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Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID‐19. Complement activation products are detected in plasma and tissues and complement blockade is considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in COVID‐19 to date, comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalized COVID‐19 patients collected across the hospitalization period as part of the UK ISARIC4C (International Acute Respiratory and Emerging Infection Consortium) study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to healthy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID‐19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples were associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID‐19 disease severity and death. The data demonstrate that early‐onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID‐19, further exacerbated in severe disease. These findings provide novel insights into COVID‐19 immunopathogenesis and inform strategies for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Patients with asthma are at risk of hospitalisation with influenza, but the reasons for this predisposition are unknown., Study Setting: A prospective observational study of adults with PCR-confirmed influenza in 11 UK hospitals, measuring nasal, nasopharyngeal and systemic immune mediators and whole-blood gene expression., Results: Of 133 admissions, 40 (30%) had previous asthma; these were more often female (70% versus 38.7%, OR 3.69, 95% CI 1.67-8.18; p=0.0012), required less mechanical ventilation (15% versus 37.6%, Chi-squared 6.78; p=0.0338) and had shorter hospital stays (mean 8.3 versus 15.3 days, p=0.0333) than those without. In patients without asthma, severe outcomes were more frequent in those given corticosteroids (OR 2.63, 95% CI 1.02-6.96; p=0.0466) or presenting >4 days after disease onset (OR 5.49, 95% CI 2.28-14.03; p=0.0002). Influenza vaccination in at-risk groups (including asthma) were lower than intended by national policy and the early use of antiviral medications were less than optimal. Mucosal immune responses were equivalent between groups. Those with asthma had higher serum interferon (IFN)-α, but lower serum tumour necrosis factor, interleukin (IL)-5, IL-6, CXCL8, CXCL9, IL-10, IL-17 and CCL2 levels (all p<0.05); both groups had similar serum IL-13, total IgE, periostin and blood eosinophil gene expression levels. Asthma diagnosis was unrelated to viral load, IFN-α, IFN-γ, IL-5 or IL-13 levels., Conclusions: Asthma is common in those hospitalised with influenza, but may not represent classical type 2-driven disease. Those admitted with influenza tend to be female with mild serum inflammatory responses, increased serum IFN-α levels and good clinical outcomes., Competing Interests: Conflict of interest: A. Jha holds a clinical lectureship at the University of Cambridge that is supported jointly by the University of Cambridge Experimental Medicine Training Initiative (EMI) programme in partnership with GlaxoSmithKline (EMI-GSK) and Cambridge University Hospitals NHS Foundation Trust. The funding received by A. Jha from the EMI-GSK programme is not relevant to the content of this manuscript. Conflict of interest: J. Dunning has nothing to disclose. Conflict of interest: T. Tunstall has nothing to disclose. Conflict of interest: R.S. Thwaites has nothing to disclose. Conflict of interest: L.T. Hoang has nothing to disclose. Conflict of interest: O.M. Kon has nothing to disclose. Conflict of interest: M.C. Zambon has nothing to disclose Conflict of interest: T.T. Hansel and Imperial Innovations are involved in setting up a medical device company called Mucosal Diagnostics (MD), which is an Imperial College spin-off company. Conflict of interest: P.J. Openshaw reports personal fees for consultancy from Janssen, grants from MRC, EU, NIHR Biomedical Research Centre, MRC/GSK, Wellcome Trust, NIHR and MRC Global Challenge Research Fund, personal fees for online presentations from European Respiratory Society, non-financial support from AbbVie, outside the submitted work; and is past president and trustee of British Society for Immunology, vice-chair and member of NERVTAG (New and Emerging Respiratory Virus Threats Advisory Group; Department of Health)., (Copyright ©ERS 2019.)