Search

On 23 March 2020, the UK Government announced a nationwide lockdown in response to the COVID-19 epidemic, with people banned from leaving their homes except for essential journeys and exercise., Impact of the UK lockdown on early COPD https://bit.ly/3laMsmi

RationaleIt has been suggested that patients with chronic obstructive pulmonary disease (COPD) experience considerable daily respiratory symptom fluctuation. A standardized measure is needed to quantify and understand the implications of day-to-day symptom variability.ObjectivesTo compare standard deviation with other statistical measures of symptom variability and identify characteristics of individuals with higher symptom variability.MethodsIndividuals in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) Exacerbations sub-study completed an Evaluating Respiratory Symptoms in COPD (E-RS) daily questionnaire. We calculated within-subject standard deviation (WS-SD) for each patient at week 0 and correlated this with measurements obtained 4 weeks later using Pearson's r and Bland Altman plots. Median WS-SD value dichotomized participants into higher versus lower variability groups. Association between WS-SD and exacerbation risk during 4 follow-up weeks was explored.Measurements and main resultsDiary completion rates were sufficient in 140 (68%) of 205 sub-study participants. Reproducibility (r) of the WS-SD metric from baseline to week 4 was 0.32. Higher variability participants had higher St George's Respiratory Questionnaire (SGRQ) scores (47.3 ± 20.3 versus 39.6 ± 21.5, p=.04) than lower variability participants. Exploratory analyses found no relationship between symptom variability and health care resource utilization-defined exacerbations.ConclusionsWS-SD of the E-RS can be used as a measure of symptom variability in studies of patients with COPD. Patients with higher variability have worse health-related quality of life. WS-SD should be further validated as a measure to understand the implications of symptom variability.

Additional file 1.

BackgroundRespiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults.MethodsA literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946–October 2016. Nine articles were identified plus 9 from other sources.ResultsFrom observational studies of natural infection and challenge studies in volunteers, biomarkers of RSV susceptibility or disease severity in adults were: (1) lower anti-RSV neutralizing antibodies, where neutralizing antibody (and local IgA) may be a correlate of susceptibility/severity; (2) RSV-specific CD8+ T cells in bronchoalveolar lavage fluid preinfection (subjects with higher levels had less severe illness); and (3) elevated interleukin-6 (IL-6), IL-8, and myeloperoxidase levels in the airway are indicative of severe infection.ConclusionsFactors determining susceptibility to and severity of RSV disease in adults have not been well defined. Respiratory mucosal antibodies and CD8+ T cells appear to contribute to preventing infection and modulation of disease severity. Studies of RSV pathogenesis in at-risk populations are needed.

Background : 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.

RATIONALE: Understanding the role of airway microbiome in chronic obstructive pulmonary disease (COPD) inflammatory endotypes may help to develop microbiome-based diagnostic and therapeutic approaches.OBJECTIVES: To understand the association of airway microbiome with neutrophilic and eosinophilic COPD at stability and exacerbations.METHODS: An integrative analysis was performed on 1,706 sputum samples collected longitudinally from 510 COPD patients recruited at four UK sites in BEAT-COPD, COPDMAP and AERIS cohorts. The microbiome was analyzed using COPDMAP and AERIS as discovery dataset and BEAT-COPD as validation dataset.RESULTS: The airway microbiome in neutrophilic COPD was heterogeneous with two primary community types differentiated by the predominance of Haemophilus. The Haemophilus-predominant subgroup had elevated sputum IL-1b and TNFa and was relatively stable over time. The other neutrophilic subgroup with a balanced microbiome profile had elevated sputum and serum IL-17A and was temporally dynamic. Patients in this state at stability were susceptible to greatest microbiome shifts during exacerbations. This subgroup can temporally switch to both neutrophilic-Haemophilus-predominant and eosinophilic states which were otherwise mutually exclusive. Time-series analysis on the microbiome showed the temporal trajectories of Campylobacter and Granulicatella were indicative of intra-patient switches from neutrophilic to eosinophilic inflammation, and in track with patient sputum eosinophilia over time. Network analysis revealed distinct host-microbiome interaction patterns between neutrophilic-Haemophilus-predominant, neutrophilic-balanced-microbiome and eosinophilic subgroups.CONCLUSIONS: The airway microbiome can stratify neutrophilic COPD into subgroups that justify different therapies. Neutrophilic and eosinophilic COPD are inter-changeable in some patients. Monitoring temporal variability of the airway microbiome may track patient inflammatory status over time.

