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  • Journal article
    Turnbull A, Pyle C, Patel D, Jackson P, Hilliard T, Regamey N, Tan H-L, Brown S, Thursfield R, Short C, Mc Fie M, Alton E, Gaggar A, Blalock JE, Lloyd C, Bush A, Davies J, Snelgrove Ret al., 2020,

    Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis

    , Journal of Cystic Fibrosis, Vol: 19, Pages: 40-48, ISSN: 1569-1993

    BackgroundProline–glycine–proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms.MethodsBroncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed.ResultsWhilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase.ConclusionsA striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.

  • Journal article
    Openshaw P, Thwaites R, 2019,

    The respiratory mucosa: Front and center in RSV disease

    , American Journal of Respiratory and Critical Care Medicine, Vol: 200, Pages: 1340-1342, ISSN: 1073-449X
  • Journal article
    Swieboda D, Guo Y, Sagawe S, Thwaites RS, Nadel S, Openshaw PJM, Culley FJet al., 2019,

    OMIP-062: A 14-Color, 16-antibody panel for immunophenotyping human innate yymphoid, myeloid and T cells in small volumes of whole blood and pediatric airway samples

    , Cytometry Part A, Vol: 95, Pages: 1231-1235, ISSN: 1552-4949

    This 14‐color, 16‐antibody OMIP was designed for enumeration of leukocyte responses in pediatric samples, where sample volumes and cell numbers can be very low. Leukocytes identified by this panel include all major members of the innate lymphoid cell (ILC) family (ILC1s, ILC2s, and ILC3s), natural killer cells (NK cells), granulocytes (neutrophils and eosinophils), T‐cells (CD4+ and CD8+), mucosal‐associated invariant T cells (MAIT cells) and NKT‐like cells. The protocol was optimized using small volumes of peripheral blood and validated in airway samples obtained from children (< 2 years of age) admitted to a pediatric intensive care unit (PICU). Given this backdrop, this OMIP is widely applicable to clinical research using low volume or paucicellular samples, such as studies of innate and adaptive immune responses in infants and children, with potential clinical application in diagnostics and monitoring of patients by pediatricians.

  • Journal article
    Southern KW, Barben J, Gartner S, Munck A, Castellani C, Mayell SJ, Davies JC, Winters V, Murphy J, Salinas D, McColley SA, Ren CL, Farrell PMet al., 2019,

    Inconclusive diagnosis after a positive newborn bloodspot screening result for cystic fibrosis; clarification of the harmonised international definition

    , JOURNAL OF CYSTIC FIBROSIS, Vol: 18, Pages: 778-780, ISSN: 1569-1993
  • Journal article
    Rosenfeld M, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, Southern KW, Chilvers M, Higgins M, Tian S, Cooke J, Davies JC, KLIMB study groupet al., 2019,

    An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

    , Journal of Cystic Fibrosis, Vol: 18, Pages: 838-843, ISSN: 1569-1993

    BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS: Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS: Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.

  • Conference paper
    Edmondson C, Westrupp N, Brownlee K, Wallenburg J, Alton E, Bush A, Davies JCet al., 2019,

    ENGAGEMENT (OR NOT) OF TEENAGERS WITH CF IN HEALTH MONITORING AT HOME: RESULTS FROM THE CLIMB-CF FEASABILITY STUDY

    , Publisher: WILEY, Pages: S430-S430, ISSN: 8755-6863
  • Conference paper
    Waller MD, Harman K, Bayfield KJ, Saunders C, Simmonds N, Davies JC, Alton Eet al., 2019,

    OPPORTUNISTIC ASSESSMENT OF UPPER AND LOWER AIRWAY ELECTROPHYSIOLOGY AND LUNG FUNCTION IN CYSTIC FIBROSIS

    , North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S163-S163, ISSN: 8755-6863
  • Conference paper
    Saleh A, Griesenbach U, Alton E, Sinadinos A, Meng Cet al., 2019,

    ASSAY DEVELOPMENT FOR A FIRST-IN-MAN LENTIVIRUS GENE THERAPY TRIAL FOR CYSTIC FIBROSIS

    , Publisher: WILEY, Pages: S358-S358, ISSN: 8755-6863
  • Conference paper
    Edmondson C, Westrupp N, Brownlee K, Wallenburg J, Alton E, Bush A, Davies JCet al., 2019,

    DOES HOME MONITORING OF CHILDREN WITH CF IMPACT DEPRESSION AND ANXIETY LEVELS IN THEIR PARENTS? RESULTS FROM THE CLIMB-CF FEASIBILITY STUDY

    , Publisher: WILEY, Pages: S405-S405, ISSN: 8755-6863
  • Journal article
    Jha A, Dunning J, Tunstall T, Thwaites R, Hoang L, The MOSAIC Investigators, Kon OM, Zambon MC, Hansel TT, Openshaw P, Openshaw P, Jha A, Dunning J, Thwaites R, Hoang Let al., 2019,

    Patterns of systemic and local inflammation in patients with asthma hospitalised with influenza

    , European Respiratory Journal, Vol: 54, ISSN: 0903-1936

    BackgroundPatients with asthma are at risk of hospitalisation with influenza, but the reasons for this predisposition are unknown.Study settingA prospective observational study of adults with PCR-confirmed influenza in 11 UK hospitals, measuring nasal, nasopharyngeal and systemic immune mediators and whole-blood gene expression.ResultsOf 133 admissions, 40 (30%) had previous asthma; these were more often female (70% vs 38.7%, OR 3.69, 95% CI 1.67 to 8.18, P = 0.0012), required less mechanical ventilation (15% vs 37.6%, χ2 6.78, P=0.0338) and had shorter hospital stays (mean 8.3 vs 15.3 d, P=0.0333) than those without. In patients without asthma, severe outcomes were more frequent in those given corticosteroids (OR=2.63, 95% CI=1.02-6.96, P=0.0466) or presenting >4 days after disease onset (OR 5.49, 95% CI 2.28–14.03, P=0.0002). Influenza vaccination in at-risk groups (including asthma) were lower than intended by national policy and the early use of antiviral medications were less than optimal. Mucosal immune responses were equivalent between groups. Those with asthma had higher serum IFN-α but lower serum TNF, IL-5, IL-6, CXCL8, CXCL9, IL-10, IL-17 and CCL2 levels (all P<0.05); both groups had similar serum IL-13, total IgE, periostin and blood eosinophil gene expression levels. Asthma diagnosis was unrelated to viral load, IFN-α, IFN-γ, IL-5 or IL-13 levels.ConclusionsAsthma is common in those hospitalised with influenza, but may not represent classical Type 2-driven disease. Those admitted with influenza tend to be female with mild serum inflammatory responses, increased serum IFN-α levels and good clinical outcomes.

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