Publications

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

Zhu J, Message SD, Mallia P, Kebadze T, Contoli M, Ward CK, Barnathan ES, Mascelli MA, Kon OM, Papi A, Stanciu LA, Edwards MR, Jeffery PK, Johnston SLet al., 2019,

Bronchial mucosal Interferon-α/β and pattern recognition receptor expression in experimental rhinovirus-induced asthma exacerbations

, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 114-125.e4, ISSN: 0091-6749

BACKGROUND: The innate immune system senses viral infection via pattern recognition receptors (PRRs) leading to type I interferon (IFN) production: their roles in rhinovirus (RV)-induced asthma exacerbations in vivo are uncertain. OBJECTIVES: To compare bronchial mucosal type I IFN and PRR expression at baseline and following RV infection in atopic asthmatic and control subjects. METHODS: Immunohistochemistry was used to detect expression of IFN-α, IFN-β and the PRRs, toll-like receptor (TLR)-3, melanoma-differentiation-associated gene-5 (MDA-5) and retinoic-acid-inducible protein-I (RIG-I) in bronchial biopsies from 10 atopic asthmatics and 15 non-asthmatic non-atopic controls at baseline and on day four and six weeks following RV infection. RESULTS: We observed IFN-α/β deficiency in bronchial epithelium at three time points in asthma in vivo. Lower epithelial IFN-α/β expression was related to greater virus load, worse airway symptoms, airway hyperresponsiveness (AHR) and reductions in lung function during RV infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/β in asthma during infection. IFN deficiency at baseline was not accompanied by deficient PRR expression in asthma. Both epithelial and subepithelial PRR expression was induced during RV infection. RV infection increased numbers of subepithelial IFN/PRRs-expressing inflammatory cells were related to greater virus load, AHR and reductions in lung function. CONCLUSIONS: Bronchial epithelial IFN-α/β expression and numbers of subepithelial IFN-α/β-expressing monocytes/macrophages during infection were both deficient in asthma. Lower epithelial IFN-α/β expression was associated with adverse clinical outcomes following RV infection in vivo. Increases in subepithelial cells expressing IFN/PRRs during infection were also related to greater virus load/illness severity.

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.

Conference paper

Miles JHA, Dubuis E, Bonvini SJ, Wortley MA, Trevisani M, Villetti G, Patacchini R, Birrell M, Belvisi MGet al., 2019,