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Gary Tse,1,2 Benjamin Emmanuel,3 Cono Ariti,1 Mona Bafadhel,4 Alberto Papi,5 Victoria Carter,1 Jiandong Zhou,1 Derek Skinner,1 Xiao Xu,3 Hana Müllerová,6 David Price1,7 1Observational and Pragmatic Research Institute, Singapore, Singapore; 2School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, People’s Republic of China; 3AstraZeneca, Gaithersburg, MD, USA; 4Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; 5Respiratory Medicine, Department of Translational Medicine, University of Ferrara, Ferrara, Italy; 6AstraZeneca, Cambridge, UK; 7Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David Price, Observational and Pragmatic Research Institute, 22 Sin Ming Lane, &num;06-76, Midview City, 573969, Singapore, Tel +65 3105 1489, Email dprice@opri.sgBackground: Oral corticosteroids (OCS) are often prescribed for chronic obstructive pulmonary disease (COPD) exacerbations.Methods: This observational, individually matched historical cohort study used electronic medical records (1987– 2019) from the UK Clinical Practice Research Datalink linked to English Hospital Episode Statistics (HES) to evaluate adverse outcomes in patients with COPD who used OCS (OCS cohort) and those not exposed to OCS (non-OCS cohort). Risk of 17 adverse outcomes was estimated using proportional hazard regression.Results: Of 323,722 patients, 106,775 (33.0%) had COPD-related OCS prescriptions. Of the 106,775 patients in the overall cohort, 58,955 had HES linkage and were eligible for inclusion in the OCS cohort. The individual matching process identified 53,299 pairs of patients to form the OCS and non-OCS cohorts. Median follow-up post-index was 6.9 years (OCS cohort) and 5.4 years (non-OCS cohort). Adjusted risk of multiple adverse outcomes was higher for the OCS cohort versus the non-OCS cohort, including osteoporosis with/without fractures (adjusted hazard ratio [aHR] 1.80; 95% confidence interval [CI] 1.70– 1.92), type 2 diabetes mellitus (aHR 1.44; 95% CI 1.37– 1.51), cardiovascular/cerebrovascular disease (aHR 1.26; 95% CI 1.21– 1.30), and all-cause mortality (aHR 1.04; 95% CI 1.02– 1.07). In the OCS cohort, risk of most adverse outcomes increased with increasing categorized cumulative OCS dose. For example, risk of cardiovascular/cerebrovascular disease was 34% higher in the 1.0–< 2.5 g group versus the < 0.5 g group (HR 1.34; 95% CI 1.26– 1.42).Conclusion: Any OCS use was associated with higher risk of adverse outcomes in patients with COPD, with risk generally increasing with greater cumulative OCS dose.Plain Language Summary: Many patients with chronic obstructive pulmonary disease (COPD) have occasions when their symptoms suddenly worsen, called flare-ups or exacerbations. To treat flare-ups, doctors might prescribe a course of steroid tablets (oral corticosteroids or OCS for short). Doctors might also prescribe “rescue packs” containing OCS and antibiotics, to keep at home and start taking when needed.While OCS may speed up recovery from flare-ups, repeated use may have negative health effects. We studied effects of OCS use in patients with COPD, using anonymized electronic patient medical records in England. These databases are made available following a high-quality research proposal to research and ethics committees.Of 323,722 patients with COPD, around one-third received OCS for flare-ups. We studied 17 outcomes including important medical diagnoses and death. We grouped patients into 53,299 pairs so that every patient who used OCS matched a similar patient (eg, the same age and sex) who never used OCS. The patients were followed for an average of 6.9 years (used OCS) and 5.4 years (never used OCS).Most diagnoses, including diabetes, osteoporosis, cardiovascular/cerebrovascular disease, and death, were more likely in patients who used OCS than those who never used OCS. Patients using larger amounts of OCS over time were generally more likely to experience diagnoses or die.These results show risks of using OCS, even occasionally, in patients with COPD. Flare-up prevention is important, for example with appropriate daily “maintenance” medication, vaccinations for infections, and quitting smoking, thereby reducing health effects from OCS use for flare-ups. Keywords: chronic obstructive pulmonary disease, cohort study, COPD, corticosteroids, observational, primary care

