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  • Journal article
    Hakim A, Khan Y, Esteban I, Meah S, Miller-Larsson A, Barnes PJ, Usmani OSet al., 2019,

    Low-dose budesonide/formoterol counteracts airway inflammation and improves lung function in COPD

    , American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 662-664, ISSN: 1073-449X

    The latest Global Initiative for Chronic Obstructive Lung Disease (GOLD) document recommends new treatment algorithms, with inhaled corticosteroids (ICS) use only in moderate-to-severely symptomatic COPD patients with repeated exacerbations, where the emphasis is to review ICS use and to reduce ICS dosing (1). Indeed, safety concerns of pneumonia (2) with high-dose ICS has further concerted focus upon using appropriate doses of ICS. It is well-established that ICS in combination with long-acting β2-adrenoceptor agonist (LABA) can decrease exacerbations, improve symptomsand increase quality of life in patients with COPD (3-4), but nonetheless, the rationale to consider step-down of ICS is supported by several clinical studies (5). The Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial studied severe COPD patients on therapy with ICS, LAMA and LABA, where stepwise withdrawal of ICS did not lead to an increase in exacerbations compared to continued ICS use (6). Determining the optimal dose of ICS and LABA combination therapy is of great biological and clinical importance in order to address safety concerns associated with high-dose ICS use. There is in vitro evidence to support the clinical practice of using low-dose ICS. Low-dose ICS in combination with LABA enhances corticosteroid function by enhancing glucocorticoid receptor (GR) activity (7) and suppresses the release of inflammatory mediators (8). However, it is unknown whether this observation of enhanced corticosteroid function with low-dose ICS/LABA has a direct effect on airways inflammation and lung function. Our study investigated the cellular function that may be relevant and underpin the clinical approach to lowering the dose of ICS therapy in COPD patients. We compared the single administra

  • Journal article
    Norris F, Mallia P, 2019,

    Lesson of the month 2: A case of nitrous oxide-induced pancytopenia

    , Clinical Medicine, Vol: 19, Pages: 129-130, ISSN: 1470-2118

    An 18-year-old female patient presented to the emergency department with non-specific neurological and gastrointestinal symptoms and was found to be pancytopenic. Her vitamin B12 level was low with a normal mean corpuscular volume and her full blood count 2 months previously had been within normal range. She reported heavy use of nitrous oxide over the previous 2 weeks and other investigations revealed no cause for her pancytopenia. Her pancytopenia resolved with discontinuation of nitrous oxide and vitamin B12 treatment. Heavy use of nitrous oxide should be considered as a cause of pancytopenia.

  • Journal article
    Ghosh B, Gaike AH, Pyasi K, Brashier B, Das VV, Londhe JD, Juvekar S, Shouche YS, Donnelly LE, Salvi SS, Barnes PJet al., 2019,

    Bacterial load and defective monocyte-derived macrophage bacterial phagocytosis in biomass-smoke COPD

    , European Respiratory Journal, Vol: 53, Pages: 1-14, ISSN: 0903-1936

    Lower airway colonisation with potentially pathogenic bacterial species (PPBs) is associated with defective bacterial phagocytosis, in monocyte-derived macrophages (MDMs) and alveolar macrophages, from tobacco-smoke associated COPD (S-COPD) subjects. In developing world, COPD among non-smokers is largely due to biomass-smoke (BMS) exposure. Yet, little is known about PPBs colonisation and its association with impaired innate immunity in these subjects.We investigated the PPBs load (Streptococcus pneumoniae, SP; Haemophilus influenzae, HI; Moraxella catarrhalis, MC; and Pseudomonas aeruginosa, PA) in BMS-exposed COPD (BMS-COPD) compared with S-COPD and spirometrically normal subjects. We also examined the association between load of PPBs with phagocytic activity of MDMs and lung function.Induced sputum and peripheral venous blood samples were collected from 18 healthy non-smokers, 15 smokers without COPD, 16 BMS-exposed healthy, 19 S-COPD and 23 BMS-COPD subjects. PPBs load in induced sputum and MDMs phagocytic activity were determined using qPCR and fluorimetry respectively.Higher bacterial load of SP, HI, and PA were observed in BMS-COPD. Increased PPBs load in BMS-exposed subjects was significantly negatively associated with defective phagocytosis in MDMs, and spirometric lung function indices (p<0.05).Increased load of PPBs in airways of BMS-COPD subjects is inversely associated with defective bacterial phagocytosis and lung function.

  • Journal article
    Schleich F, Bikov A, Mathioudakis AG, McDonnell M, Andersson C, Bonini M, Uller L, Idzko M, Singh D, Lopez-Campos JL, Bossios A, Adcock IM, Usmani O, Spanevello A, Bonvini SJet al., 2019,

    Research highlights from the 2018 European Respiratory Society International Congress: airway disease.

    , ERJ Open Research, Vol: 5, ISSN: 2312-0541

    The annual European Respiratory Society (ERS) International Congress (held in Paris in 2018) was once again a platform for discussion of the highest-quality scientific research, cutting-edge techniques and innovative new therapies within the respiratory field. This article discusses only some of the high-quality research studies presented at this year's Congress, with a particular focus on airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis and cough, as presented through Assembly 5 of the ERS (Airway Diseases: Asthma and COPD). The authors establish the key take-home messages of these studies, compare their findings and place them in the context of current understanding.