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

Rationale: Pulmonary rehabilitation (PR) after hospitalizations for exacerbations of chronic obstructive pulmonary disease (COPD) improves exercise capacity and health-related quality of life and reduces readmissions. However, posthospitalization PR uptake is low. To date, no trials of interventions to increase uptake have been conducted. Objectives: To study the effect of a codesigned education video as an adjunct to usual care on posthospitalization PR uptake. Methods: The present study was an assessor- and statistician-blinded randomized controlled trial with nested, qualitative interviews of participants in the intervention group. Participants hospitalized with COPD exacerbations were assigned 1:1 to receive either usual care (COPD discharge bundle including PR information leaflet) or usual care plus the codesigned education video delivered via a handheld tablet device at discharge. Randomization used minimization to balance age, sex, FEV1 % predicted, frailty, transport availability, and previous PR experience. Measurements and Main Results: The primary outcome was PR uptake within 28 days of hospital discharge. A total of 200 patients were recruited, and 196 were randomized (51% female, median FEV1% predicted, 36 [interquartile range, 27–48]). PR uptake was 41% and 34% in the usual care and intervention groups, respectively (P = 0.37), with no differences in secondary (PR referral and completion) or safety (readmissions and death) endpoints. A total of 6 of the 15 participants interviewed could not recall receiving the video. Conclusions: A codesigned education video delivered at hospital discharge did not improve posthospitalization PR uptake, referral, or completion.

Additional file 1: Figure S1. Flow chart of subject selection process. Figure S2. The comparison of Blood Lymphocyte counts between patients colonised with different PPMs at 6 months post-baseline. Figure S3. The comparison of sputum and blood eosinophil and neutrophil counts between patients colonised with different PPMs. Figure S4. The comparison of sputum and blood eosinophil and neutrophil counts between patients colonised with different PPMs at 6 months post-baseline. Figure S5. Sputum microbiome profiles in COPD patients at 6 months. Figure S6. Stability of Haemophilus presence over 6 months as defined by 16s rRNA Sequencing. Table S1. Composition of > 1PPM group at baseline. Table S2. Sputum inflammatory cell counts and qPCR for patients with frequent or infrequent exacerbations in the 12 months prior to baseline. Table S3. Baseline sputum inflammatory cell counts for induced versus spontaneous sputum samples. Table S4. Baseline sputum inflammatory cell counts for different PPM groups. Table S5. Baseline Demographics of patients enrolled onto this study for different PPM groups. Table S6. Baseline blood inflammatory cell counts for different PPM groups. Table S7. Sputum inflammatory cell counts for different PPM groups at 6 months. Table S8. Blood inflammatory cell counts for different PPM groups at 6 months. Table S9. Baseline sputum inflammatory cell counts for different PPM groups, × 106 copies/ml to detect PPMs. Table S10. Baseline blood inflammatory cell counts for different PPM groups, × 106 copies/ml to detect PPMs. Table S11. Sputum inflammatory cell counts for different PPM groups at 6 months, × 106 copies/ml to detect PPMs. Table S12. Blood inflammatory cell counts for different PPM groups at 6 months, × 106 copies/ml to detect PPMs. Table S13. Baseline demographics, sputum and blood inflammatory cell counts for different PPM groups, × 106 copies/ml to detect PPMs. Table S14. Baseline demographics for different PPM groups. Table S15. Sputum and blood inflammatory cell counts for different PPM groups. Table S16. Baseline demographics for different PPM groups, including those with H. influenzae + ≥ 1 PPM. Table S17. Baseline sputum inflammatory cell counts for different PPM groups, including those with H.influenzae + ≥ 1 PPM. Table S18. Occurrence and average relative abundance of contaminate genera detected in sequenced negative ‘blank’ controls by Salter et al. [5] in the COPDMAP dataset.

Additional file 1.

Additional file 1. Additional Methods.