Dave Singh,1 Gerard J Criner,2 Alvar Agustí,3 Mona Bafadhel,4 Johan Söderström,5 Gabriela Luporini Saraiva,6 Yue Song,6 Idlir Licaj,7 Maria Jison,6 Ubaldo J Martin,6 Ioannis Psallidas8 1Manchester University NHS Foundation Hospital Trust, the University of Manchester, Manchester, UK; 2Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA; 3Respiratory Institute (Hospital Clinic), IDIBAPS, CIBERES, Catedra Salud Respiratoria (University of Barcelona), Barcelona, Spain; 4School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; 5Late-stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 6Late-stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 7Cytel Inc, Cambridge, MA, USA; 8Late-Stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UKCorrespondence: Dave Singh, Medicines Evaluation Unit, Langley Building, University Hospital of South Manchester, NHS Foundation Trust, Southmoor Road, Manchester, M23 9QZ, UK, Tel +44 (0)161 946 4073, Email dsingh@meu.org.ukAbstract: Exacerbations in chronic obstructive pulmonary disease (COPD), which tend to occur in clusters and increase with disease severity, come with high societal and economic burdens. Prevention and delay of recurrent exacerbations is an unmet and significant therapeutic need for patients with COPD. GALATHEA (NCT02138916) and TERRANOVA (NCT02155660) were trials assessing efficacy of benralizumab in patients with frequent COPD exacerbations despite treatment. Although these studies found that benralizumab given as an add-on treatment did not significantly reduce annual rates of COPD exacerbations after 56 weeks of treatment, in the following exploratory post hoc analysis of the GALATHEA and TERRANOVA trials we identified a potential responder population in which treatment with benralizumab prevents recurrent COPD exacerbations during 30- and 90-day periods following an initial exacerbation, a vulnerable period for an exacerbation to occur. This responder population was characterized by high blood eosinophil counts and frequent previous exacerbations despite optimized triple therapy. These results highlight the importance of targeted therapies for high-risk populations and merit further research into the benefits of biologic therapies for COPD exacerbations.Keywords: COPD, recurrent exacerbations, benralizumab, eosinophil

Mona Bafadhel,1 Klaus F Rabe,2 Fernando J Martinez,3 Dave Singh,4 Patrick Darken,5 Martin Jenkins,6 Magnus Aurivillius,7 Mehul Patel,6 Paul Dorinsky8 1Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; 2LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 3Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA; 4Medicines Evaluation Unit, University of Manchester, Manchester University NHS Foundation Hospitals Trust, Manchester, UK; 5AstraZeneca, Gaithersburg, MD, USA; 6AstraZeneca, Cambridge, UK; 7AstraZeneca, Gothenburg, Sweden; 8Formerly of AstraZeneca, Durham, NC, USACorrespondence: Mona Bafadhel, Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, 5th floor, Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK, Tel +44 0207 188 8717, Email mona.bafadhel@kcl.ac.ukPurpose: Blood eosinophil (EOS) count can guide treatment decisions for chronic obstructive pulmonary disease (COPD). In the 52-week ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid doses reduced moderate/severe exacerbation rates and improved lung function, symptoms, and disease-related quality of life (QoL) versus dual therapy with glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) in patients with moderate-to-very severe COPD. This subgroup analysis evaluated treatment benefits in ETHOS by baseline EOS count.Methods: Patients (40− 80 years) with a COPD history were randomly assigned 1:1:1:1 to receive BGF 320/14.4/10 μg, BGF 160/14.4/10 μg, GFF 14.4/10 μg, or BFF 320/10 μg via a metered-dose inhaler. This post-hoc analysis assessed endpoints by baseline EOS count using Global Initiative for Obstructive Lung Disease thresholds (< 100, ≥ 100, ≥ 100−< 300, ≥ 300 cells/mm3), and investigated continuous relationships between treatment effects and EOS count on exacerbations, symptoms, disease-related QoL, lung function, and safety.Results: In the modified intention-to-treat population (n=8509), 82.6% had EOS counts ≥ 100 cells/mm3. BGF 320 reduced moderate/severe exacerbation rates versus GFF in the ≥ 100, ≥ 100−< 300, and ≥ 300 subgroups; treatment differences increased with EOS count. BGF 320 improved rescue medication use and lung-function outcomes across all subgroups, and St George’s Respiratory Questionnaire