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Peter MA Calverley,1 Alberto Papi,2 Clive Page,3 Paola Rogliani,4 Roberto W Dal Negro,5 Mario Cazzola,4 Arrigo F Cicero,6 Jadwiga A Wedzicha7 1Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; 2Respiratory Medicine, University of Ferrara, Ferrara, Italy; 3Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College, London, UK; 4Respiratory Medicine Unit, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 5National Centre for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy; 6Medical and Surgical Department, University of Bologna, Bologna, Italy; 7Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UKCorrespondence: Peter MA Calverley, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK, Tel +44 1515295886, Fax +44 1515295888, Email pmacal@liverpool.ac.ukPurpose: To explore the effect of erdosteine on COPD exacerbations, health-related quality of life (HRQoL), and subjectively assessed COPD severity.Patients and methods: This post-hoc analysis of the RESTORE study included participants with COPD and spirometrically moderate (GOLD 2; post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted; n = 254), or severe airflow limitation (GOLD 3; post-bronchodilator FEV1 30‒49% predicted; n = 191) who received erdosteine 300 mg twice daily or placebo added to usual maintenance therapy for 12 months. Antibiotic and oral corticosteroid use was determined together with patient-reported HRQoL (St George’s Respiratory Questionnaire, SGRQ). Patient and physician subjective COPD severity scores (scale 0‒4) were rated at baseline, 6 and 12 months. Data were analyzed using descriptive statistics for exacerbation severity, COPD severity, and treatment group. Comparisons between treatment groups used Student’s t-tests or ANCOVA as appropriate.Results: Among GOLD 2 patients, 43 of 126 erdosteine-treated patients exacerbated (7 moderate-to-severe exacerbations), compared to 62 of 128 placebo-treated patients (14 moderate-to-severe exacerbations). Among those with moderate-to-severe exacerbations, erdosteine-treated patients had a shorter mean duration of corticosteroid treatment (11.4 days vs 13.3 days for placebo, P = 0.043), and fewer patients required antibiotic treatment with/without oral corticosteroids (71.4% vs 85.8% for placebo, P < 0.001). Erdosteine-treated GOLD 2 patients who exacerbated showed significant improvements from baseline in SGRQ total scores and subjective disease severity scores (patient- and physician-rated), compared with placebo-treated patients regardless of exacerbation severity. Among GOLD 3 patients, there were no significant differences between treatment groups on any of these measures.Conclusion: Adding erdosteine to the usual maintenance therapy of COPD patients with moderate airflow limitation reduced the number of exacerbations, the duration of treatment with corticosteroids and the episodes requiring treatment with antibiotics. Additionally, treatment with erdosteine improved HRQoL and patient-reported disease severity.Keywords: antibiotic, chronic obstructive pulmonary disease, erdosteine, COPD exacerbation, health-related quality of life, systemic corticosteroid

Ruth E Barker,1,2 Lisa J Brighton,3 Matthew Maddocks,3 Claire M Nolan,1,2 Suhani Patel,1 Jessica A Walsh,1 Oliver Polgar,1 Jenni Wenneberg,4 Samantha SC Kon,4 Jadwiga A Wedzicha,2 William DC Man,1,2 Morag Farquhar5 1Harefield Respiratory Research Group, Harefield Hospital, Middlesex, UK; 2National Heart and Lung Institute, Imperial College, London, UK; 3Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation, King’s College London, London, UK; 4The Hillingdon Hospitals NHS Foundation Trust, London, UK; 5School of Health Sciences, University of East Anglia, Norwich, UKCorrespondence: Ruth E BarkerHarefield Respiratory Research Group, Harefield Hospital, Hill End Road, Middlesex, UB9 6JH, United KingdomTel +44 01895 828851Email r.barker2@rbht.nhs.ukBackground: Hospital at home (HaH) schemes allow early discharge of patients hospitalised with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Traditional outpatient pulmonary rehabilitation (PR) following an AECOPD has an established evidence-base, but there are issues with low referral, uptake and completion. One commonly cited barrier to PR post-hospitalisation relates to poor accessibility. To address this, the aim of this project was to enrol service users (patients with COPD and informal carers) and healthcare professionals to co-design a model of care that integrates home-based exercise training within a HaH scheme for patients discharged from hospital following AECOPD.Methods: This accelerated experience-based co-design project included three audio-recorded stakeholder feedback events, using key “touchpoints” from previous qualitative interviews and a recent systematic review. Audio-recordings were inductively analysed using directed content analysis. An integrated model of care was then developed and finalised through two co-design groups, with the decision-making process facilitated by the tables of changes approach.Results: Seven patients with COPD, two informal carers and nine healthcare professionals (from an existing outpatient PR service and HaH scheme) participated in the stakeholder feedback events. Four key themes were identified: 1) individualisation, 2) progression and transition, 3) continuity between services, and 4) communication between stakeholders. Two patients with COPD, one informal carer and three healthcare professionals participated in the first joint co-design group, with five healthcare professionals attending a second co-design group. These achieved a consensus on the integrated model of care. The agreed model comprised face-to-face supervised, individually tailored home-based exercise training one to three times a week, delivered during HaH scheme visits where possible by a healthcare professional competent to provide both home-based exercise training and usual HaH care.Conclusion: An integrated model of care has been co-designed by patients with COPD, informal carers and healthcare professionals to address low uptake and completion of PR following AECOPD. The co-designed model of care has now been integrated within a well-established HaH scheme.Keywords: COPD, exacerbations, rehabilitation, exercise training, integrated care, co-design

