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  • Journal article
    Preston GW, Dagnino S, Ponzi E, Sozeri O, van Veldhoven K, Barratt B, Liu S, Grigoryan H, Lu SS, Rappaport SM, Chung KF, Cullinan P, Sinharay R, Kelly FJ, Chadeau-Hyam M, Vineis P, Phillips DHet al., 2020,

    Relationships between airborne pollutants, serum albumin adducts and short-term health outcomes in an experimental crossover study

    , Chemosphere, Vol: 239, ISSN: 0045-6535

    Exposure to air pollution can have both short-term and long-term effects on health. However, the relationships between specific pollutants and their effects can be obscured by characteristics of both the pollution and the exposed population. One way of elucidating the relationships is to link exposures and internal changes at the level of the individual. To this end, we combined personal exposure monitoring (59 individuals, Oxford Street II crossover study) with mass-spectrometry-based analyses of putative serum albumin adducts (fixed-step selected reaction monitoring). We attempted to infer adducts' identities using data from another, higher-resolution mass spectrometry method, and were able to detect a semi-synthetic standard with both methods. A generalised least squares regression method was used to test for associations between amounts of adducts and pollution measures (ambient concentrations of nitrogen dioxide and particulate matter), and between amounts of adducts and short-term health outcomes (measures of lung health and arterial stiffness). Amounts of some putative adducts (e.g., one with a positive mass shift of ∼143 Da) were associated with exposure to pollution (11 associations), and amounts of other adducts were associated with health outcomes (eight associations). Adducts did not appear to provide a link between exposures and short-term health outcomes.

  • Journal article
    Radermecker C, Sabatel C, Vanwinge C, Ruscitti C, Marechal P, Perin F, Schyns J, Rocks N, Toussaint M, Cataldo D, Johnston SL, Bureau F, Marichal Tet al., 2019,

    Locally instructed CXCR4(hi) neutrophils trigger environment-driven allergic asthma through the release of neutrophil extracellular traps

    , NATURE IMMUNOLOGY, Vol: 20, Pages: 1444-+, ISSN: 1529-2908
  • Journal article
    Seys SF, Quirce S, Agache I, Akdis CA, Alvaro-Lozano M, Antolín-Amérigo D, Bjermer L, Bobolea I, Bonini M, Bossios A, Brinkman P, Bush A, Calderon M, Canonica W, Chanez P, Couto M, Davila I, Del Giacco S, Del Pozo V, Erjefält JS, Gevaert P, Hagedoorn P, G Heaney L, Heffler E, Hellings PW, Jutel M, Kalayci O, Kurowski MM, Loukides S, Nair P, Palomares O, Polverino E, Sanchez-Garcia S, Sastre J, Schwarze J, Spanevello A, Ulrik CS, Usmani O, Van den Berge M, Vasakova M, Vijverberg S, Diamant Zet al., 2019,

    Severe asthma: Entering an era of new concepts and emerging therapies: Highlights of the 4th international severe asthma forum, Madrid, 2018.

    , Allergy, Vol: 74, Pages: 2244-2248
  • Journal article
    Hiemstra PS, Tetley TD, Janes SM, 2019,

    Airway and alveolar epithelial cells in culture.

    , Eur Respir J, Vol: 54
  • Journal article
    Malekmohammad M, Folkerts G, Kashani BS, Naghan PA, Dastenae ZH, Khoundabi B, Garssen J, Mortaz E, Adcock IMet al., 2019,

    Exhaled nitric oxide is not a biomarker for idiopathic pulmonary arterial hypertension or for treatment efficacy

    , BMC Pulmonary Medicine, Vol: 19, ISSN: 1471-2466

    BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a fatal illness. Despite many improvements in the treatment of these patients, there is no unique prognostic variable available to track these patients. The aim of this study was to evaluate the association between fractional exhaled nitric oxide (FeNO) levels, as a noninvasive biomarker, with disease severity and treatment outcome. METHODS: Thirty-six patients (29 women and 7 men, mean age 38.4 ± 11.3 years) with IPAH referred to the outpatient's clinic of Masih Daneshvari Hospital, Tehran, Iran, were enrolled into this pilot observational study. Echocardiography, six-minute walking test (6MWT), FeNO, brain natriuretic peptide (BNP) levels and the functional class of patients was assessed before patients started treatment. Assessments were repeated after three months. 30 healthy non-IPAH subjects were recruited as control subjects. RESULTS: There was no significant difference in FeNO levels at baseline between patients with IPAH and subjects in the control group. There was also no significant increase in FeNO levels during the three months of treatment and levels did not correlate with other disease measures. In contrast, other markers of disease severity were correlated with treatment effect over the three months. CONCLUSION: FeNO levels are a poor non-invasive measure of IPAH severity and of treatment response in patients in this pilot study.

