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  • Journal article
    Shrine N, Portelli MA, John C, Soler Artigas M, Bennett N, Hall R, Lewis J, Henry AP, Billington CK, Ahmad A, Packer RJ, Shaw D, Pogson ZEK, Fogarty A, McKeever TM, Singapuri A, Heaney LG, Mansur AH, Chaudhuri R, Thomson NC, Holloway JW, Lockett GA, Howarth PH, Djukanovic R, Hankinson J, Niven R, Simpson A, Chung KF, Sterk PJ, Blakey JD, Adcock IM, Hu S, Guo Y, Obeidat M, Sin DD, van den Berge M, Nickle DC, Bossé Y, Tobin MD, Hall IP, Brightling CE, Wain LV, Sayers Iet al., 2019,

    Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study

    , Lancet Respiratory Medicine, Vol: 7, Pages: 20-34, ISSN: 2213-2600

    BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma. METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls. FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive im

  • Journal article
    Frent SM, Chapman KR, Larbig M, Mackay A, Fogel R, Gutzwiller FS, Shen S, Patalano F, Banerji D, Kostikas K, Wedzicha JAet al., 2019,

    Capturing exacerbations of chronic obstructive pulmonary disease with EXACT: A sub-analysis of FLAME

    , American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 43-51, ISSN: 1073-449X

    Rationale: Chronic obstructive pulmonary disease (COPD) exacerbations accelerate lung function decline, reduce quality of life, and increase mortality. A subset of patients (n=457) from the FLAME study used the EXAcerbations of COPD Tool (EXACT®) to capture symptom-defined exacerbations. Objectives: To evaluate the effect of indacaterol/glycopyrronium (IND/GLY) versus salmeterol/fluticasone (SFC) on symptom-defined exacerbations measured using EXACT, and to assess differences between these events and exacerbations requiring healthcare resource use (HCRU). Methods: All patients in FLAME used an e-Diary to record and detect symptom deteriorations; HCRU-related exacerbations were confirmed by investigators. In patients using the EXACT questionnaire, the onset, recovery and magnitude of symptom-defined exacerbations were identified by changes in total scores relative to baseline. We analyzed the annualized rate and time-to-first symptom-defined (EXACT) exacerbation, and assessed differences between symptom-defined and HCRU events in terms of number, severity and concordance. Measurements and Main Results: A non-significant 17% reduction in the annualized rate of symptom-defined (EXACT) exacerbations (rate ratio: 0.83, 95% CI: 0.60, 1.14, P = 0.242) and a numerically longer time to first symptom-defined exacerbation were observed with IND/GLY versus SFC (HR 0.76, 95% CI: 0.56, 1.03, P = 0.075). These results were consistent with data from the overall FLAME population. 23.5% of symptom-defined (EXACT) events corresponded to HCRU events, and 22.2% of HRCU events were captured by EXACT (kappa index 0.24, 95% CI: 0.15, 0.33). Conclusions: Regardless of the exacerbation definition used, our findings support the use of LABA/LAMAs as the preferred treatment option for patients at risk of future exacerbations.

  • Journal article
    Hersh CP, Adcock IM, Celedon JC, Cho MH, Christiani DC, Himes BE, Kaminski N, Mathias RA, Meyers DA, Quackenbush J, Redline S, Steiling KA, Tabor HK, Tobin MD, Wurfel MM, Yang IV, Koppelman GHet al., 2019,

    High-throughput sequencing in respiratory, critical care, and sleep medicine research. An Official American Thoracic Society Workshop Report