Konstantinos Kostikas,1 Alexander J Mackay,2 Claus F Vogelmeier,3 Stefan-Marian Frent,4 Pritam Gupta,5 Donald Banerji,6 Francesco Patalano,7 Pascal J Pfister,7 Jadwiga A Wedzicha8 1Respiratory Medicine Department, University of Ioannina Medical School, Ioannina, Greece; 2National Heart and Lung Institute, Imperial College London, London, UK; 3Department of Medicine, Pulmonary and Critical Care Medicine, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 4Department of Pulmonology, University of Medicine and Pharmacy Timisoara, Timisoara, Romania; 5Novartis Healthcare Pvt. Ltd., Hyderabad, India; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Novartis Pharma AG, Basel, Switzerland; 8Respiratory Clinical Science Section, National Heart and Lung Institute, Imperial College London, London, UKCorrespondence: Konstantinos KostikasRespiratory Medicine Department, University of Ioannina Medical School, Ioannina 45110, GreeceTel +30-6944780616Email ktkostikas@gmail.comBackground: Chronic obstructive pulmonary disease (COPD) exacerbations are difficult outcomes to measure in clinical trials. It would be valuable to be able to predict which patients are likely to benefit in terms of exacerbation prevention based on their early response in lung function and symptoms.Methods: This was a post-hoc analysis from the 52-week, randomized, double-blind, double-dummy, non-inferiority FLAME trial. Early clinically important improvement (ECII) was defined as achievement of minimal clinically important difference in trough forced expiratory volume in 1 second (FEV1; ≥ 100 mL increase) and one patient-reported outcome (PRO): either St. George’s Respiratory Questionnaire for COPD (≥ 4-unit reduction; D1), or COPD assessment test (≥ 2-point reduction; D2) at Week 4 or 12.Results: Approximately 18– 20% of patients achieved ECII at Week 4 or 12 post-randomization according to any of the two definitions. The rate of subsequent exacerbations was lower in patients who achieved ECII at Week 4 (D1: ratio of rates [95% CI], 0.85 [0.74 to 0.98]; D2, 0.88 [0.77 to 1.00]) or at Week 12 (D1, 0.85 [0.74 to 0.98]; D2, 0.86 [0.75 to 1.00]) versus patients not achieving ECII. Patients who achieved ECII experienced longer time-to-first exacerbation between Week 4 or 12 to end of study. More patients achieved ECII with indacaterol/glycopyrronium versus salmeterol/fluticasone according to both definitions at Week 4 (D1, odds ratio [95% CI], 1.69 [1.40 to 2.04]; D2, 1.61 [1.34 to 1.93]), and 12 (D1, 2.01 [1.66 to 2.44]; D2, 1.80 [1.48 to 2.18]).Conclusion: ECII is a novel composite endpoint, based on clinically relevant improvement in lung function and PROs in the early phase of treatment intervention that may predict subsequent exacerbation risk and may be used in clinical trials.Keywords: exacerbations, ECII, indacaterol/glycopyrronium, lung function, PROs

