Pediatrics, University Hospital Muenster, Muenster, Germany.
²³ Faculty of Medicine Dentistry and Health Sciences, Paediatrics, University of Melbourne, Melbourne, Australia.
²⁴ Sorbonne Université, Inserm U938, Centre de Recherche Saint-Antoine, Paris, France.
²⁵ Sorbonne Université, Assistance Publique - Hôpitaux de Paris, Hôpital Trousseau, Service de Pneumologie Pédiatrique, Paris, France.
²⁶ MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK.
²⁷ Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, University Hospital, University of Bern, Bern, Switzerland.
²⁸ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
²⁹ AP-HP, Sorbonne Université, Unité d'Exploration Fonctionnelle Respiratoire, Hôpital Armand-Trousseau, and Sorbonne Université, INSERM U938, Paris, France.
³⁰ These authors contributed equally.

PMID: 40551797
PMCID: PMC12183702
DOI: 10.1183/23120541.01115-2024

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.

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Conflict of interest statement

Conflict of interest: M. Boon reports grants from Forton (2020-J1810150-217926 and 2023-J1810150-232722); and payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex, ISMC, Cesas Medical, BEAT PCD and ERN Lung. R. Cutrera reports consultancy fees from Sanofi; payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK and AstraZeneca; support for attending meetings from Vivisol; and participation on a data safety monitoring board or advisory board with Sanofi. S. Dillenhöfer reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex. C. Hogg reports consultancy fees from ReCode. C. Koerner-Rettberg reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Berlin Chemie Menarini and RG Ärztetag Wesel. E. Lombardi reports grants from Boehringer Ingelheim, Cosmed, Novartis, Restech and Sanofi; consultancy fees from Novartis, Sanofi; payment or honoraria for lectures, presentations, manuscript writing or educational events from Alfa Sigma, Angelini, Laboratorio Chimico Deca and Recordati; support for attending meetings from Chiesi and Lusofarmaco; and a leadership role with Italian Pediatric Respiratory Society (SIMRI/IPRS). V. Martinu reports grants from Ministry of Health of the Czech Republic. A. Moreno-Galdo reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Sanofi Pasteur, AstraZeneca and Janssen; support for attending meetings from Sanofi Pasteur, AstraZeneca and Vivisol; participation on a data safety monitoring board or advisory board with Sanofi Pasteur and AstraZeneca; and a leadership role with Spanish Society of Paediatric Pulmonology. L. Morgan reports grants from ReCODE Therapeutics; consultancy fees from ReCODE Therapeutics, BI, AZ, Zambon, Insmed and GSK; payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, BI and INSMED; and a leadership role with LFA. K. Nielsen reports grants from Recode and Ethris; and consultancy fees from Parion. H. Omran reports grants from ReCODE Therapeutics; consultancy fees from ReCODE Therapeutics, Insmed and Ethris; payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed; leadership role with European Reference Network on Rare Diseases (ERN-LUNG), genetic diagnostics committee (GEKO), Human Gene Nomenclature Committee (HGNC) for Dyneins (DN; axonemal) and is a current editorial board member of ERJ Open Research. U. Ozcelik reports participation on a data safety monitoring board or advisory board with Turkish CF NBS Advisory Board; leadership role with Turkish Pediatric Respiratory Diseases and Cystic Fibrosis Society (unpaid). P. Pohunek reports grants from Ministry of Health, Czech Republic, Internal Grant Agency; consultancy fees from AstraZeneca and GlaxoSmithKline; payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline and Chiesi. S. Rovira-Amigo reports support for attending meetings from Chiesi and Vivisol. C. Pearse reports participation on a data safety monitoring board or advisory board with DMEC for the MESARCH (Multi-disciplinary Evaluation of Sexual Assault Referral Centres for better Health) study. G. Thouvenin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Sanofi; support for attending meetings from Mylan, Viatris; a leadership role with BEAT PCD CRC WP8; and receipt of equipment, materials, drugs, medical writing, gifts or other services from Trudell Medical International. P. Latzin reports grants from Vertex and OM Pharma; payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex, Vifor and OM Pharma; and participation on a data safety monitoring board or advisory board with Polyphor, Santhera (DMC), Vertex, OM Pharma, Vifor, Allecra and Sanofi Aventis. J.S. Lucas reports grants from Medical Research Council, Life Arc, NHS England, NIHR Southampton Biomedical Research Centre, AAIR charity, NIHR Research for Patient Benefit and Wessex Medical Research. B. Rubbo reports support for the present manuscript from National Institute for Health and Care Research through the NIHR Southampton Biomedical Research Centre to support salary; support for attending meetings from NIHR Biomedical Research Centre Education, Training and Career Development Fund and Southampton Academy of Research, to attend a course on multilevel modelling. The remaining authors have nothing to disclose.

Figures

**FIGURE 1**
Forced expiratory volume in 1 s (FEV₁) relative change upper limit of normal (ULN) for individuals in stable state between two consecutive clinic appointments (n=252 patients). The horizontal line shows the ULN for patients in stable status. Changes above this value would be considered physiologically relevant (*i.e.* not due to the test variability).

**FIGURE 2**
Estimates (β-coefficients) for covariates included in fully adjusted model, with individual relative variability (95% upper limit of normal) of forced expiratory volume in 1 s (FEV₁) as outcome. Model was adjusted by all covariates shown in the figure. *P. aeruginosa*: *Pseudomonas aeruginosa*; *H. influenzae*: *Haemophilus influenzae*; TEM: transmission electron microscopy; ODA: outer dynein arm defect; IDA: inner dynein arm defect; MTD: microtubular disarrangement.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References