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This meta-analysis compares the efficacy and safety of inhaled versus systemic corticosteroids for COPD exacerbations. Following a pre-registered protocol, we appraised eligible randomised controlled trials (RCTs) according to Cochrane methodology, performed random-effects meta-analyses for all outcomes prioritised in the European Respiratory Society COPD core outcome set and rated the certainty of evidence as per Grading of Recommendations Assessment, Development and Evaluation methodology. We included 20 RCTs totalling 2140 participants with moderate or severe exacerbations. All trials were at high risk of methodological bias. Low-certainty evidence did not reveal significant differences between inhaled and systemic corticosteroids for treatment failure rate (relative risk 1.75, 95% CI 0.76–4.02, n=569 participants); breathlessness (mean change: standardised mean difference (SMD) −0.11, 95% CI −0.36– 0.15, n=239; post-treatment scores: SMD −0.18, 95% CI −0.41–0.05, n=293); serious adverse events (relative risk 1.47, 95% CI 0.56–3.88, n=246); or any other efficacy outcomes. Moderate-certainty evidence implied a tendency for fewer adverse events with inhaled compared to systemic corticosteroids (relative risk 0.80, 95% CI 0.64–1.0, n=480). Hyperglycaemia and oral fungal infections were observed more frequently with systemic and inhaled corticosteroids, respectively. Limited available evidence suggests potential noninferiority of inhaled to systemic corticosteroids in COPD exacerbations. Appropriately designed and powered RCTs are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Clinical trials evaluating the management of acute exacerbations of COPD assess heterogeneous outcomes, often omitting those that are clinically relevant or more important to patients. We have developed a core outcome set, a consensus-based minimum set of important outcomes that we recommend are evaluated in all future clinical trials on exacerbations management, to improve their quality and comparability. COPD exacerbations outcomes were identified through methodological systematic reviews and qualitative interviews with 86 patients from 11 countries globally. The most critical outcomes were prioritised for inclusion in the core outcome set through a two-round Delphi survey completed by 1063 participants (256 patients, 488 health professionals and 319 clinical academics) from 88 countries in five continents. Two global, multi-stakeholder, virtual consensus meetings were conducted to 1) finalise the core outcome set and 2) prioritise a single measurement instrument to be used for evaluating each of the prioritised outcomes. Consensus was informed by rigorous methodological systematic reviews. The views of patients with COPD were accounted for at all stages of the project. Survival, treatment success, breathlessness, quality of life, activities of daily living, the need for a higher level of care, arterial blood gases, disease progression, future exacerbations and hospital admissions, treatment safety and adherence were all included in the core outcome set. Focused methodological research was recommended to further validate and optimise some of the selected measurement instruments. The panel did not consider the prioritised set of outcomes and associated measurement instruments to be burdensome for patients and health professionals to use., Competing Interests: Conflict of interest: A.G. Mathioudakis reports grants from Boehringer Ingelheim, outside the submitted work. Conflict of interest: F. Abroug has nothing to disclose. Conflict of interest: A. Agusti reports grants and personal fees for advisory board work and lectures from GSK, Menarini, Chiesi and AZ, outside the submitted work. Conflict of interest: S. Ananth has nothing to disclose. Conflict of interest: P. Bakke reports personal fees for lectures from AstraZeneca, Novartis and GlaxoSmithKline, outside the submitted work. Conflict of interest: K. Bartziokas has nothing to disclose. Conflict of interest: B. Beghe has nothing to disclose. Conflict of interest: A. Bikov has nothing to disclose. Conflict of interest: T. Bradbury reports receiving an academic scholarship funded by GlaxoSmithKline outside the submitted work. Conflict of interest: G. Brusselle reports personal fees for advisory board work and lectures from Astra Zeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Sanofi and Teva, outside the submitted work. Conflict of interest: C. Cadus reports personal fees from Mundipharma and AstraZeneca outside the submitted work. Conflict of interest: C. Coleman is an employee of the European Lung Foundation. Conflict of interest: M. Contoli reports board membership, payment for lectures, grants for research and travel expenses reimbursement from Chiesi, AstraZeneca and GlaxoSmithKline, board membership, consultancy, payment for lectures, grants for research and travel expenses reimbursement from Boehringer Ingelheim, board membership, consultancy and travel expenses reimbursement from Alk-Abello, board membership, payment for lectures, travel expenses reimbursement from Novartis and Zambon, grants from University of Ferrara, Italy, outside the submitted work. Conflict of interest: A. Corlateanu has nothing to disclose. Conflict of interest: O. Corlateanu has nothing to disclose. Conflict of interest: G.J. Criner reports grants and personal fees from GlaxoSmithKline, Boehringer Ingelheim, Chiesi, Mereo, AstraZeneca, Pulmonx, Pneumrx, Olympus, Broncus, Lungpacer, Nuvaira, ResMed, Respironics and Patara, personal fees from Verona, BTG, EOLO and NGM, grants from Alung, Fisher Paykel and Galapagos, outside the submitted work. Conflict of interest: B. Csoma has nothing to disclose. Conflict of interest: A. Emelyanov has nothing to disclose. Conflict of interest: R. Faner reports grants and other (advisory board) from GSK, grants from Menarini and AstraZeneca, other (lecture fee) from Chiesi, outside the submitted work. Conflict of interest: G. Fernandez Romero has nothing to disclose. Conflict of interest: Z. Hammouda has nothing to disclose. Conflict of interest: P. Horváth has nothing to disclose. Conflict of interest: A. Huerta Garcia has nothing to disclose. Conflict of interest: M. Jacobs has nothing to disclose. Conflict of interest: C. Jenkins reports personal fees for advisory board work and educational content from AstraZeneca and Boehringer Ingelheim, grants and personal fees for advisory board work and educational content from GlaxoSmithKline, personal fees for consultancy, advisory board work and educational content from Novartis, outside the submitted work. Conflict of interest: G. Joos reports grants, personal fees for lectures and advisory board work, and non-financial support from AstraZeneca and GlaxoSmithKline, grants from Chiesi, personal fees for lectures from Novartis and Lapharcon, outside the submitted work; all fees were paid to his department. Conflict of interest: O. Kharevich has nothing to disclose. Conflict of interest: K. Kostikas was an employee and shareholder of Novartis Pharma AG until 2018; he has received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, ELPEN, GSK, Menarini, Novartis, Sanofi Genzyme and WebMD; his department has received funding and grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Innovis, ELPEN, GSK, Menarini, Novartis and NuvoAir; and he is a member of the GOLD Assembly. Conflict of interest: E. Lapteva has nothing to disclose. Conflict of interest: Z. Lazar has nothing to disclose. Conflict of interest: J.D. Leuppi is supported by grants from the Swiss National Science Foundation (SNF 160072 and 185592) as well as by Swiss Personalised Health Network (SPHN 2018DR108); and has also received unrestricted grants from AstraZeneca AG Switzerland, Boehringer Ingelheim GmbH Switzerland, GSK AG Switzerland, and Novartis AG Switzerland. Conflict of interest: C. Liddle has nothing to disclose. Conflict of interest: J. Linnell has nothing to disclose. Conflict of interest: A. López-Giraldo has nothing to disclose. Conflict of interest: V.M. McDonald reports grants and personal fees from GSK and AZ, personal fees from Novartis, outside the submitted work. Conflict of interest: R. Nielsen reports grants from GlaxoSmithKline Norway and Boehringer Ingelheim, grants and personal fees from AstraZeneca, outside the submitted work. Conflict of interest: A. Papi report grants, personal fees, non-financial support, and other interests at AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma and Teva; personal fees and non-financial support from Menarini, Novartis and Zambon; and grants from Sanofi. Conflict of interest: I. Saraiva has nothing to disclose. Conflict of interest: G. Sergeeva has nothing to disclose. Conflict of interest: A. Sioutkou has nothing to disclose. Conflict of interest: P. Sivapalan reports personal fees for lectures from Boehringer Ingelheim, AstraZeneca and GSK, outside the submitted work. Conflict of interest: E. Stovold has nothing to disclose. Conflict of interest: H. Wang has nothing to disclose. Conflict of interest: F. Wen has nothing to disclose. Conflict of interest: J. Yorke has nothing to disclose. Conflict