total score, Transition Dyspnea Index focal score, and Exacerbations of Chronic Pulmonary Disease Tool total score in all except the < 100 subgroup versus GFF. Benefits of BGF 320 versus BFF were generally consistent across subgroups. Safety data were comparable across subgroups.Conclusion: Benefits of BGF versus GFF were observed across EOS counts, particularly at ≥ 100 cells/mm³; versus BFF, benefits were largely independent of EOS. These findings confirm that benefits of ICS-containing triple therapy are not restricted to EOS counts ≥ 300 cells/mm³, supporting recommendations to consider triple therapy in patients with an exacerbation history and EOS counts ≥ 100 cells/mm³.Graphical Abstract: Keywords: eosinophils, inhaled corticosteroids, triple therapy

Dave Singh,1 Steve Holmes,2 Claire Adams,3 Mona Bafadhel,4 John R Hurst5 1Medicines Evaluation Unit, University of Manchester, Manchester University NHS Foundation Hospitals Trust, Manchester, UK; 2The Park Medical Practice, Shepton Mallet, UK; 3Tees Valley Clinical Commissioning Group, Middlesbrough, UK; 4Nuffield Department Clinical Medicine, University of Oxford, Oxford, UK; 5UCL Respiratory, University College London, London, UKCorrespondence: John R HurstUCL Respiratory, Royal Free Campus, University College London, London, NW3 2QG, UKTel +44 207 472 6260Email j.hurst@ucl.ac.ukBackground: Therapeutic inertia, defined as failure to escalate or initiate adequate therapy when treatment goals are not met, contributes to poor management of COPD exacerbations.Methods: A multidisciplinary panel of five expert clinicians actively managing COPD and representative of UK practice developed action points to reduce exacerbation risk, based on evidence, clinical expertise, and experience. The action points are applicable despite changing circumstances (eg, virtual clinics). The panel agreed areas where further evidence is needed.Results: The four action points were (1) an experienced HCP, such as a GP or member of the multi-professional COPD team should review patients within one month of every exacerbation that requires oral steroids, antibiotics, or hospitalization to address modifiable risk factors, optimize non-pharmacological measures, and evaluate pharmacological therapy. (2) Presenting to hospital with an exacerbation defines an important window of opportunity to reduce the risk of further exacerbations. Follow-up by a GP, or member of the multi-professional specialist COPD team within one month of discharge with a full management review and appropriate escalation of pharmacological treatment is essential. (3) Healthcare professionals (HCPs) in all healthcare settings should be able to recognize COPD exacerbations, refer as appropriate and document the episode accurately in medical records across service boundaries. HCPs should support patients to recognize and report exacerbations. (4) HCPs should intervene proactively based on risk assessments, disease activity and any treatable traits at or as soon as possible after diagnosis and annually thereafter. Delivering these action points needs coordinated action with policymakers, funders, and service providers.Conclusion: These action points should be a fundamental part of clinical practice to determine if a change in management is necessary to reduce the risk of exacerbations. Policymakers should use these action points to develop systems and initiatives that reduce the risk of further exacerbations.Keywords: control, inhaled therapy, primary care, mortality, biomarkers, health policy

Jennifer Cane,1,2 Laura Tregidgo,1 Samantha Thulborn,1,2 Donna Finch,3 Mona Bafadhel1,2 1Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 2Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK; 3Alchemab Therapeutics, Cambridge, UKCorrespondence: Jennifer Cane Email Jennifer.cane@ndm.ox.ac.ukBackground: Chronic obstructive pulmonary disease (COPD) and asthma have heterogeneous inflammation with inhaled corticosteroids (ICS) as a mainstay of treatment. There is increased prevalence of non-typeable Haemophilus influenzae (NTHi) persistence in airways of patients with neutrophilic airway inflammation, potentially due to suppressed host defence after corticosteroid treatment. Antimicrobial peptides (AMPs) have antimicrobial activity against pathogens and immunomodulatory effects. We investigated whether AMPs associate with NTHi presence in COPD and asthma, and whether ICS alter this.Methods: Secretory leukocyte