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  • Journal article
    Dhariwal J, Cameron A, Wong E, Trujillo-Torralbo B, Del Rosario A, Bakhsoliani E, Paulsen M, Jackson D, Hansel TT, Edwards M, Cousins D, Walton RP, Johnston SLet al., 2021,

    Pulmonary innate lymphoid cell responses during rhinovirus-induced asthma exacerbations

    , Journal of Allergy and Clinical Immunology, ISSN: 0091-6749

    Rationale Type 2 innate lymphoid cells (ILC2s) are significant sources of type 2 cytokines, which are implicated in the pathogenesis of asthma and asthma exacerbations. The role of ILC2s in virus-induced asthma exacerbations is not well-characterized. Objectives To characterize pulmonary ILC responses following experimental rhinovirus challenge in patients with moderate asthma and healthy subjects. Methods Patients with moderate asthma and healthy subjects were inoculated with rhinovirus-16, and underwent bronchoscopy at baseline, day 3 and day 8 post-inoculation. Pulmonary ILC1s and ILC2s were quantified in bronchoalveolar lavage (BAL) using flow cytometry. The ratio of BAL ILC2:ILC1 was assessed to determine their relative contributions to the clinical and immune response to rhinovirus challenge. Measurements and Main Results At baseline, ILC2s were significantly higher in patients with asthma than healthy subjects. At day 8, ILC2s significantly increased from baseline in both groups, which was significantly higher in asthma than in healthy subjects (all comparisons P<0.05). In healthy subjects, ILC1s increased from baseline at day 3 (P=0.001), while in patients with asthma, ILC1s increased from baseline at day 8 (P=0.042). Patients with asthma had significantly higher ILC2:ILC1 ratios at baseline (P=0.024) and day 8 (P=0.005). Increased ILC2:ILC1 ratio in asthma correlated with clinical exacerbation severity and type 2 cytokines in nasal mucosal lining fluid. Conclusions An ILC2-predominant inflammatory profile in asthma was associated with increased severity and duration of rhinovirus infection compared with healthy subjects, supporting the potential role of ILC2s in the pathogenesis of virus-induced asthma exacerbations. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01773590

  • Journal article
    Openshaw P, 2020,

    Global disease burden estimates of respiratory syncytial virus associated with acute respiratory infections in older adults in 015: a systemic review and meta-analysis

    , Journal of Infectious Diseases, Vol: 222, Pages: S577-S583, ISSN: 0022-1899

    Respiratory syncytial virus associated acute respiratory infection (RSV-ARI)constitutes a substantial disease burden in older adults≥65 years. We aimed to identify all studies worldwide investigating the disease burden ofRSV-ARIin this population. We estimated thecommunityincidence, hospitalisationrate and in-hospital case fatality ratio (hCFR) of RSV-ARI in older adults stratified by industrialized anddeveloping regions, with data from a systematic review ofstudies published between January 1996 and April 2018, and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015, to calculate the global and regional burdenin older adults with RSV-ARIin community and in hospital duringthat year. We estimated thenumber ofin-hospital RSV-ARIdeaths by combining hCFR with hospital admission estimates from hospital-based studies. In 2015, there were about 1.5million(95% CI 0.3-6.9) episodes of RSV-ARIin older adults in41industrialised countries (data missing in developing countries), and of these 214,000 (~14.5%; 95% CI 100,000-459,000) were admitted to hospitals. The global number of hospital admissionsforRSV-ARI in older adults was estimated at 336,000 (UR 186,000-614,000).We further estimated about 14,000 (UR 5,000-50,000) in-hospital deaths related to RSV-ARIglobally.The hospital admission rate and hCFR were higher for those ≥65 years than those aged 50-64 years. The disease burden of RSV-ARIamong older adults is substantialwith limited data from developing countries; appropriate prevention and management strategiesare needed to reduce this burden.

  • 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
    Swieboda D, Guo Y, Sagawe S, Thwaites RS, Nadel S, Openshaw PJM, Culley FJ, Culley F, Swieboda D, Guo Y, Thwaites R, Nadel S, Openshaw Pet 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
    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
    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
    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,

    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
    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

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