  • Journal article
    Meldrum K, Robertson S, Römer I, Marczylo T, Gant TW, Smith R, Tetley TD, Leonard MOet al., 2019,

    Diesel exhaust particle and dust mite induced airway inflammation is modified by cerium dioxide nanoparticles.

    , Environ Toxicol Pharmacol, Vol: 73

    Cerium dioxide nanoparticles (CeO2NPs) have been used as diesel fuel-borne catalysts for improved efficiency and pollutant emissions. Concerns that such material may influence diesel exhaust particle (DEP) effects within the lung upon inhalation, prompted us to examine particle responses in mice in the presence and absence of the common allergen house dust mite (HDM). Repeated intranasal instillation of combined HDM and DEP increased airway mucin, eosinophils, lymphocytes, IL-5, IL-13, IL-17A and plasma IgE, which were further increased with CeO2NPs co-exposure. A single co-exposure of CeO2NPs and DEP after repeated HDM exposure increased macrophage and IL-17A levels above DEP induced levels. CeO2NPs exposure in the absence of HDM also resulted in increased levels of plasma IgE and airway mucin staining, changes not observed with repeated DEP exposure alone. These observations indicate that CeO2NPs can modify exhaust particulate and allergen induced inflammatory events in the lung with the potential to influence conditions such as allergic airway disease.

  • Journal article
    Belchamber K, Singh R, Batista C, Moira W, Dockrell D, Kilty I, Matthew R, Wedzicha J, Barnes P, Donnelly Let al., 2019,

    Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages

    , European Respiratory Journal, Vol: 54, Pages: 1-14, ISSN: 0903-1936

    Background: Increased reactive oxygen species (ROS) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). Objective: This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD. Methods: Monocyte-derived macrophages (MDM) were generated from non-smoker, smoker and COPD subjects, differentiated in either GM-CSF (G-Mϕ) or M-CSF (M-Mϕ). Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage. Macrophages were incubated +/- 200M H2O2 for 24 hours, then exposed to fluorescently-labelled H. influenzae or S. pneumoniae for 4 hours, after which phagocytosis, mitochondrial ROS (mROS), and mitochondrial membrane potential (m) were measured. Results: Phagocytosis of bacteria was significantly decreased in both G-Mϕ and M-Mϕ from COPD patients, compared to non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or m, however in COPD, phagocytosis increased early mROS and decreased m in both G-Mϕ and M-Mϕ. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages, and non-smoker MDM, associated with reduced mROS production. Conclusion: COPD macrophages show defective phagocytosis, which is associated with altered mitochondrial function and an inability to regulate mROS production. Targeting mitochondrial dysfunction may restore the phagocytic defect in COPD.

  • Journal article
    Hopkinson NS, Arnott D, Voulvoulis N, 2019,

    Environmental consequences of tobacco production and consumption (vol 394, pg 1007, 2019)

    , LANCET, Vol: 394, Pages: 1324-1324, ISSN: 0140-6736
  • Journal article
    Philip K, Gaduzo S, Rogers J, Laffan M, Hopkinson Net al., 2019,

    Patient experience of COPD care – outcomes from the British Lung Foundation Patient Passport