protease inhibitor (SLPI), osteopontin, elafin and beta defensin-1 were measured in sputum supernatants from healthy donors (n=9), asthmatics (n=21) and patients with COPD (n=14). Elafin and beta defensin-1 were measured in a primary human bronchial epithelial cells (HBECs) from healthy and COPD donors infected with NTHi and pre-treated with fluticasone propionate (FP) and budesonide (BUD). Internalised NTHi was quantified by qPCR.Results: Sputum SLPI was negatively correlated with FEV1 (p< 0.001, r=− 0.610), FEV1% predicted (p< 0.001, r=− 0.583) and FEV1/FVC (p=0.001, r=− 0.528). Sputum beta defensin-1 was negatively associated with FEV1 (p< 0.001***r=− 0.594). SLPI and beta defensin-1 levels in sputum were higher in the healthy controls and COPD group compared to the asthma group (p=0.001 and p=0.014) and (p< 0.001 and p=0.007, respectively). ICS use was associated with higher sputum osteopontin compared to those with no ICS use. NTHi infection of COPD HBECs produced higher levels of beta defensin-1 compared to healthy donors (mean (SD) release: 45.1pg/mL (7.3) vs 21.2pg/mL (7.3) respectively, p=0.014). Elafin release from HBECs from COPD donors did not change following NTHi infection; however, elafin from healthy donors was significantly reduced (%mean reduction: 23.7%, 95% confidence intervals (CI) of reduction: 5.3– 38.4%, p< 0.01).Conclusion: Sputum SLPI and beta defensin-1 may be markers to identify those patients with declining lung function. ICS use was associated with higher sputum osteopontin compared to those with no ICS use.Keywords: antimicrobial peptide, non-typeable haemophilus influenzae, chronic obstructive pulmonary disease

Jean Bourbeau,1 Mona Bafadhel,2 Neil C Barnes,3,4 Chris Compton,3 Valentina Di Boscio,3 David A Lipson,5,6 Paul W Jones,3,7 Neil Martin,3,8 Gudrun Weiss,3 David MG Halpin9 1Respiratory Epidemiology and Clinical Research Unit, Department of Medicine, McGill University and Research Institute of the McGill University Health Centre, Montreal, QC, Canada; 2Nuffield Department of Medicine, University of Oxford, Oxford, Oxfordshire, UK; 3Respiratory Therapy Area, GlaxoSmithKline, Brentford, Middlesex, UK; 4William Harvey Institute, Bart’s and the London School of Medicine and Dentistry, London, UK; 5Clinical Sciences, GlaxoSmithKline, Collegeville, PA, USA; 6Pulmonary, Allergy and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 7Institute of Infection and Immunity, St George’s, University of London, London, UK; 8University of Leicester, Leicester, UK; 9University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UKCorrespondence: Jean BourbeauMcGill University Health Centre (MUHC), 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, CanadaTel +1 514 934-1934Fax +1 514 934-8577Email jean.bourbeau@mcgill.caAbstract: Chronic obstructive pulmonary disease (COPD) is associated with major healthcare and socioeconomic burdens. International consortia recommend a personalized approach to treatment and management that aims to reduce both symptom burden and the risk of exacerbations. Recent clinical trials have investigated single-inhaler triple therapy (SITT) with a long-acting muscarinic antagonist (LAMA), long-acting β2-agonist (LABA), and inhaled corticosteroid (ICS) for patients with symptomatic COPD. Here, we review evidence from randomized controlled trials showing the benefits of SITT and weigh these against the reported risk of pneumonia with ICS use. We highlight the challenges associated with cross-trial comparisons of benefit/risk, discuss blood eosinophils as a marker of ICS responsiveness, and summarize current treatment recommendations and the position of SITT in the management of COPD, including potential advantages in terms of improving patient adherence. Evidence from trials of SITT versus dual therapies in symptomatic patients with moderate to very severe airflow limitation and increased risk of exacerbations shows benefits in lung function and patient-reported outcomes. Moreover, the key benefits reported with SITT are significant reductions in exacerbations and hospitalizations, with data also suggesting reduced all-cause mortality. These benefits outweigh the ICS-class effect of higher incidence of study-reported pneumonia compared with LAMA/LABA. Important differences in trial design, baseline population characteristics, such as exacerbation history, and assessment of outcomes, have significant implications for interpreting data from cross-trial comparisons. Current understanding interprets the blood eosinophil count as a continuum that can help predict response to ICS and has utility alongside other clinical factors to aid treatment decision-making. We conclude that treatment decisions in COPD should be guided by an approach that considers benefit versus risk, with early optimization of treatment essential for maximizing long-term benefits and patient outcomes.Keywords: all-cause mortality, exacerbations, hospitalizations, ICS, LABA, LAMA