of interest: P.R. Williamson reports personal fees from European Respiratory Society, during the conduct of the study. Conflict of interest: J. Vestbo reports personal fees for consultancy and lectures from AstraZeneca, Chiesi and Novartis, grants and personal fees for consultancy and lectures from Boehringer Ingelheim, personal fees for consultancy from GSK, outside the submitted work; and the author's son works for Chiesi. Conflict of interest: J-U. Jensen has nothing to disclose., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Randomised controlled trials (RCTs) on the management of COPD exacerbations evaluate heterogeneous outcomes, often omitting those that are clinically important and patient relevant. This limits their usability and comparability. A core outcome set (COS) is a consensus-based minimum set of clinically important outcomes that should be evaluated in all RCTs in specific areas of health care. We present the study protocol of the COS-AECOPD ERS Task Force, aiming to develop a COS for COPD exacerbation management, that could remedy these limitations. For the development of this COS we follow standard methodology recommended by the COMET initiative. A comprehensive list of outcomes is assembled through a methodological systematic review of the outcomes reported in relevant RCTs. Qualitative research with patients with COPD will also be conducted, aiming to identify additional outcomes that may be important to patients, but are not currently addressed in clinical research studies. Prioritisation of the core outcomes will be facilitated through an extensive, multi-stakeholder Delphi survey with a global reach. Selection will be finalised in an international, multi-stakeholder meeting. For every core outcome, we will recommend a specific measurement instrument and standardised time points for evaluation. Selection of instruments will be based on evidence-informed consensus. Our work will improve the quality, usability and comparability of future RCTs on the management of COPD exacerbations and, ultimately, the care of patients with COPD. Multi-stakeholder engagement and societal support by the European Respiratory Society will raise awareness and promote implementation of the COS., Competing Interests: Conflict of interest: A.G. Mathioudakis reports grants from Boehringer Ingelheim outside the submitted work. Conflict of interest: F. Abroug has nothing to disclose. Conflict of interest: A. Agusti reports personal fees from AstraZeneca, grants and personal fees from Menarini, personal fees from Chiesi, grants and personal fees from GSK, and personal fees from Nuvaira, outside the submitted work. Conflict of interest: P. Bakke reports personal fees from GlaxoSmithKline, Chiesi, AstraZeneca and Boehringer Ingelheim outside the submitted work. Conflict of interest: K. Bartziokas has nothing to disclose. Conflict of interest: B. Beghe has nothing to disclose. Conflict of interest: A. Bikov has nothing to disclose. Conflict of interest: T. Bradbury reports being the recipient of an ongoing 3-year top-up scholarship funded by GlaxoSmithKline. Conflict of interest: G. Brusselle reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Sanofi and Teva, outside the submitted work. Conflict of interest: C. Cadus reports support from AstraZeneca and Mundipharma, outside the submitted work. Conflict of interest: C. Coleman is an employee of the European Lung Foundation. Conflict of interest: M. Contoli reports grants from Chiesi, personal fees from Chiesi, AstraZeneca, Boehringer Ingelheim, ALK-Abello, Novartis and Zambon, and grants from University of Ferrara, outside the submitted work. Conflict of interest: A. Corlateanu has nothing to disclose. Conflict of interest: O. Corlateanu has nothing to disclose. Conflict of interest: G. Criner has nothing to disclose. Conflict of interest: B. Csoma has nothing to disclose. Conflict of interest: A. Emelyanov has nothing to disclose. Conflict of interest: R. Faner reports grants from GSK and Menarini outside the submitted work. Conflict of interest: G. Fernandez Romero has nothing to disclose. Conflict of interest: Z. Hammouda has nothing to disclose. Conflict of interest: P. Horváth has nothing to disclose. Conflict of interest: A. Huerta Garcia has nothing to disclose. Conflict of interest: M. Jacobs has nothing to disclose. Conflict of interest: C. Jenkins has nothing to disclose. Conflict of interest: G. Joos reports grants and personal fees from AstraZeneca, personal fees from Bayer, grants from Chiesi, personal fees from Eureca vzw, grants and personal fees from GlaxoSmithKline and personal