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Background: Navafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and β-agonist, developed for the treatment of COPD. This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD., Methods: This phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434) compared 2 weeks' treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol (UMEC/VI); 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough forced expiratory volume in 1 s (FEV 1 ) on day 15. Secondary end-points included change from baseline in peak FEV 1 ; change from baseline in Breathlessness, Cough and Sputum Scale (BCSS); change from baseline in COPD Assessment Tool (CAT); adverse events; and pharmacokinetics., Results: 73 participants were randomised. After 14 days, trough FEV 1 was significantly improved with navafenterol compared with placebo (least-squares (LS) mean difference 0.202 L; p<0.0001). There was no significant difference in FEV 1 between navafenterol and UMEC/VI (LS mean difference -0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all p<0.005). Novel objective monitoring (VitaloJAK) showed that cough was reduced with both active treatments compared with placebo. Safety profiles were similar across the treatment groups and no serious adverse events were reported in the navafenterol treatment period., Conclusion: Once-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator., Competing Interests: Conflict of interest: D. Singh has received grants and personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Epiendo, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Mundipharma, Novartis, Pfizer, Pulmatrix, Sanofi, Teva, Theravance and Verona, and personal fees from Cipla, Genentech and Peptinnovate. J. Beier has received consultation fees from AstraZeneca, Berlin Chemie/Menarini, Chiesi and Pohl-Boskamp, and participated in scientific advisory boards that were funded by AstraZeneca and Chiesi. C. Astbury, M.G. Belvisi, C.A. Da Silva, A. Jauhiainen, E. Jimenez, A. Lei, S. Necander, U. Wählby Hamrén, W. Xin and I. Psallidas are employees of AstraZeneca and may hold stock or stock options. The VitaloJAK algorithm has been licensed by Manchester University Foundation Trust (MFT) and the University of Manchester to Vitalograph Ltd and Vitalograph Ireland (Ltd); MFT receives royalties which may be shared with the clinical division in which J.A. Smith works, and J.A. Smith has received personal fees from AstraZeneca., (Copyright ©The authors 2022.)

Background: Over 30% of adult patients with pleural infection either die and/or require surgery. There is no robust means of predicting at baseline presentation which patients will suffer a poor clinical outcome. A validated risk prediction score would allow early identification of high-risk patients, potentially directing more aggressive treatment thereafter., Objectives: To prospectively assess a previously described risk score (the RAPID (Renal (urea), Age, fluid Purulence, Infection source, Dietary (albumin)) score) in adults with pleural infection., Methods: Prospective observational cohort study that recruited patients undergoing treatment for pleural infection. RAPID score and risk category were calculated at baseline presentation. The primary outcome was mortality at 3 months; secondary outcomes were mortality at 12 months, length of hospital stay, need for thoracic surgery, failure of medical treatment and lung function at 3 months., Results: Mortality data were available in 542 out of 546 patients recruited (99.3%). Overall mortality was 10% at 3 months (54 out of 542) and 19% at 12 months (102 out of 542). The RAPID risk category predicted mortality at 3 months. Low-risk mortality (RAPID score 0-2): five out of 222 (2.3%, 95% CI 0.9 to 5.7%); medium-risk mortality (RAPID score 3-4): 21 out of 228 (9.2%, 95% CI 6.0 to 13.7%); and high-risk mortality (RAPID score 5-7): 27 out of 92 (29.3%, 95% CI 21.0 to 39.2%). C-statistics for the scores at 3 months and 12 months were 0.78 (95% CI 0.71-0.83) and 0.77 (95% CI 0.72-0.82), respectively., Conclusions: The RAPID score stratifies adults with pleural infection according to increasing risk of mortality and should inform future research directed at improving outcomes in this patient population., Competing Interests: Conflict of interest: J.P. Corcoran reports grants from the UK Medical Research Council (MRC; grant number G1001128), during the conduct of the study. Conflict of interest: I. Psallidas reports grants from the UK MRC (grant number G1001128), during the conduct of the study, as well as grants and personal fees from the European Respiratory Society (ERS), outside the submitted work. Conflict of interest: S. Gerry has nothing to disclose. Conflict of interest: F. Piccolo has nothing to disclose. Conflict of interest: C.F. Koegelenberg has nothing to disclose. Conflict of interest: T. Saba has nothing to disclose. Conflict of interest: C. Daneshvar has nothing to disclose. Conflict of interest: I. Fairbairn has nothing to disclose. Conflict of interest: R. Heinink has nothing to disclose. Conflict of interest: A. West has nothing to disclose. Conflict of interest: A.E. Stanton has nothing to disclose. Conflict of interest: J. Holme has nothing to disclose. Conflict of interest: J.A. Kastelik has nothing to disclose. Conflict of interest: H. Steer has nothing to