Sanjay Ramakrishnan,1– 3 Wim Janssens,4 Pierre-Regis Burgel,5 Marco Contoli,6 Frits ME Franssen,7 Neil J Greening,8 Timm Greulich,9 Iwein Gyselinck,4 Andreas Halner,1 Arturo Huerta,10 Rebecca L Morgan,11 Jennifer K Quint,12 Lowie EGW Vanfleteren,13 Kristina Vermeersch,4 Henrik Watz,14 Mona Bafadhel1 1Respiratory Medicine Unit, Nuffield Department of Medicine - Experimental Medicine, University of Oxford, Oxford, UK; 2 National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), University of Oxford, Oxford, UK; 3School of Medical and Health Sciences, Edith Cowan University, Perth, Australia; 4Department of Respiratory Diseases, UZ Leuven, Research Group BREATHE, KU Leuven, Leuven, Belgium; 5Faculty of Medicine, University of Paris and INSERM 1016 Institut Cochin, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; 6Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; 7Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, Netherlands; 8Department of Respiratory Sciences, NIHR Leicester Biomedical Research Centre (Respiratory), Glenfield Hospital, Leicester, UK; 9Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps University, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 10Pulmonary and Critical Care Division, Clinica Sagrada Familia, IDIBAPS August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; 11Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Canada; 12National Heart & Lung Institute, Imperial College, London, UK; 13COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Department of Internal Medicine and Clinical Nutrition at Institute of Medicine, SU Sahlgrenska, Göteborg, Sweden; 14Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, GermanyCorrespondence: Mona BafadhelRespiratory Medicine Unit, Nuffield Department of Medicine Experimental Medicine, University of Oxford, Oxford, UKTel +44 1865 612898Email mona.bafadhel@ndm.ox.ac.ukBackground: Despite hospitalization for exacerbation being a high-risk event for morbidity and mortality, there is little consensus globally regarding the assessment and management of hospitalised exacerbations of COPD. We aimed to establish a consensus list of symptoms, physiological measures, clinical scores, patient questionnaires and investigations to be obtained at time of hospitalised COPD exacerbation and follow-up.Methods: A modified Delphi online survey with pre-defined consensus of importance, feasibility and frequency of measures at hospitalisation and follow-up of a COPD exacerbation was undertaken.Findings: A total of 25 COPD experts from 18 countries contributed to all 3 rounds of the survey. Experts agreed that a detailed history and examination were needed. Experts also agreed on which treatments are needed and how soon these should be delivered. Experts recommended that a full blood count, renal function, C-reactive protein and cardiac blood biomarkers (BNP and troponin) should be measured within 4 hours of admission and that the modified Medical Research Council dyspnoea scale (mMRC) and COPD assessment test (CAT) should be performed at time of exacerbation and follow-up. Experts encouraged COPD clinicians to strongly consider discussing palliative care, if indicated, at time of hospitalisation.Interpretation: This Europe-wide consensus document is the first attempt to standardise the assessment and care of patients hospitalised for COPD exacerbations. This should be regarded as the starting point to build knowledge and evidence on patients hospitalised for COPD exacerbations.Keywords: COPD, disease exacerbation, hospitalisation, patient care, consensus development, expert opinion

