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S19 Peak Nasal Inspiratory Flow and Nasal Cytokines Are Useful Biomarkers of Nasal Inflammation in Cystic Fibrosis Gene Therapy

THORAX(2019)

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Abstract
Introduction The UK Cystic Fibrosis Gene Therapy Consortium has developed a programme of gene therapy for cystic fibrosis (CF). Studies include administration in the nasal respiratory epithelium to confirm molecular efficacy and safety in advance of lung trials. The aim of this study is to validate the measurement of peak nasal inspiratory flow (PNIF) and cytokines in nasal secretions from stable CF subjects and controls, for use as safety outcome measures to detect immune inflammatory responses. Methods Study participants were asked to perform a short maximal sniff manoeuvre using an In-Check device (Clement Clarke) and the best of 2 proficient attempts was used. PNIF was measured in 19 subjects with stable CF and 23 healthy controls. Smokers and subjects with significant nasal pathology or steroid use were excluded. Repeat visits were performed in 7 patients with CF to assess intra-subject variability. Nasal secretions were obtained from 12 CF subjects and 6 healthy controls within the cohort using open cell polyurethane sponges. Cytokines correlating with innate (IL-1β, IL-8, TNFα, IFNα and CXCL11) and adaptive (IL-4, IL-6, IL-10, RANTES and IFNγ) viral immune responses were analysed using a MagPix bead assay. Results PNIF was not significantly different in between healthy subjects and those with CF and there was no significant difference between male and female subjects overall. PNIF was stable between visits 1 and 2 in CF (%CV 16.6). IL-1β, IL-8, IL-6, IFNγ, TNFα, CXCL11 and RANTES were detectable in most samples. Nasal IFNγ was higher in nasal secretions from subjects with CF (5.8 (0–10.75) pg/ul) compared with healthy controls (0 (0–0), p=0.002) whereas differences were non-significant for other cytokines. In CF subjects, median cytokine level did not vary significantly between visit 1 and 2 for any cytokine. However, mean coefficient of variation for all cytokines was 63%. Conclusions We show for the first time that peak inspiratory nasal flow and detection of cytokines can be rapidly undertaken and are well-tolerated measurements in CF. Group medians for PNIF and all nasal cytokines were stable on repeat visits. These biomarker assays are suitable for safety outcome measures reporting nasal inflammation at clinical trial.
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