A recent editorial in the European Respiratory Journal highlighted the strategic importance of the Clinical Research Collaborations (CRCs) launched in 2013 by the European Respiratory Society (ERS) [1]. These have the aim of 1) promoting the exchange of research ideas among clinicians and affiliated scientists in Europe and/or globally; 2) building an infrastructure for prospective clinical research; 3) securing additional funding through national and European Union funding streams; and 4) facilitating the planning, implementation, evaluation and publication of clinical and translational studies at pan-European level and beyond. So far, there are currently 17 ongoing CRCs that cover eight major respiratory disease domains (airway diseases, interstitial lung diseases, pulmonary vascular diseases, sleep and breathing disorders, respiratory critical care, paediatric respiratory diseases, respiratory infections and thoracic oncology), all of them linked to one or more ERS assemblies [2–12]. CADSET, an acronym that stands for “Chronic Airway Diseases Early Stratification”, is the latest addition to the list of ongoing CRCs (www.ersnet.org/research/clinical-research-collaborations). This editorial presents the rationale, goals and research strategy for CADSET.

Acute respiratory tract infections (ARI) constitute a substantial disease burden in adults and elderly individuals. We aimed to identify all case-control studies investigating the potential role of respiratory viruses in the etiology of ARI in older adults aged ≥65 years. We conducted a systematic literature review (across 7 databases) of case-control studies published from 1996 to 2017 that investigated the viral profile of older adults with and those without ARI. We then computed a pooled odds ratio (OR) with a 95% confidence interval and virus-specific attributable fraction among the exposed (AFE) for 8 common viruses: respiratory syncytial virus (RSV), influenza virus (Flu), parainfluenza virus (PIV), human metapneumovirus (HMPV), adenovirus (AdV), rhinovirus (RV), bocavirus (BoV), and coronavirus (CoV). From the 16 studies included, there was strong evidence of possible causal attribution for RSV (OR, 8.5 [95% CI, 3.9–18.5]; AFE, 88%), Flu (OR, 8.3 [95% CI, 4.4–15.9]; AFE, 88%), PIV (OR, not available; AFE, approximately 100%), HMPV (OR, 9.8 [95% CI, 2.3–41.0]; AFE, 90%), AdV (OR, not available; AFE, approximately 100%), RV (OR, 7.1 [95% CI, 3.7–13.6]; AFE, 86%) and CoV (OR, 2.8 [95% CI, 2.0–4.1]; AFE, 65%) in older adults presenting with ARI, compared with those without respiratory symptoms (ie, asymptomatic individuals) or healthy older adults. However, there was no significant difference in the detection of BoV in cases and controls. This review supports RSV, Flu, PIV, HMPV, AdV, RV, and CoV as important causes of ARI in older adults and provides quantitative estimates of the absolute proportion of virus-associated ARI cases to which a viral cause can be attributed. Disease burden estimates should take into account the appropriate AFE estimates (for older adults) that we report., The etiological roles of common respiratory viruses in acute respiratory infections in older adults are important and should be taken into consideration in disease burden estimates.

Background: The burden of chronic obstructive lung disease (COPD) is increasing in women, with recent evidence suggesting gender differences in disease characteristics and potentially in treatment outcomes. Methods: FLAME was a 52-week randomized controlled trial in patients with severe-to-very-severe COPD and a history of exacerbations. In this post-hoc analysis, gender-based baseline differences and treatment outcomes between indacaterol/glycopyrronium 110/50 μg once daily (IND/GLY) and salmeterol/fluticasone 50/500 twice daily (SFC) were assessed in terms of rate of exacerbations, time-to-first exacerbation, lung function, health status, and rescue medication use. Results: This post-hoc analysis included 2557 men and 805 women. Baseline characteristics differed between genders, with women being younger, having better lung function and more often experiencing ≥2 exacerbations in the previous year. Compared with SFC, IND/GLY treatment was associated with reductions in the annualized rates of moderate/severe exacerbations (rate ratio [95% CI]: 0.81 [0.73-0.91], 0.89 [0.74-1.07] in men and women, respectively). Similarly, time-to-first moderate/severe exacerbation was also delayed (hazard ratio [95% CI]: 0.79 [0.70-0.89] and 0.76 [0.63-0.91] in men and women, respectively). Results were similar for all (mild/moderate/severe) exacerbations. Improvements in lung function, health status and rescue medication use with IND/GLY vs SFC were comparable between men and women. The smaller sample size for women may account for some observed discrepancies in treatment responses. Conclusions: Although there were gender differences in baseline characteristics, IND/GLY demonstrated similar trends for exacerbation prevention and lung function improvement in men and women with moderate-to-very-severe COPD and a history of exacerbations compared with SFC. Small differences in the effects seen between genders may be attributed to the different sizes of the two groups and need to be further evaluated in randomized trials that are appropriately powered for gender analysis. Trial registration: Post hoc analysis of the FLAME study.