fees from Teva, outside the submitted work; these grants and fees were paid to his institution. Conflict of interest: O. Kharevich has nothing to disclose. Conflict of interest: K. Kostikas reports grants, personal fees and nonfinancial support from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Menarini and Novartis, grants from NuvoAir, and personal fees from Sanofi, outside the submitted work; and was an employee and shareholder of Novartis Pharma AG until 31 October 2018. Conflict of interest: E. Lapteva has nothing to disclose. Conflict of interest: Z. Lazar has nothing to disclose. Conflict of interest: J.D. Leuppi has nothing to disclose. Conflict of interest: C. Liddle has nothing to disclose. Conflict of interest: A. López-Giraldo has nothing to disclose. Conflict of interest: V.M. McDonald reports grants and personal fees from GSK and AstraZeneca, and personal fees from Menarini, outside the submitted work. Conflict of interest: R. Nielsen reports grants and personal fees from AstraZeneca and Boehringer Ingelheim, grants from Novartis, and grants and personal fees from GlaxoSmithKline, outside the submitted work. Conflict of interest: A. Papi reports grants, personal fees, nonfinancial support and other from GlaxoSmithKline; grants, personal fees and nonfinancial support from AstraZeneca; grants, personal fees, nonfinancial support and other from Boehringer Ingelheim; grants, personal fees, nonfinancial support and other from Chiesi Farmaceutici; grants, personal fees, nonfinancial support and other from TEVA; personal fees, non-financial support and other from Mundipharma; personal fees, non-financial support and other from Zambon; personal fees, non-financial support and other from Novartis; grants, personal fees and non-financial support from Menarini; personal fees, non-financial support and other from Sanofi/Regeneron; personal fees from Roche; grants from Fondazione Maugeri; grants from Fondazione Chiesi; and personal fees from Edmondpharma, all outside the submitted work. Conflict of interest: I. Saraiva has nothing to disclose. Conflict of interest: G. Sergeeva has nothing to disclose. Conflict of interest: A. Sioutkou has nothing to disclose. Conflict of interest: P. Sivapalan reports personal fees from Boehringer Ingelheim outside the submitted work. Conflict of interest: E. Stovold has nothing to disclose. Conflict of interest: H. Wang has nothing to disclose. Conflict of interest: F. Wen has nothing to disclose. Conflict of interest: J. Yorke has nothing to disclose. Conflict of interest: P.R. Williamson has nothing to disclose. Conflict of interest: J. Vestbo reports personal fees from AstraZeneca, grants and personal fees from Boehringer-Ingelheim, personal fees from Chiesi, personal fees from GSK, and personal fees from Novartis, outside the submitted work; and his son is an employee of Chiesi. Conflict of interest: J-U. Jensen has nothing to disclose., (Copyright ©ERS 2020.)

Challenges in the differentiation of the aetiology of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have led to significant overuse of antibiotics. Serum procalcitonin, released in response to bacterial infections, but not viral infections, could possibly identify AECOPD requiring antibiotics. In this meta-analysis we assessed the clinical effectiveness of procalcitonin-based protocols to initiate or discontinue antibiotics in patients presenting with AECOPD.Based on a prospectively registered protocol, we reviewed the literature and selected randomised or quasi-randomised trials comparing procalcitonin-based protocols to initiate or discontinue antibiotics versus standard care in AECOPD. We followed Cochrane and GRADE (Grading of Recommendations, Assessment, Development and Evaluation) guidance to assess risk of bias, quality of evidence and to perform meta-analyses.We included eight trials evaluating 1062 patients with AECOPD. Procalcitonin-based protocols decreased antibiotic prescription (relative risk (RR) 0.56, 95% CI 0.43-0.73) and total antibiotic exposure (mean difference (MD) -3.83, 95% CI (-4.32--3.35)), without affecting clinical outcomes such as rate of treatment failure (RR 0.81, 0.62-1.06), length of hospitalisation (MD -0.76, -1.95-0.43), exacerbation recurrence rate (RR 0.96, 0.69-1.35) or mortality (RR 0.99, 0.58-1.69). However, the quality of the available evidence is low to moderate, because of methodological limitations and small overall study population.Procalcitonin-based protocols appear to be clinically effective; however, confirmatory trials with rigorous methodology are required., (Copyright ©ERS 2017.)