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Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19.
Siggins, Matthew K; Davies, Kate; Fellows, Rosie; Thwaites, Ryan S; Baillie, J Kenneth; Semple, Malcolm G; Openshaw, Peter J M; Zelek, Wioleta M; Harris, Claire L; Morgan, B Paul.
  • Siggins MK; National Heart & Lung Institute, Imperial College London, London, UK.
  • Davies K; Division of Infection and Immunity and UK Dementia Research Institute Cardiff, Cardiff University, Cardiff, UK.
  • Fellows R; Translational & Clinical Research Institute, Newcastle University, Newcastle, UK.
  • Thwaites RS; National Heart & Lung Institute, Imperial College London, London, UK.
  • Baillie JK; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Semple MG; NIHR Health Protection Research Unit, Institute of Infection, Veterinary, and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
  • Openshaw PJM; National Heart & Lung Institute, Imperial College London, London, UK.
  • Zelek WM; Division of Infection and Immunity and UK Dementia Research Institute Cardiff, Cardiff University, Cardiff, UK.
  • Harris CL; Translational & Clinical Research Institute, Newcastle University, Newcastle, UK.
  • Morgan BP; Division of Infection and Immunity and UK Dementia Research Institute Cardiff, Cardiff University, Cardiff, UK.
Immunology ; 2022 Sep 29.
Article in English | MEDLINE | ID: covidwho-2281411
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Language: English Year: 2022 Document Type: Article Affiliation country: Imm.13585

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Language: English Year: 2022 Document Type: Article Affiliation country: Imm.13585