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

Fig S1. Kaplan–Meier curves and Cox proportional hazard model on time to first moderate-to-severe COPD exacerbation after the first dose of CID. Fig S2. Kaplan–Meier curves and Cox proportional hazard model on SGRQ total score from baseline of CID. Fig S3. Kaplan–Meier curves and Cox proportional hazard model on pre-dose FEV1 of CID. Table S1. Summary statistics Kaplan–Meier and Cox proportional hazard model analysis on time to first moderate-to-severe COPD exacerbation from baseline. Table S2. Summary statistics, Kaplan–Meier and Cox proportional hazard model analysis on first SGRQ total score deterioration from baseline. Table S3. Summary statistics, Kaplan–Meier and Cox proportional hazard model analysis on first trough FEV1 deterioration from baseline. Table S4. Kappa statistics between events in first CID. Table S5. List of institutional review boards or ethics committees. (DOCX 293 kb)

The change in blood eosinophil count between RV negative and RV positive exacerbations. (PPTX 18.8 kb)

Baseline characteristics of patients who declined to GOLD D, according to reason (FEV1 and Exacerbation). (DOCX 18 kb)

Outline of the methods used for the processing of sputum qPCR and differential cell count samples. (PPTX 64.1 kb)

The sputum neutrophil % at baseline and exacerbation in patients defined as PPM positive or PPM negative at exacerbation. PPM=potentially pathogenic microorganisms. Dotted lines represent median values. (PPTX 189 kb)

A summary of the number of patients with blood / sputum eosinophil counts and qPCR data at exacerbation alone, or coupled to baseline measurements. PPM=potentially pathogenic microorganisms. (PPTX 51.6 kb)

Additional methods supplement. (DOCX 38.7 kb)

Comparison of baseline demographics, symptoms and lung function between patients categorised as GOLD B and D. (DOCX 17 kb)

Baseline characteristics of patients who declined to GOLD D, according to reason (FEV1 and Exacerbation). (DOCX 18 kb)

A summary of the number of patients with blood / sputum eosinophil counts and qPCR data at exacerbation alone, or coupled to baseline measurements. PPM=potentially pathogenic microorganisms. (PPTX 51.6 kb)

The sputum neutrophil % at baseline and exacerbation in patients defined as PPM positive or PPM negative at exacerbation. PPM=potentially pathogenic microorganisms. Dotted lines represent median values. (PPTX 189 kb)

Baseline characteristics of patients categorised as GOLD C and D. (DOCX 17 kb)

This document provides clinical recommendations for treatment of chronic obstructive pulmonary disease (COPD) exacerbations. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the Task Force's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of COPD experts. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made: 1) a strong recommendation for noninvasive mechanical ventilation of patients with acute or acute-on-chronic respiratory failure; 2) conditional recommendations for oral corticosteroids in outpatients, oral rather than intravenous corticosteroids in hospitalised patients, antibiotic therapy, home-based management, and the initiation of pulmonary rehabilitation within 3 weeks after hospital discharge; and 3) a conditional recommendation against the initiation of pulmonary rehabilitation during hospitalisation. The Task Force provided recommendations related to corticosteroid therapy, antibiotic therapy, noninvasive mechanical ventilation, home-based management, and early pulmonary rehabilitation in patients having a COPD exacerbation. These recommendations should be reconsidered as new evidence becomes available.

Outline of the methods used for the processing of sputum qPCR and differential cell count samples. (PPTX 64.1 kb)

OBJECTIVE: To assess the accuracy of Global Registry of Acute Coronary Events (GRACE) scores in predicting mortality at 6 months for people with chronic obstructive pulmonary disease (COPD) and to investigate how it might be improved. METHODS: Data were obtained on 481 849 patients with acute coronary syndrome admitted to UK hospitals between January 2003 and June 2013 from the Myocardial Ischaemia National Audit Project (MINAP) database. We compared risk of death between patients with COPD and those without COPD at 6 months, adjusting for predicted risk of death. We then assessed whether several modifications improved the accuracy of the GRACE score for people with COPD. RESULTS: The risk of death after adjusting for GRACE score predicted that risk of death was higher for patients with COPD than that for other patients (RR 1.29, 95% CI 1.28 to 1.33). Adding smoking into the GRACE score model did not improve accuracy for patients with COPD. Either adding COPD into the model (relative risk (RR) 1.00, 0.94 to 1.02) or multiplying the GRACE score by 1.3 resulted in better performance (RR 0.99, 0.96 to 1.01). CONCLUSIONS: GRACE scores underestimate risk of death for people with COPD. A more accurate prediction of risk of death can be obtained by adding COPD into the GRACE score equation, or by multiplying the GRACE score predicted risk of death by 1.3 for people with COPD. This means that one third of patients with COPD currently classified as low risk should be classified as moderate risk, and could be considered for more aggressive early treatment after non-ST-segment elevation myocardial infarction or unstable angina.