    , BMJ Open Respiratory Research, Vol: 6, ISSN: 2052-4439

    Introduction The British Lung Foundation COPD Patient Passport (www.blf.org.uk/passport) was developed as a resource to help people with COPD and clinicians to consider the care received and identify essential omissions. We used the online data collected to evaluate the delivery of COPD care in the UK from a patient perspective. MethodsThe patient passport consists of 13 questions relating to key aspects of COPD care including: spirometry confirmation of diagnosis, understanding their diagnosis, support and a written management plan, vaccinations, smoking cessation, physical activity, exercise, eating well, pulmonary rehabilitation, exacerbations, medications, and yearly reviews. Data were presented as proportions with an answer corresponding to good care, and plotted over time to identify trends.ResultsAfter removing identifiable duplicates, data from 41,769 entries, completed online between November 2014 and April 2019, remained (Table 1). 24% reported getting support to manage their care and a written action plan; 53% could spot the signs of an acute exacerbation; 34% had discussed pulmonary rehabilitation; and 41% stated they understood their COPD, and their doctor or nurse had explained where to find information, advice and emotional support. A quarter reported not receiving flu vaccination and a third of those who smoke were not offered support to quit smoking. Even the strongest areas including spirometry-confirmed diagnosis, and knowing the importance of being active and eating well, achieved only around 80%. Response patterns remained stable or worsened over time. DiscussionResponses to the BLF COPD Patient Passport identify substantial gaps in patients’ experience of care, which did not appear to improve during the 5 years covered. These data provide a unique yet commonly overlooked perspec

  • Journal article
    Rabe KF, Martinez FJ, Ferguson GT, Wang C, Singh D, Wedzicha JA, Trivedi R, St Rose E, Ballal S, McLaren J, Darken P, Reisner C, Dorinsky Pet al., 2019,

    A phase III study of triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler 320/18/9.6 μg and 160/18/9.6 μg using co-suspension delivery technology in moderate-to-very severe COPD: The ETHOS study protocol

    , Respiratory Medicine, Vol: 158, Pages: 59-66, ISSN: 0954-6111

    BACKGROUND: Single inhaler triple therapies providing an inhaled corticosteroid, a long-acting muscarinic antagonist, and a long-acting β2-agonist (ICS/LAMA/LABAs) are an emerging treatment option for chronic obstructive pulmonary disease (COPD). Nevertheless, questions remain regarding the optimal patient population for triple therapy as well as the benefit:risk ratio of ICS treatment. METHODS: ETHOS is an ongoing, randomized, double-blind, multicenter, parallel-group, 52-week study in symptomatic patients with moderate-to-very severe COPD and a history of exacerbation(s) in the previous year. Two doses of single inhaler triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI 320/18/9.6 μg and 160/18/9.6 μg) will be compared to glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg and budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, all formulated using co-suspension delivery technology. Outcomes include the rate of moderate/severe (primary endpoint) and severe COPD exacerbations, symptoms, quality of life, and all-cause mortality. Sub-studies will assess lung function and cardiovascular safety. STUDY POPULATION: From June 2015-July 2018, 16,044 patients were screened and 8572 were randomized. Preliminary baseline demographics show that 55.9% of patients had experienced ≥2 moderate/severe exacerbations in the previous year, 79.1% were receiving an ICS-containing treatment at study entry, and 59.9% had blood eosinophil counts ≥150 cells/mm3. CONCLUSIONS: ETHOS will provide data on exacerbations, patient-reported outcomes, mortality, and safety in 8572 patients with moderate-to-very severe COPD receiving triple and dual fixed-dose combinations. For the first time, ICS/LAMA/LABA triple therapy with two different doses of ICS will be compared to dual ICS/LABA and LAMA/LABA therapies. CLINICAL TRIAL REGISTRATION NUMBER: NCT02465567.

  • Journal article
    Wedzicha JA, Ritchie AI, Martinez FJ, 2019,

    Can macrolide antibiotics prevent hospital readmissions?

    , American Journal of Respiratory and Critical Care Medicine, Vol: 200, Pages: 796-798, ISSN: 1073-449X
  • Journal article
    Celli BR, Wedzicha JA, 2019,

    Update on clinical aspects of chronic obstructive pulmonary disease

    , New England Journal of Medicine, Vol: 381, Pages: 1257-1266, ISSN: 0028-4793

    Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; COPD led to 3.2 million deaths in 2017, a toll expected to reach 4.4 million yearly by 2040.1,2 With a worldwide prevalence of 10.1%, COPD afflicts many people in low-income, middle-income, and wealthy countries (Figure 1), and years of life lost prematurely increased 13.2% between 2007 and 2017.1 Although COPD has traditionally been considered a disease that affects men, in some countries, the prevalence and associated mortality are higher among women than among men. In this review, we update the clinical face of COPD, concentrating on the pulmonary aspects of the disease, which also affects many other organ systems. The pathogenesis of COPD is discussed in a companion article by Agustí and Hogg in this issue of the Journal,3 and the review of muco-obstructive lung diseases in a recent issue of the Journal4 complements this article.