  • Journal article
    Chapman KR, Hurst JR, Fogel RB, Pfister P, Kostikas K, Wedzicha JA, SUNSET investigatorset al., 2019,

    Reply to: Different background, short duration, inappropriate participants may harm your conclusion

    , American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 390-392, ISSN: 1073-449X
  • Journal article
    Tregoning JS, Mallia P, 2019,

    Modulating airway glucose to reduce respiratory infections

    , Expert Review of Respiratory Medicine, Vol: 13, Pages: 121-124, ISSN: 1747-6348
  • Journal article
    Erriah M, Pabreja K, Fricker M, Baines KJ, Donnelly LE, Bylund J, Karlsson A, Simpson JLet al., 2019,

    Galectin-3 enhances monocyte-derived macrophage efferocytosis of apoptotic granulocytes in asthma

    , Respiratory Research, Vol: 20, ISSN: 1465-9921

    BackgroundGalectin-3 is a 32 kDa protein secreted by macrophages involved in processes such as cell activation, chemotaxis and phagocytosis. Galectin-3 has previously been shown to improve the ability of airway macrophages to ingest apoptotic cells (efferocytosis) in chronic obstructive pulmonary disease (COPD) and may be of interest in non-eosinophilic asthma (NEA) which is also characterised by impaired efferocytosis. It was hypothesised that the addition of exogenous galectin-3 to monocyte-derived macrophages (MDMs) derived from donors with NEA would enhance their ability to engulf apoptotic granulocytes.MethodsEligible non-smoking adults with asthma (n = 19), including 7 with NEA and healthy controls (n = 10) underwent a clinical assessment, venepuncture and sputum induction. MDMs were co-cultured with apoptotic granulocytes isolated from healthy donors with or without exogenous recombinant galectin-3 (50 μg/mL) and efferocytosis was assessed by flow cytometry. Galectin-3 expression and localisation in MDMs was visualised by immunofluorescence staining and fluorescence microscopy. Galectin-3, interleukin (IL)-6 and CXCL8 secretion were measured in cell culture supernatants by ELISA and cytometric bead array.ResultsBaseline efferocytosis (mean (±standard deviation)) was lower in participants with asthma (33.2 (±17.7)%) compared with healthy controls (45.3 (±15.9)%; p = 0.081). Efferocytosis did not differ between the participants with eosinophilic asthma (EA) (31.4 (±19.2)%) and NEA (28.7 (±21.5)%; p = 0.748). Addition of galectin-3 significantly improved efferocytosis in asthma, particularly in NEA (37.8 (±18.1)%) compared with baseline (30.4 (±19.7)%; p = 0.012). Efferocytosis was not associated with any of the clinical outcomes but was negatively correlated with sputum macrophage numbers (Spearman r = −&thi

  • Conference paper
    Fischer M, Kirkman-Thomas A, Mallia P, Johnston SL, Johnson Set al., 2019,

    Elastase Activity as an Indicator of Exacerbation and Disease Severity in COPD

    , 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
    Wortley MA, Bonvini SJ, Adcock JJ, Dubuis ED, Maher SA, Penn RB, Belvisi MG, Birrell MAet al., 2019,

    Agonism of EP4 Receptors Expressed on Airway Sensory Nerves Inhibits Cough

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Conference paper
    Miles JHA, Dubuis E, Bonvini SJ, Wortley MA, Trevisani M, Villetti G, Patacchini R, Birrell M, Belvisi MGet al., 2019,

    Monitoring Cough in a Preclinical Guinea Pig Model of Idiopathic Pulmonary Fibrosis

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • 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
  • Journal article
    Pavlidis S, Takahashi K, Kwong FNK, Xie J, Hoda U, Sun K, Elyasigomari V, Agapow P, Loza M, Baribaud F, Chanez P, Fowler SJ, Shaw DE, Fleming LJ, Howarth PH, Sousa AR, Corfield J, Auffray C, De Meulder B, Knowles R, Sterk PJ, Guo Y, Adcock IM, Djukanovic R, Chung KF, U-BIOPRED study groupet al., 2019,

    "T2-high" in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin

    , European Respiratory Journal, Vol: 53, ISSN: 0903-1936

    BACKGROUND: Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild-moderate asthma into a T2-high phenotype. We examined whether currently-available clinical biomarkers can predict AEC-defined T2-high phenotype within U-BIOPRED cohort. METHODS: The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from IL-13-exposed AECs. RESULTS: 37% of asthmatics (45% non-smoking severe asthma, n=49, 33% of smoking or ex-smoking severe asthma, n=18 and 28% mild-moderate asthma, n=36) were T2-high using AEC gene expression. They were more symptomatic with higher levels of nitric oxide in exhaled breath (FeNO) and of blood and sputum eosinophils but not of serum IgE or periostin. Sputum eosinophilia correlated best with the T2-high signature. FeNO (≥30 ppb) and blood eosinophils (≥300/µL) gave a moderate prediction of T2-high asthma. Sputum IL-4, IL-5 and IL-13 protein levels did not correlate with gene expression. CONCLUSION: T2-high severe asthma can be predicted to some extent from raised levels of FeNO, blood and sputum eosinophil counts, but serum IgE or serum periostin were poor predictors. Better bedside biomarkers are needed to detect T2-high.

  • 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.

  • 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
    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
  • 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
    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

  • 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

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