Publisher Summary There has been considerable recent interest into the causes and mechanisms of exacerbations of chronic obstructive pulmonary disease (COPD) as COPD exacerbations are an important cause of the considerable morbidity and mortality found in COPD. COPD exacerbations increase with increasing severity of COPD. Earlier descriptions of COPD exacerbations had concentrated mainly on studies of hospital admission, though most COPD exacerbations are treated in the community and not associated with hospital admission. Exacerbation frequency is an important determinant of health status in COPD and is thus one of the important outcome measures in COPD. Factors predictive of frequent exacerbations included daily cough and sputum and frequent exacerbations in the previous year. In a further prospective analysis of 504 exacerbations, where daily monitoring was performed, there was some deterioration in symptoms, though no there were significant peak expiratory flow changes. Recovery was longer in the presence of increased dyspnoea or symptoms of a common cold at exacerbation. The changes observed in lung function at exacerbation were smaller than those observed at asthmatic exacerbations. The reasons for the incomplete recovery of symptoms and lung function are not clear, but may involve inadequate treatment or persistence of the causative agent. The incomplete physiological recovery after an exacerbation could contribute to the decline in lung function with time in patients with COPD. The association of the symptoms of increased dyspnoea and of the common cold at exacerbation with a prolonged recovery suggests that viral infections may lead to more prolonged exacerbations.

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

Oxidative stress contributes to chronic obstructive pulmonary disease (COPD) exacerbations and antioxidants can decrease exacerbation rates, although we lack data about the effect of such drugs on exacerbation duration.The RESTORE (Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD) study was a prospective randomised, double-blind, placebo-controlled study, enrolling patients aged 40–80 years with Global Initiative for Chronic Obstructive Lung Disease stage II/III. Patients received erdosteine 300 mg twice daily or placebo added to usual COPD therapy for 12 months. The primary outcome was the number of acute exacerbations during the study.In the pre-specified intention-to-treat population of 445 patients (74% male; mean age 64.8 years, forced expiratory volume in 1 s 51.8% predicted) erdosteine reduced the exacerbation rate by 19.4% (0.91 versus. 1.13 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.01), due to an effect on mild events; the reduction in the rate of mild exacerbations was 57.1% (0.23 versus 0.54 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.002). No significant difference was observed in the rate of moderate and severe exacerbations (0.68 versus 0.59 exacerbations·patient−1·year−1 for erdosteine and placebo, respectively; p=0.054) despite a trend in favour of the comparison group. Erdosteine decreased the exacerbation duration irrespective of event severity by 24.6% (9.55 versus 12.63 days for erdosteine and placebo, respectively; p=0.023). Erdosteine significantly improved subject and physician subjective severity scores (p=0.022 and p=0.048, respectively), and reduced the use of reliever medication (pIn patients with COPD, erdosteine can reduce both the rate and duration of exacerbations. The percentage of patients with adverse events was similar in both the placebo and erdosteine treatment groups.

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

BACKGROUND: During most COPD exacerbations, patients continue to live in the community but there is little information on changes in activity during exacerbations due to the difficulties of obtaining recent, prospective baseline data. METHODS: Patients recorded on daily diary cards any worsening in respiratory symptoms, peak expiratory flow (PEF) and the number of steps taken per day measured with a Yamax Digi-walker pedometer. Exacerbations were defined by increased respiratory symptoms and the number of exacerbations experienced in the 12 months preceding the recording of daily step count used to divide patients into frequent (> = 2/year) or infrequent exacerbators. RESULTS: The 73 COPD patients (88% male) had a mean (+/-SD) age 71(+/-8) years and FEV1 53(+/-16)% predicted. They recorded pedometer data on a median 198 days (IQR 134-353). At exacerbation onset, symptom count rose by 1.9(+/-1.3) and PEF fell by 7(+/-13) l/min. Mean daily step count fell from 4154(+/-2586) steps/day during a preceding baseline week to 3673(+/-2258) step/day during the initial 7 days of exacerbation (p = 0.045). Patients with larger falls in activity at exacerbation took longer to recover to stable level (rho = -0.56; p < 0.001). Recovery in daily step count was faster (median 3.5 days) than for exacerbation symptoms (median 11 days; p < 0.001). Recovery in step count was also faster in untreated compared to treated exacerbation (p = 0.030).Daily step count fell faster over time in the 40 frequent exacerbators, by 708 steps/year, compared to 338 steps/year in 33 infrequent exacerbators (p = 0.002). CONCLUSIONS: COPD exacerbations reduced physical activity and frequent exacerbations accelerate decline in activity over time.