Peter MA Calverley,1 Clive Page,2 Roberto W Dal Negro,3 Giovanni Fontana,4 Mario Cazzola,5 Arrigo F Cicero,6 Edoardo Pozzi7,†, Jadwiga A Wedzicha8 1Department of Medicine, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK; 2Faculty of Life Sciences and Medicine, King’s College, London, UK; 3Lung Unit, National Centre for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy; 4Pulmonology Department, Cough Centre, Careggi University Hospital, Firenze, Italy; 5Department of Systems Medicine, Chair of Respiratory Medicine, University of Rome ‘Tor Vergata’, Rome, Italy; 6Medical and Surgical Department, University of Bologna, Bologna, Italy; 7Medical Affairs Department, Edmond Pharma, Paderno, Italy; 8Respiratory Division, National Heart And Lung Institute, Imperial College London, London, UK†Dr Pozzii passed away on 9th July, 2019Correspondence: Peter MA CalverleyDepartment of Medicine, University Hospital Aintree, Lower Lane, Liverpool, Merseyside, UKTel +44 1515295886Fax +44 1515295888Email pmacal@liverpool.ac.ukBackground: The RESTORE study, a multi-national randomized, placebo-controlled study, showed that erdosteine – a muco-active antioxidant that modulates bacterial adhesiveness – reduced the rate and duration of exacerbations in moderate and severe COPD with a history of exacerbations. How much benefit patients with less severe disease experience when taking this drug remains unclear.Methods: This post hoc analysis of the 254 RESTORE participants with spirometrically-defined moderate COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted) examined exacerbation rate and duration, time to first exacerbation, and exacerbation-free time. Data were analyzed using descriptive statistics and comparisons between treatment groups used Wilcoxon rank-sum tests, Mann–Whitney U-tests, or log rank tests.Results: Patients with moderate COPD received erdosteine 300 mg twice daily (n=126) or placebo (n=128) added to usual COPD therapy for 12 months. During this time, there were 53 exacerbations in the erdosteine group and 74 in the placebo group, with 42.1% and 57.8% of patients, respectively, experiencing an exacerbation. There was a 47% reduction in the mean exacerbation rate with erdosteine compared to placebo (0.27 vs 0.51 exacerbations per-patient per-year, respectively, P=0.003), and a 58.3% reduction in the mild exacerbation rate (0.23 vs 0.53 mild exacerbations per-patient per-year, P=0.001). Mean duration of exacerbations was 26% shorter in erdosteine-treated patients (9.1 vs 12.3 days for placebo, P=0.022), with significant reductions in the duration of mild and moderate-to-severe exacerbations. Mean time to first exacerbation was prolonged by 7.7% (182 days for erdosteine vs 169 days for placebo, P

Claus F Vogelmeier,1 Kenneth R Chapman,2 Marc Miravitlles,3 Nicolas Roche,4 Jørgen Vestbo,5 Chau Thach,6 Donald Banerji,6 Robert Fogel,6 Francesco Patalano,7 Petter Olsson,8 Konstantinos Kostikas,7 Jadwiga A Wedzicha9 1Member of the German Center for Lung Research (DZL), Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany; 2Asthma and Airway Centre, University Health Network and University of Toronto, Toronto, ON, Canada; 3Pneumology Department, Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 4Service de Pneumologie AP-HP, Cochin Hospital, University Paris Descartes (EA2511), Paris, France; 5Institute of Infection, Immunity and Respiratory Medicine, The University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Novartis Pharma AG, Basel, Switzerland; 8Novartis Sverige AB, Täby, Sweden; 9National Heart and Lung Institute, Imperial College London, London, UK Background: The FLAME study compared once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 µg with twice-daily salmeterol/fluticasone (SFC) 50/500 µg in symptomatic patients with moderate to very severe COPD and a history of exacerbations in the previous year. Methods: This prespecified and post hoc subgroup analysis evaluated treatment efficacy on 1) moderate/severe exacerbations according to prior exacerbation history and treatment, and 2) types of exacerbations according to health care resource utilization (HCRU) during 1-year follow-up. Results: IND/GLY reduced the rate of moderate/severe exacerbations versus SFC in patients with a history of 1 exacerbation (rate ratio [RR]: 0.83, 95% CI: 0.75–0.93), ≥2 exacerbations (RR: 0.85, 95% CI: 0.70–1.03) and ≥2 exacerbations or ≥1 hospitalization in the previous year (RR: 0.86, 95% CI: 0.74–1.00). Prolonged time-to-first exacerbation was observed in all the groups according to exacerbation history. Moderate/severe exacerbations decreased with IND/GLY versus SFC, independent of previous treatment. IND/GLY significantly reduced rates of moderate/severe exacerbations treated with antibiotics (RR: 0.79, 95% CI: 0.67–0.93) and systemic corticosteroids and antibiotics (RR: 0.80, 95% CI: 0.70–0.91); rates of exacerbations treated with systemic corticosteroids alone were comparable (RR: 0.99, 95% CI: 0.80–1.22). Conclusion: Overall, IND/GLY demonstrated consistent beneficial effects versus SFC on moderate/severe exacerbations, independent of prior exacerbation history or treatment. The efficacy of IND/GLY on exacerbation prevention was superior to SFC for exacerbations treated with antibiotics with/without systemic corticosteroids and was similar for exacerbations treated with systemic corticosteroids alone. Keywords: indacaterol/glycopyrronium, salmeterol/fluticasone, LABA/LAMA, LABA/ICS