Samantha J Thulborn,1,2 Alessandro Ceroni,3 Koirobi Haldar,4 Vijay Mistry,4 Jennifer L Cane,1,2 Christopher E Brightling,4,5 Michael R Barer,4 Mona Bafadhel1 1Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 2Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK; 3Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 4Department of Immunity, Infection and Inflammation, University of Leicester, Leicester, UK; 5Institute for Lung Health, University of Leicester, Leicester, UKCorrespondence: Mona BafadhelRespiratory Medicine Unit, NDM Research Building, Old Campus Road, University of Oxford, Oxford OX3 7FZ, UKTel +44 1865 612898Email mona.bafadhel@ndm.ox.ac.ukBackground: Non-typeable Haemophilus influenzae (NTHi) is the most commonly found pathogen in the lower respiratory airways of patients with COPD. NTHi is predominantly regarded as an intracellular pathogen; however, like most pathogens, it can exist and co-exist in two broad forms: cell-associated (intracellularly or adhered to cells) or cell-dissociated (biofilm dispersed or planktonic). We sought to investigate if cell-dissociated NTHi can be detected from the sputum of COPD patients and assess this relationship to disease severity and airway inflammation.Methods: DNA was extracted from the sputum plug and cell-free supernatant to quantify absolute (cell-associated and cell-dissociated NTHi) and cell-dissociated NTHi, respectively, from 87 COPD subjects attending an observational longitudinal COPD exacerbation study. NTHi was quantified using TaqMan hydrolysis probes, targeting the OMP P6 gene using qPCR.Results: At stable state cell-dissociated NTHi was detected 56% of subjects with a median (IQR) of 9.95x102 gene copies (1.26x102 to 1.90x104). Cell-dissociated NTHi correlated with absolute NTHi levels (r=0.34, p< 0.01) but not airway inflammation or spirometry at stable state. At exacerbation, cell-dissociated NTHi correlated with lung function (FEV1 r=0.629, p=0.005; FEV1%predicted r=0.564, p=0.015; FVC r=0.476 p=0.046) and sputum neutrophilic inflammation (% neutrophils r=0.688, p=0.002; total neutrophils r=0.518, p=0.028).Conclusion: In patients with COPD, NTHi can exist in both cell-associated and cell-dissociated forms. Cell-dissociated NTHi is associated with neutrophilic airway inflammation during exacerbations of COPD and may be a driving factor in worsening lung function during these episodes.Keywords: NTHi, infection, neutrophils, COPD

REK Russell,1,2 S Beer,3 ID Pavord,1,2 R Pullinger,3 M Bafadhel11Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 2NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; 3Department of Emergency Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UKIntroduction: There has been an increase in interest in the peripheral blood eosinophil count as a biomarker in COPD. Few studies have examined the eosinophil count in patients attending the emergency department (ED) with acute exacerbations of COPD (AECOPD). We investigated the relationship between the blood eosinophil and other variables collected routinely at ED presentation and outcomes.Methods: Retrospective case note review of patients attending the ED with an AECOPD over 18 months. Demographic, clinical and pharmacological data were analyzed at the time of presentation, and clinical outcomes relating to hospital admission, length of hospital stay and mortality were investigated.Results: There were 743 AECOPD index events in 537 patients. Over half (57%) of all attendees were admitted to hospital. They were older, reported an increased number of exacerbations and higher levels of total leukocytes and neutrophils. Length of stay was shorter in patients with a blood eosinophil count ≥2% compared to

Kirsty Hambleton, Clare M Connolly, Catherine Borg, Joanne H Davies, Helen P Jeffers, Richard EK Russell, Mona Bafadhel Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK Abstract: Near-patient testing (NPT) allows clinical decisions to be made in a rapid and convenient manner and is often cost effective. In COPD the peripheral blood eosinophil count has been demonstrated to have utility in providing prognostic information and predicting response to treatment during an acute exacerbation. For this potential to be achieved having a reliable NPT of blood eosinophil count would be extremely useful. Therefore, we investigated the use of the HemoCue® WBC Diff System and evaluated its sensitivity and specificity in healthy, asthmatic and COPD subjects. This method requires a simple skin prick of blood and was compared to standard venepuncture laboratory analysis. The HemoCue® WBC Diff System measured the peripheral blood eosinophil count in healthy, asthma and COPD subjects with very close correlation to the eosinophil count as measured by standard venepuncture. The correlations were unaffected by disease status. This method for the measurement of the peripheral blood eosinophil count has the potential to provide rapid near-patient results and thus influence the speed of management decisions in the treatment of airway diseases. Keywords: asthma, chronic obstructive pulmonary disease, eosinophils, near-patient testing

