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Conference paperSaleh A, Meng C, Chan M, et al., 2018,
RNA in-situ hybridisation is able to quantify lentiviral transduction of respiratory epithelium
, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A7-A7, ISSN: 1043-0342 -
Journal articleRosenfeld M, Wainwright CE, Higgins M, et al., 2018,
Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study
, Lancet Respiratory Medicine, Vol: 6, Pages: 545-553, ISSN: 2213-2600BACKGROUND: Ivacaftor is generally safe and effective in patients aged 2 years and older who have cystic fibrosis and specific CFTR mutations. We assessed its use in children aged 12 to <24 months. METHODS: The ARRIVAL study is a phase 3, single-arm, two-part, multicentre study. Eligible children were aged 12 to <24 months at enrolment and had a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele and could participate in one or both parts of the study. Children received 50 mg (bodyweight 7 to <14 kg) or 75 mg (bodyweight ≥14 to <25 kg) ivacaftor orally every 12 h. In study part A, children received ivacaftor for 3 days plus one morning. In study part B, children received 24 weeks of treatment. Children were enrolled into part A at seven sites in Australia (one site), the UK (one), and the USA (five) and into part B at 13 sites in Australia (two sites), Canada (one), the UK (three), and the USA (seven). Primary endpoints were pharmacokinetics (part A) and safety (parts A and B) in children who received at least one dose of ivacaftor. Secondary endpoints in part B were pharmacokinetics in children who received at least one dose of ivacaftor and absolute change from baseline in sweat chloride concentration. We also explored changes in growth parameters and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02725567. FINDINGS: Children aged 12 to <24 months were enrolled between Aug 25, 2016, and Nov 1, 2017. Seven children were enrolled in part A, of whom five received 50 mg and two received 75 mg ivacaftor. All completed treatment. Of 19 children enrolled in part B, including one from part A, all received 50 mg ivacaftor and 18 completed treatment (one withdrew because of difficulty with blood draws). All children received at least one dose of ivacaftor. Pharmacokinetics indicated exposure was similar to that in children aged 2 to <6 years and adults. No children discont
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Journal articleTurnbull AR, Murphy R, Behrends V, et al., 2018,
Impact of T2R38 receptor polymorphisms on pseudomonas aeruginosa infection in cystic fibrosis
, American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1635-1638, ISSN: 1073-449X -
Journal articleSchwarze J, Openshaw P, Jha A, et al., 2018,
Influenza burden, prevention and treatment in asthma - a scoping review by the EAACI Influenza in Asthma Task Force
, Allergy, Vol: 73, Pages: 1151-1181, ISSN: 0105-4538To address uncertainties in the prevention and management of influenza in people with asthma, we performed a scoping review of the published literature on influenza burden; current vaccine recommendations; vaccination coverage; immunogenicity, efficacy, effectiveness and safety of influenza vaccines; and the benefits of antiviral drugs in people with asthma. We found significant variation in the reported rates of influenza detection in individuals with acute asthma exacerbations making it unclear to what degree influenza causes exacerbations of underlying asthma. The strongest evidence of an association was seen in studies of children. Countries in the European Union currently recommend influenza vaccination of adults with asthma; however, coverage varied between regions. Coverage was lower among children with asthma. Limited data suggest that good seroprotection and seroconversion can be achieved in both children and adults with asthma and that vaccination confers a degree of protection against influenza illness and asthma related morbidity to children with asthma. There were insufficient data to determine efficacy in adults. Overall, influenza vaccines appeared to be safe for people with asthma. We identify knowledge gaps and make recommendations on future research needs in relation to influenza in patients with asthma. This article is protected by copyright. All rights reserved.
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Journal articleDunning J, Blankley S, Hoang LT, et al., 2018,
Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza
, Nature Immunology, Vol: 19, Pages: 625-635, ISSN: 1529-2916Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.
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Journal articleThwaites RS, Gunawardana NC, Broich V, et al., 2018,
Biphasic activation of complement and fibrinolysis during the human nasal allergic response
, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 1892-1895.e6, ISSN: 0091-6749Complement, coagulation and fibrinolysis contribute to the pathology of many respiratory diseases. Here we detail the biphasic activation of these pathways following nasal allergen challenge. Understanding these mechanisms may lead to therapeutic insight in common respiratory diseases.
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Journal articleEdmondson C, Davies JC, 2018,
Predicting the Future of Cystic Fibrosis Lung Disease: Gene Expression Holds Some of the Answers.
, Ann Am Thorac Soc, Vol: 15, Pages: 556-557 -
Journal articleThwaites RS, Coates M, Ito K, et al., 2018,
Reduced nasal viral load and IFN responses in infants with RSV bronchiolitis and respiratory failure
, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 1074-1084, ISSN: 1073-449XRATIONALE: Respiratory syncytial virus (RSV) bronchiolitis is a major cause of morbidity and mortality in infancy. Severe disease is thought to result from uncontrolled viral replication, an excessive immune response, or both. OBJECTIVES: To determine RSV load and immune mediator levels in nasal mucosal lining fluid by serial sampling of nasal fluids from cases of moderate and severe bronchiolitis over the course of infection. METHODS: Infants with viral bronchiolitis necessitating admission (n=55) were recruited from a paediatric centre during 2016/17. Of these, 30 were RSV infected (18 'moderate', and 12 mechanically ventilated 'severe'). Nasal fluids were sampled frequently over time using nasosorption devices and nasophayngeal aspiration (NPA). Hierarchical clustering of time weighted averages (TWA) was performed to investigate cytokine and chemokine levels, and gene expression profiling was conducted. MEASUREMENTS AND MAIN RESULTS: Unexpectedly, cases of severe RSV bronchiolitis had lower nasal viral loads and reduced interferon (IFN)-γ and CCL5/RANTES levels compared to those with moderate disease, especially when allowance was made for disease duration (all P<0.05). Reduced cytokine/chemokine levels in severe disease were also seen in children with other viral infections. Gene expression analysis of NPA samples (n=43) confirmed reduced type-I IFN gene expression in severe bronchiolitis accompanied by enhanced expression of MUC5AC and IL17A. CONCLUSIONS: Infants with severe RSV bronchiolitis have lower nasal viral load, IP-10/CXCL10 and type-I IFNs levels compared to moderately ill children, but enhanced MUC5AC and IL17A gene expression in nasal cells.
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Conference paperCai F, Abreu F, Ding HT, et al., 2018,
Nasal Biomarkers Characterization In Lebrikizumab Bronchoscopy Study (CLAVIER)
, American-Academy-of-Allergy-Asthma-and-Immunology / World-Allergy-Organization Joint Congress, Publisher: MOSBY-ELSEVIER, Pages: AB118-AB118, ISSN: 0091-6749- Author Web Link
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- Citations: 2
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Journal articleDhariwal J, Cameron A, Wong E, et al., 2018,
Pulmonary Innate Lymphoid Cell Responses During Rhinovirus-Induced Asthma Exacerbations
, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 141, Pages: AB195-AB195, ISSN: 0091-6749- Author Web Link
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- Citations: 1
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