disclose. Conflict of interest: N.J. Downer has nothing to disclose. Conflict of interest: M. Haris has nothing to disclose. Conflict of interest: E.H. Baker has nothing to disclose. Conflict of interest: C.F. Everett has nothing to disclose. Conflict of interest: J. Pepperell has nothing to disclose. Conflict of interest: T. Bewick has nothing to disclose. Conflict of interest: L. Yarmus has nothing to disclose. Conflict of interest: F. Maldonado has nothing to disclose. Conflict of interest: B. Khan has nothing to disclose. Conflict of interest: A. Hart-Thomas has nothing to disclose. Conflict of interest: G. Hands has nothing to disclose. Conflict of interest: G. Warwick has nothing to disclose. Conflict of interest: D. De Fonseka has nothing to disclose. Conflict of interest: M. Hassan reports grants from the UK MRC (grant number G1001128), during the conduct of the study. Conflict of interest: M. Munavvar has nothing to disclose. Conflict of interest: A. Guhan has nothing to disclose. Conflict of interest: M. Shahidi has nothing to disclose. Conflict of interest: Z. Pogson has nothing to disclose. Conflict of interest: L. Dowson has nothing to disclose. Conflict of interest: N.D. Popowicz has nothing to disclose. Conflict of interest: J. Saba has nothing to disclose. Conflict of interest: N.R. Ward has nothing to disclose. Conflict of interest: R.J. Hallifax reports grants from the UK MRC (grant number G1001128), during the conduct of the study. Conflict of interest: M. Dobson reports grants from the UK MRC (grant number G1001128), during the conduct of the study. Conflict of interest: R. Shaw reports grants from the UK MRC (grant number G1001128), during the conduct of the study. Conflict of interest: E.L. Hedley reports grants from the UK MRC (grant number G1001128), during the conduct of the study. Conflict of interest: A. Sabia reports grants from the UK MRC (grant number G1001128), during the conduct of the study. Conflict of interest: B. Robinson reports grants from the UK MRC (grant number G1001128), during the conduct of the study. Conflict of interest: G.S. Collins has nothing to disclose. Conflict of interest: H.E. Davies has nothing to disclose. Conflict of interest: L-M. Yu has nothing to disclose. Conflict of interest: R.F. Miller has nothing to disclose. Conflict of interest: N.A. Maskell has nothing to disclose. Conflict of interest: N.M. Rahman reports grants from the UK MRC (grant number G1001128), during the conduct of the study, as well as personal fees from the UK National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, outside the submitted work., (Copyright ©ERS 2020.)

The European Respiratory Society (ERS)/European Society of Thoracic Surgeons (ESTS)/European Association for Cardio-Thoracic Surgery (EACTS)/European Society for Radiotherapy and Oncology (ESTRO) task force brought together experts to update previous 2009 ERS/ESTS guidelines on management of malignant pleural mesothelioma (MPM), a rare cancer with globally poor outcome, after a systematic review of the 2009-2018 literature. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. The evidence syntheses were discussed and recommendations formulated by this multidisciplinary group of experts. Diagnosis: pleural biopsies remain the gold standard to confirm the diagnosis, usually obtained by thoracoscopy but occasionally via image-guided percutaneous needle biopsy in cases of pleural symphysis or poor performance status. Pathology: standard staining procedures are insufficient in ∼10% of cases, justifying the use of specific markers, including BAP-1 and CDKN2A ( p16 ) for the separation of atypical mesothelial proliferation from MPM. Staging: in the absence of a uniform, robust and validated staging system, we advise using the most recent 2016 8th TNM (tumour, node, metastasis) classification, with an algorithm for pre-therapeutic assessment. Monitoring: patient's performance status, histological subtype and tumour volume are the main prognostic factors of clinical importance in routine MPM management. Other potential parameters should be recorded at baseline and reported in clinical trials. Treatment: (chemo)therapy has limited efficacy in MPM patients and only selected patients are candidates for radical surgery. New promising targeted therapies, immunotherapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres., Competing Interests: Conflict of interest: A. Scherpereel reports personal fees for advisory board work from AstraZeneca, BMS, MSD, Roche and Janssen, non-financial support for meeting attendance from BMS, MSD and Roche, institutional support for clinical trial participation from Astra-Zeneca/MedImmune, BMS, Verastem and Bayer, grants from BMS, outside the submitted work. Conflict of interest: I. Opitz has nothing to disclose. Conflict of interest: T. Berghmans has nothing to disclose. Conflict of interest: I. Psallidas works as a Medical Science Director for AstraZeneca, outside the submitted work; membership of the task force was resigned when this position became effective. Conflict of interest: M. Glatzer has nothing to disclose. Conflict of interest: D. Rigau works as methodologist for the European Respiratory Society. Conflict of interest: P. Astoul has nothing to disclose. Conflict of interest: S. Bölükbas has nothing to disclose. Conflict of interest: J. Boyd is an employee of the European Respiratory