Identifying subjects for clinical trials is difficult and the evidence base for recruitment strategies is limited, particularly in the field of COPD. We compared the efficiency and patient characteristics of different community-based recruitment strategies during a non-commercial COPD trial in the UK. Recruiting from general practice COPD registers was less efficient and identified patients with significantly milder disease than recruiting through pulmonary rehabilitation and patient groups. We report our experience and propose that pulmonary rehabilitation and patient groups may represent an enriched pool of COPD patients to recruit into clinical trials. Trial registration number: EudraCT 2011-001063-43

Background: Substantial benefits are associated with early pulmonary rehabilitation (PR) following severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) requiring hospitalisation. However, referral for, and uptake of, early PR are poor. Methods and findings: In a prospective cohort study of 291 hospitalisations for AECOPD, COPD discharge bundles delivered by PR practitioners were associated with increased PR referral (60% vs 12%, p

This thesis examines novel aspects of exacerbations and chronic bronchitis spanning across the spectrum of chronic obstructive pulmonary disease (COPD). Both are important to study since they are implicated in the progression, morbidity and mortality of COPD. This thesis presents work from a recently recruited, novel longitudinal patient cohort dedicated to the serial sampling of individuals at risk of developing COPD (10pyh, 30-45yrs). It describes the characteristics of Early COPD in this group and the exacerbation events that they exhibit. This is a new approach to understanding the pathogenesis which underpins COPD development. To date, the majority of COPD studies attempting to examine the concept of Early COPD have included populations with mean ages older than 60 years1 which inform on late “mild disease as opposed to “early disease”.2 The methodology involved using symptom and treatment diary cards to record an increase in cardinal symptoms associated with an AECOPD. Patients were then seen clinically and data was compared to their baseline state. It found that CT changes consistent with Early COPD are more common than obstructive spirometry . It went on to show that exacerbation events in the Early COPD cohort may exhibit modest inflammatory changes but do find corresponding symptomatic and pathophysiological changes. There is evidence that a proportion do not fully recover and further work is required to ascertain the effect of these events on the development of established COPD. Whilst examining the effect of intermittent bronchitis on COPD progression over a 9-year period in participants of the London exacerbation cohort, this study concluded that, the identification of chronic bronchitis through disease burden questionnaires can be objectively validated with sample tracking data. This thesis found that the higher percentage of baseline visits with sputum collected, the faster FEV1 declined. Finally, this thesis presents the effect of retreatment in incompletely recovered AECOPD. This randomized, placebo control trial found no benefit of treatment with ciprofloxacin of exacerbations with persistent respiratory symptoms or a raised CRP (>=8 mg/dl) at 14 days post exacerbation onset. This suggests that non-recovered exacerbations which may lead to hospital readmission potentially need to be targeted with anti-inflammatory therapies and further research is now warranted to investigate exacerbation recovery. Open Access