Samantha J Thulborn,1 Madiha Dilpazir,2 Koirobi Haldar,3 Vijay Mistry,3 Christopher E Brightling,3 Michael R Barer,3 Mona Bafadhel1 1Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, 2Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, 3Department of Immunity, Infection & Inflammation, University of Leicester, Leicester, UK Background: Pentraxin 3 (PTX3) is an acute phase protein, involved in antibacterial resistance. Recent studies have shown PTX3 levels to be elevated in the presence of a bacterial infection and in a murine sepsis model.Objective: We aim to investigate if sputum PTX3 can be used as a biomarker for bacterial infection in subjects with COPD.Materials and methods: Sputum samples from 142 COPD patients (102 men) with a mean (range) age of 69 years (45–85) and mean (SD) post-bronchodilator percentage predicted forced expiratory volume in 1 second (FEV1) of 50% (19) were analyzed for PTX3, using a commercial assay at stable state and during an exacerbation. Association with bacteria, from culture, quantitative real-time polymerase chain reaction (qPCR) and colony-forming units (CFU) was investigated.Results: The geometric mean (95% CI) PTX3 level at stable state was 50.5 ng/mL (41.4–61.7). PTX3 levels correlated with absolute neutrophil count in sputum (r=0.37; P105 CFU/mL at stable state) with a receiver-operating characteristic (ROC) area under the curve (AUC) of 0.59 and 95% confidence interval (CI) 0.43–0.76 (P=0.21). During an exacerbation, there was a modest increase in PTX3 (fold difference 0.15, 95% of difference 0.02–0.29; P=0.02), and PTX3 fared better at identifying a bacteria-associated exacerbation (ROC AUC 0.65, 95% CI 0.52–0.78, P=0.03).Conclusion: PTX3 is associated with bacterial infection in patients with COPD, but its utility as a biomarker for identifying a bacteria-associated exacerbation warrants further studies. Keywords: TNF-inducible gene 14 protein, infection, sputum

Mona Bafadhel,1 Koirobi Haldar,2 Bethan Barker,2,3 Hemu Patel,4 Vijay Mistry,2,3 Michael R Barer,2–4 Ian D Pavord,1 Christopher E Brightling2,3 1Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 2Department of Infection, Immunity and Inflammation, University of Leicester, 3Institute for Lung Health, National Institute for Health Research Respiratory Biomedical Research Unit, Glenfield Hospital, University of Leicester, 4Department of Clinical Microbiology, University Hospitals of Leicester NHS Trust, Leicester, UK Background: Potentially pathogenic microorganisms can be detected by quantitative real-time polymerase chain reaction (qPCR) in sputum from patients with COPD, although how this technique relates to culture and clinical measures of disease is unclear. We used cross-sectional and longitudinal data to test the hypotheses that qPCR is a more sensitive measure of bacterial presence and is associated with neutrophilic airway inflammation and adverse clinical outcomes.Methods: Sputum was collected from 174 stable COPD subjects longitudinally over 12 months. Microbial sampling using culture and qPCR was performed. Spirometry and sputum measures of airway inflammation were assessed.Findings: Sputum was qPCR-positive (>106 copies/mL) in 77/152 samples (Haemophilus influenzae [n=52], Moraxella catarrhalis [n=24], Streptococcus pneumoniae [n=19], and Staphylococcus aureus [n=7]). Sputum was culture-positive in 50/174 samples, with 49 out of 50 culture-positive samples having pathogen-specific qPCR bacterial loads >106 copies/mL. Samples that had qPCR copy numbers >106/mL, whether culture-positive or not, had increased sputum neutrophil counts. H. influenzae qPCR copy numbers correlated with sputum neutrophil counts (r=0.37, P106/mL three or more times in 19 patients, eight of whom were repeatedly sputum culture-positive. Persistence, whether defined by culture, qPCR, or both, was associated with a higher sputum neutrophil count, lower forced expiratory volume in 1 second (FEV1), and worsened quality of life.Interpretation: qPCR identifies a significant number of patients with potentially bacteria-associated neutrophilic airway inflammation and disease that are not identified by traditional culture-based methods. Keywords: H. influenzae, qPCR, sputum