    , Annals of the American Thoracic Society, Vol: 16, Pages: 1-16, ISSN: 2329-6933

    High-throughput, “next-generation” sequencing methods are now being broadly applied across all fields of biomedical research, including respiratory disease, critical care, and sleep medicine. Although there are numerous review articles and best practice guidelines related to sequencing methods and data analysis, there are fewer resources summarizing issues related to study design and interpretation, especially as applied to common, complex, nonmalignant diseases. To address these gaps, a single-day workshop was held at the American Thoracic Society meeting in May 2017, led by the American Thoracic Society Section on Genetics and Genomics. The aim of this workshop was to review the design, analysis, interpretation, and functional follow-up of high-throughput sequencing studies in respiratory, critical care, and sleep medicine research. This workshop brought together experts in multiple fields, including genetic epidemiology, biobanking, bioinformatics, and research ethics, along with physician-scientists with expertise in a range of relevant diseases. The workshop focused on application of DNA and RNA sequencing research in common chronic diseases and did not cover sequencing studies in lung cancer, monogenic diseases (e.g., cystic fibrosis), or microbiome sequencing. Participants reviewed and discussed study design, data analysis and presentation, interpretation, functional follow-up, and reporting of results. This report summarizes the main conclusions of the workshop, specifically addressing the application of these methods in respiratory, critical care, and sleep medicine research. This workshop report may serve as a resource for our research community as well as for journal editors and reviewers of sequencing-based manuscript submissions in our research field.

  • Conference paper
    Anders KL, Belchamber KBR, Gaboriau DCA, Barnes PJ, Donnelly LEet al., 2019,

    Dynein Has Defective Activity in COPD Macrophage Phagocytosis

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Conference paper
    Wortley MA, Bonvini SJ, Adcock JJ, Dubuis ED, Maher SA, Penn RB, Belvisi MG, Birrell MAet al., 2019,

    Agonism of EP<sub>4</sub> Receptors Expressed on Airway Sensory Nerves Inhibits Cough

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Conference paper
    Chen X, Bonvini SJ, Dubuis ED, Ariyasu T, Ushio S, Birrell MA, Belvisi MGet al., 2019,

    Cromoglycate Inhibits Oxidative Stress Triggered Airway Sensory Nerves Through Its Actions on the Ion Channel TRPV2: A New Insight into Biological Mechanism of Action

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Conference paper
    Ritchie AI, Donaldson GC, El-Emir E, Calverley PM, Vestbo J, Wedzicha JAet al., 2019,

    The British Lung Foundation Early COPD Consortium - Recruitment and Results from an Initial Pilot

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Conference paper
    Wiseman DJ, Kamal F, Finney L, Ritchie AI, Gent J, Edwards MR, Johnston SL, Donaldson GC, Openshaw PJ, Wedzicha JAet al., 2019,

    Respiratory Syncytial Virus (RSV) Detection Is Associated with an Increased Inflammatory Response in Stable (non-Exacerbating) Chronic Obstructive Pulmonary Disease (COPD) Patients

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Conference paper
    Finney L, Fenwick PS, Kemp S, Bakhsoliani E, Belchamber KBR, Edwards MR, Donaldson GC, Donnelly L, Mallia P, Johnston SL, Wedzicha JAet al., 2019,

    Interferon Response to Human Rhinovirus Is Impaired in Alveolar Macrophages but Not Bronchial Epithelial Cells in Chronic Obstructive Pulmonary Disease

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Journal article
    Garcia-Marcos L, Edwards J, Kennington E, Aurora P, Baraldi E, Carraro S, Gappa M, Louis R, Moreno-Galdo A, Peroni DG, Pijnenburg M, Priftis KN, Sanchez-Solis M, Schuster A, Walker S, Blakey J, Compton C, Fleming L, Fowler S, Gaillard E, Gibson F, Glenn Crater G, Niven R, Roberts A, Ryan D, Seppala U, Usmani O, van der Schee M, van Sont Jet al., 2018,

    Priorities for future research into asthma diagnostic tools: A PAN-EU consensus exercise from the European asthma research innovation partnership (EARIP)