Society. Conflict of interest: J. Coolen has nothing to disclose. Conflict of interest: C. De Bondt has nothing to disclose. Conflict of interest: D. De Ruysscher reports grants from Bristol-Myers-Squibb AstraZeneca, Celgene, Roche/Genentech and Merck/ Pfizer, outside the submitted work. Conflict of interest: V. Durieux has nothing to disclose. Conflict of interest: C. Faivre-Finn has nothing to disclose. Conflict of interest: D. Fennell reports personal fees and non-financial support from BMS and MSD, non-financial support from Eli Lilly, Clovis, Bergen Bio and Pierre Fabre, grants, personal fees and non-financial support from Roche-Genentech, personal fees from Aldeyra, during the conduct of the study. Conflict of interest: F. Galateau-Salle has nothing to disclose. Conflict of interest: L. Greillier reports grants, personal fees and non-financial support from Roche and Novartis, personal fees and non-financial support from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, Abbvie and MSD, outside the submitted work. Conflict of interest: M.A. Hoda has nothing to disclose. Conflict of interest: W. Klepetko has nothing to disclose. Conflict of interest: A. Lacourt has nothing to disclose. Conflict of interest: P. McElnay was employed by GlaxoSmithKline, outside the submitted work. Conflict of interest: N.A. Maskell has nothing to disclose. Conflict of interest: L. Mutti has nothing to disclose. Conflict of interest: J-C. Pairon reports grants from Santé Publique France Agency and French National Health Insurance (CNAM-TS), outside the submitted work. Conflict of interest: P. Van Schil has nothing to disclose. Conflict of interest: J.P. van Meerbeeck has nothing to disclose. Conflict of interest: D. Waller has nothing to disclose. Conflict of interest: W. Weder reports personal fees from AstraZeneca for advisory board work and lectures, grants and personal fees for lectures from Covidien. Conflict of interest: G. Cardillo has nothing to disclose. Conflict of interest: P.M. Putora reports grants from AstraZeneca and Celgene, outside the submitted work., (The article has been co-published with permission in the European Respiratory Journal and the European Journal of Cardio-Thoracic Surgery. All rights reserved in respect of European Respiratory Journal, © European Respiratory Society 2020 and European Journal of Cardio-Thoracic Surgery, © European Association for Cardio-Thoracic Surgery 2020. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. Either citation can be used when citing this article.)

Background and Objectives: Pleural infection is a major cause of morbidity and mortality among adults. Identification of the offending organism is key to appropriate antimicrobial therapy. It is not known whether the microbiological pattern of pleural infection is variable temporally or geographically. This systematic review aimed to investigate available literature to understand the worldwide pattern of microbiology and the factors that might affect such pattern., Data Sources and Eligibility Criteria: Ovid MEDLINE and Embase were searched between 2000 and 2018 for publications that reported on the microbiology of pleural infection in adults. Both observational and interventional studies were included. Studies were excluded if the main focus of the report was paediatric population, tuberculous empyema or post-operative empyema., Study Appraisal and Synthesis Methods: Studies of ≥20 patients with clear reporting of microbial isolates were included. The numbers of isolates of each specific organism/group were collated from the included studies. Besides the overall presentation of data, subgroup analyses by geographical distribution, infection setting (community versus hospital) and time of the report were performed., Results: From 20 980 reports returned by the initial search, 75 articles reporting on 10 241 patients were included in the data synthesis. The most common organism reported worldwide was Staphylococcus aureus . Geographically, pneumococci and viridans streptococci were the most commonly reported isolates from tropical and temperate regions, respectively. The microbiological pattern was considerably different between community- and hospital-acquired infections, where more Gram-negative and drug-resistant isolates were reported in the hospital-acquired infections. The main limitations of this systematic review were the heterogeneity in the method of reporting of certain bacteria and the predominance of reports from Europe and South East Asia., Conclusions: In pleural infection, the geographical location and the setting of infection have considerable bearing on the expected causative organisms. This should be reflected in the choice of empirical antimicrobial treatment., Competing Interests: Conflict of interest: M. Hassan has nothing to disclose. Conflict of interest: T. Cargill has nothing to disclose. Conflict of interest: E. Harriss has nothing to disclose. Conflict of interest: R. Asciak has nothing to disclose. Conflict of interest: R.M. Mercer has nothing to disclose. Conflict of interest: E.O. Bedawi has nothing to disclose. Conflict of interest: D.J. McCracken has nothing to disclose. Conflict of interest: I. Psallidas has nothing to disclose. Conflict of interest: J.P. Corcoran has nothing to disclose. Conflict of interest: N.M. Rahman has nothing to disclose., (Copyright ©ERS 2019.)