Rationale Human rhinovirus (HRV) is a common cause of COPD exacerbations. Some patients with COPD experience frequent exacerbations. The biological mechanisms underlying exacerbation frequency are unknown. Interferons are produced by alveolar macrophages and bronchial epithelial cells (BECS), limiting viral replication. The role of interferons in COPD remains controversial. Secondary bacterial infection is also common. Alveolar macrophages clear bacteria from the lung. The effect of HRV on macrophage function is unknown. Hypotheses IFN responses to HRV are impaired in BECS and alveolar macrophages from COPD patients compared to healthy subjects. In patients with frequent exacerbations, IFN responses will be further impaired leading to increased exacerbation frequency. HRV impairs phagocytosis of bacteria in macrophages from COPD subjects increasing risk of secondary bacterial infection. Methods Alveolar macrophages and BECS were obtained by bronchoscopy from COPD patients and healthy controls. Alveolar macrophages and BECS were infected with HRV16 or medium for 24 hours. IFNs and proinflammatory were measured in supernatants by meso-scale discovery (MSD). Macrophages and MDM were exposed to HRV or medium for 24 hours. Phagocytosis of fluorescently labelled bacteria was assessed by fluorimetry. Main Results IFN responses to HRV16 were significantly impaired in alveolar macrophages but not BECS from patients with COPD compared to healthy controls. IFN-β response to HRV16 was significantly reduced in BECS and alveolar macrophages from frequent exacerbators compared to infrequent exacerbators. HRV significantly impaired phagocytosis of bacteria by in MDM and alveolar macrophages in COPD. There was no effect in healthy controls. Conclusions IFN response to HRV was impaired in alveolar macrophages from COPD patients and further impaired in patients with frequent exacerbations. HRV impaired phagocytosis of bacteria in alveolar macrophages in COPD which may lead to an outgrowth of bacteria. These findings suggest an impaired anti-viral response may drive increased risk of frequent exacerbations in COPD. Open Access

Chronic Obstructive Pulmonary Disease (COPD) is a common, progressive disease responsible for substantial morbidity and mortality worldwide. However, current concepts of COPD are based upon studies of older individuals with already established disease leaving early stage COPD development relatively unstudied. This thesis explores potential early stage COPD development by analysing data collected across the life course of individuals within the National Survey of Health and Development. This thesis examines how the relationship between chronic mucus hypersecretion (CMH) and smoking develops with ageing and how CMH relates to both FEV1 decline during adulthood and airflow limitation in the seventh decade. This thesis also investigates how the impact of smoking upon adult lung function trajectory may be modified by early life exposures. This thesis demonstrates that CMH followed a dynamic course across life, strongly reflecting concurrent smoking behaviour, and that CMH duration reflected FEV1 loss. The relationship between smoking and CMH also evolved with ageing. CMH prevalence escalated among smokers between ages 36 and 43 years, consistent with increasing susceptibility to the effects of smoking, and at these ages CMH symptoms identified smokers more likely to have developed airflow limitation by age 60-64 years. This suggests that CMH is a biomarker of airway disease activity and that, during mid-life, CMH among smokers indicates an early phase of COPD development. This thesis also demonstrates that smoking interacts synergistically with infant exposures such that infant respiratory infection and infant poverty only impacted adult lung function among smokers. This is consistent with adolescent growth facilitating recovery from infant insults if catch-up growth is not impeded by smoking. This thesis provides new insights into how and when COPD may begin to develop. Further research investigating the pathophysiology accompanying CMH development during mid-life may reveal novel therapeutic targets to prevent the development of irreversible airway damage. Open Access

This thesis investigates the airway microbiome in chronic obstructive pulmonary disease (COPD). The relationship of the airway microbiome to clinical disease characteristics and prophylactic antibiotic therapy is unknown, as are the ideal methods of community recruitment into clinical trials of COPD. Direct comparative data between bacterial culture and newer molecular techniques are also lacking. We used a randomised controlledantibiotic trial of patients with COPD to investigate these areas. During recruitment to this study we hypothesised that within primary care, different sources would have particular advantages when recruiting patients to clinical studies of COPD. We proposed that in stable COPD there would be aspects of the microbiome composition that would relate clinically to disease characteristics, and that when antibiotic therapy was given for three months there would be measurable changes in the microbiome as well as in bacterial resistance and clinical disease measures. We found that pulmonary rehabilitation and patient groups represented the most efficient and cost-effective way to recruit COPD patients. Our comparison between culture and molecular methods showed concordance between the techniques, but that different aspects of the microbiome are being assessed. Analysis of the microbiome at baseline showed that in one quarter of patients the COPD microbiome is dominated by the genus Haemophilus, predominantly Haemophilus influenzae, with greater levels of airway inflammation. Therapy with three months of moxifloxacin, but not azithromycin or doxycycline, was effective against placebo in reducing the burden of Haemophilus species with a concurrent reduction in inflammation. Antimicrobial resistance increased in all treatment groups. Our findings suggest that COPD patients whose microbiota is dominated by Haemophilus may derive particular benefit from prophylactic antibiotic therapy, although this drives antimicrobial resistance. Open Access