    , Clinical and Experimental Allergy, Vol: 48, Pages: 104-120, ISSN: 0954-7894

    The diagnosis of asthma is currently based on clinical history, physical examination and lung function, and to date, there are no accurate objective tests either to confirm the diagnosis or to discriminate between different types of asthma. This consensus exercise reviews the state of the art in asthma diagnosis to identify opportunities for future investment based on the likelihood of their successful development, potential for widespread adoption and their perceived impact on asthma patients. Using a two-stage e-Delphi process and a summarizing workshop, a group of European asthma experts including health professionals, researchers, people with asthma and industry representatives ranked the potential impact of research investment in each technique or tool for asthma diagnosis and monitoring. After a systematic review of the literature, 21 statements were extracted and were subject of the two-stage Delphi process. Eleven statements were scored 3 or more and were further discussed and ranked in a face-to-face workshop. The three most important diagnostic/predictive tools ranked were as follows: “New biological markers of asthma (eg genomics, proteomics and metabolomics) as a tool for diagnosis and/or monitoring,” “Prediction of future asthma in preschool children with reasonable accuracy” and “Tools to measure volatile organic compounds (VOCs) in exhaled breath.”.

  • Journal article
    Farne H, Groves H, Gill S, stokes I, Mccolloch S, karoly E, Trujillo-Torralbo M, Johnston S, Mallia P, Tregoning Jet al., 2018,

    Comparative metabolomic sampling of upper and lower airways by four different methods to identify biochemicals that may support bacterial growth

    , Frontiers in Cellular and Infection Microbiology, Vol: 8, ISSN: 2235-2988

    Bacteria need nutrients from the host environment to survive, yet we know little about which biochemicals are present in the airways (the metabolome), which of these biochemicals are essential for bacterial growth and how they change with airway disease. The aims of this pilot study were to develop and compare methodologies for sampling the upper and lower airway metabolomes and to identify biochemicals present in the airways that could potentially support bacterial growth. Eight healthy human volunteers were sampled by four methods: two standard approaches - nasal lavage and induced sputum, and two using a novel platform, synthetic adsorptive matrix (SAM) strips—nasosorption and bronchosorption. Collected samples were analyzed by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Five hundred and eighty-one biochemicals were recovered from the airways belonging to a range of metabolomic super-pathways. We observed significant differences between the sampling approaches. Significantly more biochemicals were recovered when SAM strips were used, compared to standard sampling techniques. A range of biochemicals that could support bacterial growth were detected in the different samples. This work demonstrates for the first time that SAM strips are a highly effective method for sampling the airway metabolome. This work will assist further studies to understand how changes in the airway metabolome affect bacterial infection in patients with underlying airway disease.

  • Journal article
    Grigg J, Nibber A, Paton JY, Chisholm A, Guilbert TW, Kaplan A, Turner S, Roche N, Hillyer E, Price DB, Collaborators from REG Small Airways Working Group and Child Health Working Group includes, van Aalderen WMC, Murray CS, Phipatanakul W, Sonnappa S, Hoe TO, Martin RJ, Papi A, Szefler SJ, Skinner D, McQueen RB, Usmani OSet al., 2018,

    Matched cohort study of therapeutic strategies to prevent preschool wheezing/asthma attacks

    , Journal of Asthma and Allergy, Vol: 11, ISSN: 1178-6965

    Background: An inhaled corticosteroid (ICS) or leukotriene receptor antagonist (LTRA) may prevent wheezing/asthma attacks in preschoolers with recurrent wheeze when added to short-acting β-agonist (SABA).Objective: The aim of this historical matched cohort study was to assess the effectiveness of these treatments for preventing wheezing/asthma attacks.Methods: Electronic medical records from the Optimum Patient Care Research Database were used to characterize a UK preschool population (1–5 years old) with two or more episodes of wheezing during 1 baseline year before first prescription (index date) of ICS or LTRA, or repeat prescription of SABA. Children initiating ICS or LTRA on the index date were matched 1:4 to those prescribed only SABA for age, sex, year of index prescription, mean baseline SABA dose, baseline attacks, baseline antibiotic prescriptions, and eczema diagnosis. Wheezing/asthma attacks (defined as asthma-related emergency attendance, hospital admission, or acute oral corticosteroid prescription) during 1 outcome year were compared using conditional logistic regression.Results: Matched ICS and SABA cohorts included 990 and 3,960 children, respectively (61% male; mean [SD] age 3.2 [1.3] years), and matched LTRA and SABA cohorts included 259 and 1,036 children, respectively (65% male; mean [SD] age 2.6 [1.2] years). We observed no significant difference between matched cohorts in the odds of a wheezing/asthma attack: ICS vs SABA, OR (95% CI) 1.01 (0.85–1.19) and LTRA vs SABA, OR (95% CI) 1.28 (0.96–1.72).Conclusion: We found no evidence that initiation of ICS or LTRA therapy is associated with fewer attacks during 1 outcome year than SABA alone for a heterogeneous group of preschool children with recurrent wheeze in the real-life clinical setting.