The MIST2 (Second Multicentre Intrapleural Sepsis Trial) trial showed that combined intrapleural use of tissue plasminogen activator (t-PA) and recombinant human DNase was effective when compared with single agents or placebo. However, the treatment costs are significant and overall cost-effectiveness of combined therapy remains unclear.An economic evaluation of the MIST2 trial was performed to assess the cost-effectiveness of combined therapy. Costs included were those related to study medications, initial hospital stay and subsequent hospitalisations. Outcomes were measured in terms of life-years gained. All costs were reported in euro and in 2016 prices.Mean annual costs were lowest in the t-PA-DNase group (EUR 10 605 for t-PA, EUR 17 856 for DNase, EUR 13 483 for placebo and EUR 7248 for t-PA-DNase; p=0.209). Mean 1-year life expectancy was 0.988 for t-PA, 0.923 for DNase, and 0.969 for both placebo and t-PA-DNase (p=0.296). Both DNase and placebo were less effective, in terms of life-years gained, and more costly than t-PA. When placebo was compared with t-PA-DNase, the incremental cost per life-year gained of placebo was EUR 1.6 billion, with a probability of 0.85 of t-PA-DNase being cost-effective.This study demonstrates that combined t-PA-DNase is likely to be highly cost-effective. In light of this evidence, a definitive trial designed to facilitate a thorough economic evaluation is warranted to provide further evidence on the cost-effectiveness of this promising combined intervention., Competing Interests: Conflict of interest: R. Luengo-Fernandez has nothing to disclose. Conflict of interest: E. Penz reports personal fees (participation in advisory boards) from AstraZeneca, GlaxoSmithKline and Boehringer Ingelheim, outside the submitted work. Conflict of interest: M. Dobson has nothing to disclose. Conflict of interest: I. Psallidas works as a Medical Science Director in AstraZeneca in a different scientific area not relevant to the article. Conflict of interest: A.J. Nunn reports an unrestricted educational grant from Roche UK, during the conduct of the study. Conflict of interest: N.A. Maskell has nothing to disclose. Conflict of interest: N.M. Rahman reports an unrestricted educational grant from Roche UK, during the conduct of the study., (Copyright ©ERS 2019.)

Malignant pleural effusions (MPE) are a common pathology, treated by respiratory physicians and thoracic surgeons alike. In recent years, several well-designed randomised clinical trials have been published that have changed the landscape of MPE management. The European Respiratory Society (ERS) and the European Association for Cardio-Thoracic Surgery (EACTS) established a multidisciplinary collaboration of clinicians with expertise in the management of MPE with the aim of producing a comprehensive review of the scientific literature.Six areas of interest were identified, including the optimum management of symptomatic MPE, management of trapped lung in MPE, management of loculated MPE, prognostic factors in MPE, whether there is a role for oncological therapies prior to intervention for MPE and whether a histological diagnosis is always required in MPE.The literature revealed that talc pleurodesis and indwelling pleural catheters effectively manage the symptoms of MPE. There was limited evidence regarding the management of trapped lung or loculated MPE. The LENT score was identified as a validated tool for predicting survival in MPE, with Brims' prognostic score demonstrating utility in mesothelioma prognostication. There was no evidence to support the use of oncological therapies as an alternative to MPE drainage, and the literature supported the use of tissue biopsy as the gold standard for diagnosis and treatment planning., Competing Interests: Conflict of interest: A.C. Bibby reports grants from National Institute of Health Research (DRF-2016-09-065), outside the submitted work. Conflict of interest: I. Psallidas is a Medical Science Director for AstraZeneca in a different research area than the submitted work. Conflict of interest: P. Licht reports personal fees (speaker's honorarium) from Ethicon, outside the submitted work. Conflict of interest: A. Scherpereel reports personal fees (for advisory board participation) from BMS, MSD, Boehringer Ingelheim and Roche, and has been an investigator in clinical trials (fees paid to institution, CHU de Lille, France) for AstraZeneca, Lilly, BMS, MSD, Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: N.M. Rahman reports personal fees for consultancy work from Rocket Medical UK, outside the submitted work. Conflict of interest: N.A. Maskell reports unrestricted research grants from Becton Dickinson and Rocket, outside the submitted work, and is a member of the advisory board for Becton Dickinson., (The article has been co-published with permission in the European Respiratory Journal and the European Journal of Cardio-Thoracic Surgery. All rights reserved in respect of European Respiratory Journal, © European Respiratory Society 2018 and European Journal of Cardio-Thoracic Surgery, © European Association for Cardio-Thoracic Surgery 2018. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. Either citation can be used when citing this article.)

Small cell lung cancer (SCLC) presents multiple interdisciplinary challenges with several paradigm shifts in its treatment in recent years. SCLC treatment requires multidisciplinary management and timely treatment. The aim of this review is to focus on the team management aspects in the treatment of limited disease SCLC and how this can contribute towards improving outcomes., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2017.)