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Withdrawal of dornase alfa increases ventilation inhomogeneity in children with cystic fibrosis

  • Christian Voldby
    Affiliations
    CF Centre Copenhagen, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark
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  • Kent Green
    Affiliations
    CF Centre Copenhagen, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark
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  • Lue Philipsen
    Affiliations
    CF Centre Copenhagen, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark
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  • Rikke Mulvad Sandvik
    Affiliations
    CF Centre Copenhagen, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark
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  • Marianne Skov
    Affiliations
    CF Centre Copenhagen, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark
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  • Frederik Buchvald
    Affiliations
    CF Centre Copenhagen, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark
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  • Tacjana Pressler
    Affiliations
    CF Centre Copenhagen, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark

    CF Centre Copenhagen, Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark
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  • Kim Gjerum Nielsen
    Correspondence
    Corresponding author.
    Affiliations
    CF Centre Copenhagen, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark

    Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Published:February 19, 2021DOI:https://doi.org/10.1016/j.jcf.2021.02.004

      Highlights

      • A randomised, controlled pilot study in school-age children with cystic fibrosis.
      • One month's withdrawal of dornase alfa caused a significant increase in LCI.
      • Short-term discontinuation of dornase alfa may affect LCI values.
      • When using LCI as endpoint, dornase alfa adherence optimally needs to be addressed.

      Abstract

      Background

      The lung clearance index (LCI) is increasingly used as an outcome in clinical trials of patients with mild cystic fibrosis (CF) lung disease. Yet, understanding the impact of standard CF respiratory therapy on LCI is needed. We assessed to what degree withdrawal of nebulised dornase alfa affected LCI in school-age children with CF not receiving CFTR modulators or hydrator therapy.

      Methods

      A single-centre, randomised, controlled, parallel group study to determine effects of one month's withdrawal of nebulised dornase alfa (intervention) in 5-18 years old children with CF. Remaining chronic maintenance therapy stayed unchanged. Outcome measures were assessed at two visits one month apart. Primary outcome was absolute change in LCI. Secondary outcomes were FEV1, FEF25–75 and CF Questionnaire-revised (CFQ-R) respiratory symptom score. Possible harmful effects were assessed by comparing the occurrence of pulmonary exacerbations between groups.

      Results

      Twenty-eight children (median age 10.4 [interquartile range: 7.6; 13.5] years) with CF received standard care (n = 14) or intervention (n = 14). Compared with the control group, LCI increased (worsened) 1.74 (95% confidence interval: 0.62; 2.86) during withdrawal of dornase alfa, while FEV1 (-6.8% predicted) and FEF25–75 (-13.1% predicted) decreased significantly. Change in CFQ-R respiratory symptom score and the occurrence of pulmonary exacerbations did not differ significantly between groups.

      Conclusions

      One month's withdrawal of dornase alfa caused increasing ventilation inhomogeneity and deteriorating FEV1 and FEF25–75 in school-age children with mild CF. Hence, adherence to dornase alfa optimally needs to be addressed when using LCI and spirometric parameters as endpoints, even in short-term clinical trials.

      Keywords

      Abbreviations:

      LCI (lung clearance index), CF (cystic fibrosis), FEV1 (forced expired volume in 1 second), FEF25–75 (the forced expired flow at 25–75% of the forced vital capacity), CFQ-R (cystic fibrosis questionnaire-revised), MBW (multiple breath washout), CFTR (cystic fibrosis transmembrane conductance regulator), IQR (interquartile range), 95%CI (95% confidence interval), OSM (online supplementary material), n (number), SD (standard deviation)
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