  • Journal article
    Cowie MR, Gallagher AM, Simonds AK, 2018,

    Treating central sleep apnoea in heart failure: is pull better than push?

    , European Journal of Heart Failure, Vol: 20, Pages: 1755-1759, ISSN: 1388-9842
  • Journal article
    Loeckx M, Rabinovich RA, Demeyer H, Louvaris Z, Tanner R, Rubio N, Frei A, De Jong C, Gimeno-Santos E, Rodrigues FM, Buttery SC, Hopkinson NS, Busching G, Strassmann A, Serra I, Vogiatzis I, Garcia-Aymerich J, Polkey MI, Troosters Tet al., 2018,

    Smartphone-based physical activity telecoaching in chronic obstructive pulmonary disease: Mixed-methods study on patient experiences and lessons for implementation

    , JMIR mHealth and uHealth, Vol: 6, ISSN: 2291-5222

    Background: Telecoaching approaches can enhance physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD). However, their effectiveness is likely to be influenced by intervention-specific characteristics.Objective: This study aimed to assess the acceptability, actual usage, and feasibility of a complex PA telecoaching intervention from both patient and coach perspectives and link these to the effectiveness of the intervention.Methods: We conducted a mixed-methods study based on the completers of the intervention group (N=159) included in an (effective) 12-week PA telecoaching intervention. This semiautomated telecoaching intervention consisted of a step counter and a smartphone app. Data from a project-tailored questionnaire (quantitative data) were combined with data from patient interviews and a coach focus group (qualitative data) to investigate patient and coach acceptability, actual usage, and feasibility of the intervention. The degree of actual usage of the smartphone and step counter was also derived from app data. Both actual usage and perception of feasibility were linked to objectively measured change in PA.Results: The intervention was well accepted and perceived as feasible by all coaches present in the focus group as well by patients, with 89.3% (142/159) of patients indicating that they enjoyed taking part. Only a minority of patients (8.2%; 13/159) reported that they found it difficult to use the smartphone. Actual usage of the step counter was excellent, with patients wearing it for a median (25th-75th percentiles) of 6.3 (5.8-6.8) days per week, which did not change over time (P=.98). The smartphone interface was used less frequently and actual usage of all daily tasks decreased significantly over time (P<.001). Patients needing more contact time had a smaller increase in PA, with mean (SD) of +193 (SD 2375) steps per day, +907 (SD 2306) steps per day, and +1489 (SD 2310) steps per day in high, medium, and low contact

  • Conference paper
    Finney LJ, Belchamber KBR, Kemp SV, Fenwick P, Mallia P, Donaldson G, Johnston SL, Donnelly L, Wedzicha JAet al., 2018,

    HUMAN RHINOVIRUS IMPAIRS THE INNATE IMMUNE RESPONSE TO BACTERIA IN MACROPHAGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    , Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A9-A9, ISSN: 0040-6376
  • Conference paper
    Moore AJS, Dean LSN, Fraceto LF, Lima R, Tetley TDet al., 2018,

    THE EFFECTS OF A NOVEL POLY(EPSILON-CAPROLACTONE) NANOCAPSULE CONTAINING THE PESTICIDE ATRAZINE ON HUMAN ALVEOLAR EPITHELIUM

    , Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A20-A21, ISSN: 0040-6376
  • Journal article
    Li F, Xu M, Wang M, Wang L, Wang H, Zhang H, Chen Y, Gong J, Zhang JJ, Adcock IM, Chung KF, Zhou Xet al., 2018,

    Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema

    , Respiratory Research, Vol: 19, ISSN: 1465-9921

    BackgroundMitochondrial damage leading to oxidant stress may play an important role in the pathogenesis of airflow obstruction and emphysema. NLPR3 inflammasome can be activated by mitochondrial ROS (mtROS) and other stimuli. We examined the importance of mtROS and NLRP3 inflammasome and their interactions in multiple ozone-induced lung inflammation and emphysema.MethodsC57/BL6 mice were exposed to ozone (2.5 ppm, 3 h) or filtered air twice a week over 6 weeks. MitoTEMPO (20 mg/kg), an inhibitor of mtROS, and VX765 (100 mg/kg), an inhibitor of caspase-1 activity, were administered by intraperitoneal or intragastric injection respectively 1 h prior to each ozone exposure for 6 weeks.ResultsOzone-exposed mice had increased bronchoalveolar lavage (BAL) total cells and levels of IL-1β, KC and IL-6, augmented lung tissue inflammation scores, enhanced oxidative stress with higher serum 8-OHdG concentrations, emphysema with greater mean linear intercept (Lm), airway remodeling with increased airway smooth muscle mass and airflow limitation as indicated by a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Both MitoTEMPO and VX765 reduced lung inflammation scores, cytokine levels, oxidative stress and increased mitochondrial fission proteins. VX765 also attenuated emphysema, airway remodeling and airflow limitation. MitoTEMPO inhibited the increased expression of mitochondrial complex II and IV and of NLPR3 while VX765 inhibited the expression and activity of NLRP3 and caspase-1 pathway in the lung.ConclusionsBoth mtROS and NLRP3 inflammasome play a role in ozone-induced lung inflammation while only NLRP3 is involved in ozone-induced emphysema.

  • Journal article
    Compte M, Lykke Harwood S, Munoz IG, Navarro R, Zonca M, Perez-Chacon G, Erce-Llamazares A, Merino N, Tapia-Galisteo A, Cuesta AM, Mikkelsen K, Caleiras E, Nunez-Prado N, Aznar MA, Lykkemark S, Martinez-Torrecuadrada J, Melero I, Blanco FJ, Bernardino de la Serna J, Zapata JM, Sanz L, Alvarez-Vallina Let al., 2018,

    A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

    , Nature Communications, Vol: 9, ISSN: 2041-1723

    The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8N/CEGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy.

  • Journal article
    Simonds AK, 2018,

    Happy ever after? A new assessment tool for long-term noninvasive ventilation: the S<SUP>3</SUP>-NIV questionnaire

    , EUROPEAN RESPIRATORY JOURNAL, Vol: 52, ISSN: 0903-1936
  • Journal article
    Buttery S, Kemp S, Shah P, Waller D, Jordan S, Lee JL, Banya W, Steiner M, Hopkinson Net al., 2018,

    The CELEB trial: Comparative effectiveness of lung volume reduction surgery for emphysema and bronchoscopic lung volume reduction with valve placement. A protocol for a randomised controlled trial

    , BMJ Open, Vol: 8, ISSN: 2044-6055

    Introduction: Although lung volume reduction surgery and bronchoscopic lung volume reduction with endobronchial valves have both been shown to improve lung function, exercise capacity and quality of life in appropriately selected patients with emphysema, there are no direct comparison data between the two procedures to inform clinical decision making. Methods and Analysis: We describe the protocol of the CELEB study (ISRCTN19684749), a randomised controlled trial which will compare outcomes at 1 year between the two procedures, using a composite disease severity measure, the iBODE score, which includes body mass index, lung function, breathlessness and exercise capacity.Ethics and Dissemination: Ethical approval to conduct the study has been obtained from the Fulham Research Ethics Committee, London (16/LO/0286). The outcome of this trial will provide information to guide treatment choices in this population and will be presented at national and international meetings and published in peer-reviewed journals. We will also disseminate the main results to all participants in a letter.

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