Jadwiga A Wedzicha,1 Nanshan Zhong,2 Masakazu Ichinose,3 Michael Humphries,4 Robert Fogel,5 Chau Thach,5 Francesco Patalano,6 Donald Banerji5 1National Heart and Lung Institute, Imperial College London, London, UK; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 4Beijing Novartis Pharma Co. Ltd., Shanghai, People’s Republic of China; 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 6Novartis Pharma AG, Basel, Switzerland Background: The FLAME study demonstrated that indacaterol/glycopyrronium (IND/GLY), the fixed-dose combination of a long-acting β2-agonist (LABA, IND) and a long-acting muscarinic antagonist (LAMA, GLY), was superior to salmeterol/fluticasone combination (SFC) in preventing exacerbations in COPD patients with a high risk of exacerbations. In this study, we report a prespecified analysis of the efficacy and safety of IND/GLY versus SFC in Asian patients from the FLAME study.Patients and methods: Patients from Asian centers with moderate-to-very severe COPD and ≥1 exacerbation in the previous year from the 52-week, randomized FLAME study were included. IND/GLY was compared versus SFC for effects on exacerbations, lung function (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]), health status (St George’s Respiratory Questionnaire [SGRQ]), rescue medication use, and safety.Results: A total of 510 Asian patients (IND/GLY, n=250 or SFC, n=260) were included. Compared to the overall FLAME population, the Asian cohort had more males, a shorter duration of COPD, fewer patients using inhaled corticosteroid (ICS) at screening, fewer current smokers, and more patients with very severe COPD. IND/GLY significantly reduced the rate of moderate/severe exacerbations (rate ratio: 0.75; 95% confidence interval: 0.58–0.97; P=0.027) and prolonged time to first moderate/severe exacerbation versus SFC (hazard ratio: 0.77; 95% confidence interval: 0.59–1.01; P=0.055). Predose trough FEV1 and FVC significantly improved in Asian patients (P

Jadwiga A Wedzicha,1 Peter MA Calverley,2 Klaus F Rabe3,41Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, 2Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK; 3Department of Internal Medicine, Christian-Albrechts University, Kiel, 4Department of Pulmonary Medicine and Medical Director, LungenClinic Grosshansdorf, Airway Research Centre North, German Centre for Lung Research, Grosshansdorf, Germany Abstract: COPD is a progressive condition involving chronic inflammation and parenchymal destruction with resulting airflow limitation. COPD is associated with worsening airflow limitation over time and increased frequency of COPD exacerbations, leading to increased mortality and morbidity. The effects of COPD extend beyond the lungs, as multiple comorbidities may occur with COPD, including cardiovascular disease, diabetes mellitus, osteoporosis, depression, and pneumonia. COPD exacerbations are associated with a rapid worsening of baseline symptoms that requires prompt management and may necessitate hospitalization in the case of a severe episode. Patients with COPD exacerbations require urgent management of symptoms to prevent further worsening, and preventative steps may be taken to help reduce the number and frequency of future exacerbations. Roflumilast is a potent and selective inhibitor of the enzyme phosphodiesterase-4 that targets the systemic inflammation associated with COPD. Roflumilast has a variety of anti-inflammatory effects including decreasing inflammatory mediators and the expression of cell surface markers and inhibition of apoptosis. Several clinical trials evaluating roflumilast in the treatment of COPD have demonstrated significant improvements from baseline versus placebo in lung function, including increases in mean pre- and postbronchodilator forced expiratory volume in 1 second and forced vital capacity. Data suggest that roflumilast reduces moderate to severe exacerbations with the benefit most well established in patients with severe disease. Given this evidence, roflumilast, as part of a combination regimen with long-acting bronchodilators, appears to be a reasonable treatment option for patients with severe to very severe COPD associated with chronic bronchitis and a history of exacerbations. Keywords: COPD, exacerbations, phosphodiesterase-4 inhibitors, roflumilast, chronic bronchitis