Bethan L Barker,1 Susan McKenna,1 Vijay Mistry,1 Mitesh Pancholi,1 Hemu Patel,2 Koirobi Haldar,3 Michael R Barer,3 Ian D Pavord,4 Michael C Steiner,1 Christopher E Brightling,1 Mona Bafadhel4 1Institute for Lung Health, NIHR Respiratory Biomedical Research Unit, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; 2Department of Clinical Microbiology, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom; 3Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, United Kingdom; 4Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Oxford, United Kingdom Background: Nutritional depletion is an important manifestation of chronic obstructive pulmonary disease (COPD), which has been related to systemic inflammation. It remains unclear to what degree airway inflammation contributes to the presence or progression of nutritional depletion. Objectives: To determine whether airway inflammation and lung bacterial colonization are related to nutritional status or predict progressive weight loss and muscle atrophy in patients with COPD. Methods: Body composition using dual energy X-ray absorptiometry, indices of airway inflammation, and bacterial colonization were measured in 234 COPD patients. Systemic inflammation was assessed from serum C reactive protein (CRP) and circulating total and differential leukocyte counts. Nutritional depletion was defined as a body mass index (BMI) less than 21 kg/m2 and/or fat-free mass index (FFMI) less than 15 or 17 kg/m2 in women and men, respectively. FFMI was calculated as the fat-free mass (FFM) corrected for body surface area. Measurements were repeated in 94 patients after a median 16-month follow-up. Regression analysis was used to assess the relationships of weight change and FFM change with indices of bacterial colonization and airway and systemic inflammation. Results: Nutritional depletion occurred in 37% of patients. Lung function was worsened in patients with nutritional depletion compared to those without (forced expiratory volume in 1 second 1.17 L versus 1.41 L, mean difference 0.24, 95% confidence interval 0.10 to 0.38, P

Roshan Siva,1 Mona Bafadhel,2 William Monteiro,3 Christopher E Brightling,3 Ian D Pavord2 1Department of Respiratory Medicine, Croydon University Hospital, Croydon Health Services NHS Trust, London, 2Department of Respiratory Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Oxford, 3Institute for Lung Health, NIHR Respiratory Biomedical Research Unit, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK Rationale: Airway inflammation persists after smoking cessation in established chronic obstructive pulmonary disease (COPD), suggesting that other factors drive the airway inflammatory response. Objectives: We tested the hypothesis that high levels of bacterial colonization are associated with increased levels of neutrophilic airway inflammation in stable COPD by examining the cross-sectional relationship between these measurements and by conducting a randomized, double-blind, placebo-controlled study of the effect of levofloxacin in patients with stable COPD. Methods: Patients were randomized to receive either levofloxacin 500 mg daily or placebo for 7 days and underwent sputum induction for a differential cell count and quantitative bacterial analysis at baseline and at days 7, 14, and 28. Results: Sputum percentage neutrophil count correlated with airway bacterial load at baseline (r=0.56; P=0.003). Levofloxacin reduced bacterial load compared with placebo by 4.9-fold (95% confidence interval, 1.4–25.7; P=0.02) at day 7 but had no effect at any point on any marker of neutrophilic airway inflammation. In patients with a baseline bacterial load of more than 106 cfu/mL, levofloxacin treatment was associated with a 26.5% (95% confidence interval, 1.8%–51.3%; P=0.04) greater reduction in the percentage neutrophil count compared with placebo at day 7. Change in percentage neutrophil count correlated significantly with baseline airway bacterial load and change in airway bacterial load. Conclusion: In stable COPD, levofloxacin treatment causes a short-term reduction in bacterial load. This is associated with a reduction in neutrophilic airway inflammation in patients with high bacterial loads. Further studies are required to investigate whether this effect is clinically advantageous. Keywords: bacteria, antibiotics, sputum