  • Journal article
    Hopkinson NS, Arnott D, Voulvoulis N, 2019,

    Environmental consequences of tobacco production and consumption

    , The Lancet, Vol: 394, Pages: 1007-1008, ISSN: 0140-6736
  • Journal article
    Singanayagam A, Loo S-L, Calderazzo MA, Finney LJ, Trujillo Torralbo M-B, Bakhsoliani E, Girkin J, Veerati PC, Pathinayake PS, Nichol KS, Reid AT, Footitt J, Johnston SL, Bartlett NW, Mallia Pet al., 2019,

    Anti-viral immunity is impaired in COPD patients with frequent exacerbations

    , American Journal of Physiology: Lung Cellular and Molecular Physiology, ISSN: 1040-0605

    Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) sub-group requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations. In vitro immune responses to rhinovirus infection in differentiated primary bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (>2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the anti-viral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. A role for epithelial cell-intrinsic innate immune dysregulation was identified: induction of interferons and ISGs during in vitro RV-infection was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators additionally had increased sputum bacterial loads at 2 weeks following virus-associated exacerbation onset. These data implicate deficient airway innate immunity involving epithelial cells in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate anti-microbial immunity in the lung could be a viable strategy for prevention/treatment of frequent exacerbations.

  • Journal article
    Boutou AK, Raste Y, Demeyer H, Troosters T, Polkey M, Vogiatzis I, Louvaris Z, Rabinovich RA, van der Molen T, Garcia-Aymerich J, Hopkinson Net al., 2019,

    Progression of physical inactivity in COPD patients: the effect of time and climate conditions – a multicentre prospective cohort study

    , International Journal of COPD, Vol: 14, Pages: 1979-1992, ISSN: 1176-9106

    Purpose: Longitudinal data on the effect of time and environmental conditions on physical activity (PA) among COPD patients are currently scarce, but this is an important factor in the design of trials to test interventions that might impact on it. Thus, we aimed to assess the effect of time and climate conditions (temperature, day length and rainfall) on progression of PA in a cohort of COPD patients.Patients and methods: This is a prospective, multicentre, cohort study undertaken as part of the EU/IMI PROactive project, in which we assessed 236 COPD patients simultaneously wearing two activity monitors (Dynaport MiniMod and Actigraph GT3X). A multivariable generalised linear model analysis was conducted to describe the effect of the explanatory variables on PA measures, over three time points (baseline, 6- and 12-month). Results: At 12 months (n=157; Forced Expiratory Volume in 1 second (FEV1) %predicted=57.7±21.9) there was a significant reduction in all PA measures (Actigraph step count (4284±3533 vs. 3533±293), Actigraph moderate- to vigorous-intensity physical activity ratio (8.8 (18.8) vs. 6.1(15.7)), Actigraph vector magnitude units (374902.4 (265269) vs. 336240 (214432)), Minimod walking time (59.1(34.9) vs. 56.9(38.7) minutes) and Minimod PA intensity (0.183(0) vs. 0.181(0)). Time had a significant, negative effect on most PA measures in multivariable analysis, after correcting for climate factors, study centre, age, FEV1 %predicted, 6 Minute Walking Distance and other disease severity measures. Rainfall was the only climate factor with a negative effect on most PA parameters. Conclusions:COPD patients demonstrate a significant decrease in physical activity over 1 year follow up, which is further affected by hours of rainfall, but not by other climate considerations.

  • Journal article
    Bourdin A, Bjermer L, Brightling C, Brusselle GG, Chanez P, Chung KF, Custovic A, Diamant Z, Diver S, Djukanovic R, Hamerlijnck D, Horvath I, Johnston SL, Kanniess F, Papadopoulos N, Papi A, Russell RJ, Ryan D, Samitas K, Tonia T, Zervas E, Gaga Met al., 2019,

    ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions

    , EUROPEAN RESPIRATORY JOURNAL, Vol: 54, ISSN: 0903-1936
  • Journal article
    Laverty AA, Vamos EP, Millett C, Chang KC-M, Filippidis FT, Hopkinson NSet al., 2019,

    Child awareness of and access to cigarettes: impacts of the point-of-sale display ban in England.