Simon E Brill, Jadwiga A Wedzicha Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK Abstract: Acute exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the history of this debilitating lung condition. Associated health care utilization and morbidity are high, and many patients require supplemental oxygen or ventilatory support. The last 2 decades have seen a substantial increase in our understanding of the best way to manage the respiratory failure suffered by many patients during this high-risk period. This review article examines the evidence underlying supplemental oxygen therapy during exacerbations of COPD. We first discuss the epidemiology and pathophysiology of respiratory failure in COPD during exacerbations. The rationale and evidence underlying oxygen therapy, including the risks when administered inappropriately, are then discussed, along with further strategies for ventilatory support. We also review current recommendations for best practice, including methods for improving oxygen provision in the future. Keywords: chronic obstructive pulmonary disease (COPD), exacerbation, oxygen therapy, respiratory failure, hypercapnia

Gavin C Donaldson, Jadwiga A Wedzicha Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK Abstract: The time of year when patients experience exacerbations of chronic obstructive pulmonary disease is a much-overlooked feature of the disease. The higher incidence of exacerbations in winter has important consequences for patients in terms of increased morbidity and mortality. The seasonality also imposes a considerable burden on already-overloaded health care services, with both primary care consultations and hospital admissions increasing in number. The seasonality of exacerbations varies with latitude, and is greater in more temperate climates, where there may be less protection from outdoor and indoor cold exposure. The precise causes of the seasonality are unknown, but thought to be partly due to the increased prevalence of respiratory viral infections circulating in cold, damp conditions. Increased susceptibility to viral infection may also be a mechanism mediated through increased airway inflammation or possibly reduced vitamin D levels. The seasonality of exacerbations informs us about the triggers of exacerbations and suggests possible strategies to reduce their number. Keywords: exacerbations of COPD, seasonality, winter mortality, winter morbidity

Seemungal TA, Lun JC, Davis G, et al. Plasma homocysteine is elevated in COPD patients and is related to COPD severity.International Journal of COPD. 2007;2(3):313–321. Dr Lexley Pinto Pereira’s name was incorrectly listed as ‘PintoPereira L’, instead of ‘Pinto Pereira L’.Original Article

Abstract Background Irreversible airflow obstruction in Chronic Obstructive Pulmonary Disease (COPD) is thought to result from airway remodelling associated with aberrant inflammation. Patients who experience frequent episodes of acute deterioration in symptoms and lung function, termed exacerbations, experience a faster decline in their lung function, and thus over time greater disease severity However the mechanisms by which these episodes may contribute to decreased lung function are poorly understood. This study has prospectively examined changes in sputum levels of inflammatory cells, MMP-9 and TIMP-1 during exacerbations comparing with paired samples taken prior to exacerbation. Methods Nineteen COPD patients ((median, [IQR]) age 69 [63 to 74], forced expiratory volume in one second (FEV1) 1.0 [0.9 to1.2], FEV1% predicted 37.6 [27.3 to 46.2]) provided sputa at exacerbation. Of these, 12 were paired with a samples collected when the patient was stable, a median 4 months [2 to 8 months] beforehand. Results MMP-9 levels increased from 10.5 μg/g [1.2 to 21.1] prior to exacerbation to 17.1 μg/g [9.3 to 48.7] during exacerbation (P < 0.01). TIMP-1 levels decreased from 3.5 μg/g [0.6 to 7.8] to 1.5 μg/g [0.3 to 4.9] (P = 0.16). MMP-9/TIMP-1 Molar ratio significantly increased from 0.6 [0.2 to 1.1] to 3.6 [2.0 to 25.3] (P < 0.05). Neutrophil, eosinophil and lymphocyte counts all showed significant increase during exacerbation compared to before (P < 0.05). Macrophage numbers remained level. MMP-9 levels during exacerbation showed highly significant correlation with both neutrophil and lymphocyte counts (Rho = 0.7, P < 0.01). Conclusion During exacerbation, increased inflammatory burden coincides with an imbalance of the proteinase MMP-9 and its cognate inhibitor TIMP-1. This may suggest a pathway connecting frequent exacerbations with lung function decline.