    , Tob Control, Vol: 28, Pages: 526-531

    INTRODUCTION: England introduced a tobacco display ban for shops with >280 m2 floor area ('partial ban') in 2012, then a total ban in 2015. This study assessed whether these were linked to child awareness of and access to cigarettes. METHODS: Data come from the Smoking, Drinking and Drug Use survey, an annual survey of children aged 11-15 years for 2010-2014 and 2016. Multivariate logistic regression models assessed changes in having seen cigarettes on display, usual sources and ease of access to cigarettes in shops RESULTS: During the partial display ban in 2012, 89.9% of children reported seeing cigarettes on display in the last year, which was reduced to 86.0% in 2016 after the total ban (adjusted OR 0.58, 95% CI 0.50 to 0.66). Reductions were similar in small shops (84.1% to 79.3%)%) and supermarkets (62.6% to 57.3%)%). Although the ban was associated with a reduction in the proportion of regular child smokers reporting that they bought cigarettes in shops (57.0% in 2010 to 39.8% in 2016), we did not find evidence of changes in perceived difficulty or being refused sale among those who still did. DISCUSSION: Tobacco point-of-sale display bans in England reduced the exposure of children to cigarettes in shops and coincided with a decrease in buying cigarettes in shops. However, children do not report increased difficulty in obtaining cigarettes from shops, highlighting the need for additional measures to tackle tobacco advertising, stronger enforcement of existing laws and measures such as licencing for tobacco retailers.

  • Journal article
    Singanayagam A, Glanville N, Cuthbertson L, Bartlett NW, Finney LJ, Turek E, Bakhsoliani E, Calderazzo MA, Trujillo-Torralbo M-B, Footitt J, James PL, Fenwick P, Kemp SV, Clarke TB, Wedzicha JA, Edwards MR, Moffatt M, Cookson WO, Mallia P, Johnston SLet al., 2019,

    Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease

    , Science Translational Medicine, Vol: 11, Pages: 1-13, ISSN: 1946-6234

    Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp-/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.

  • Journal article
    Gilworth G, Lewin S, Wright AJ, Taylor SJ, Tuffnell R, Hogg L, Hopkinson NS, Singh SJ, White Pet al., 2019,

    The lay health worker-patient relationship in promoting pulmonary rehabilitation (PR) in COPD: What makes it work?

    , Chronic Respiratory Disease, Vol: 16, ISSN: 1479-9723

    Lay health workers (LHWs) can improve access to services and adherence to treatment, as well as promoting self-care and prevention. Their effect in promoting uptake and adherence in pulmonary rehabilitation (PR) for chronic obstructive pulmonary disease (COPD) has not been tested. PR is the most effective treatment for the symptoms and disability of COPD, but this effectiveness is undermined by poor rates of completion. Trained LHWs with COPD, who also have first-hand experience of PR, are well placed to help overcome the documented barriers to its completion. The relationship between LHWs and patients may be one of the keys to their effectiveness but it has been little explored. Semi-structured qualitative interviews were used with the aim of examining the LHW-patient partnership in a feasibility study of trained PR-experienced LHWs used to support COPD patients referred to PR. Twelve volunteers with COPD who completed LHW training supported 66 patients referred for PR. All 12 of these LHWs gave end-of-study interviews, 21 COPD patients supported by LHWs were also interviewed. Patients reported that the LHWs were keen to share their experiences of PR, and that this had a positive impact. The enthusiasm of the LHWs for PR was striking. The common bond between LHWs and patients of having COPD together with the LHWs positive, first-hand experience of PR were dominant and recurring themes in their relationship.

  • Journal article
    Mills JT, Schwenzer A, Marsh EK, Edwards MR, Sabroe I, Midwood KS, Parker LCet al., 2019,

    Airway Epithelial Cells Generate Pro-inflammatory Tenascin-C and Small Extracellular Vesicles in Response to TLR3 Stimuli and Rhinovirus Infection

    , FRONTIERS IN IMMUNOLOGY, Vol: 10, ISSN: 1664-3224

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