AUTHOR=Tierney Anna L. , Alali Wajd Mohammed , Scott Thomas , Rees-Unwin Karen S. ,  CITIID-NIHR BioResource COVID-19 Collaboration , Clark Simon J. , Unwin Richard D. , Baker Stephen , Bradley John , Chinnery Patrick , Cooper Daniel , Dougan Gordon , Goodfellow Ian , Gupta Ravindra , Kingston Nathalie , Lehner Paul J. , Lyons Paul A. , Matheson Nicholas J. , Saunders Caroline , Smith Kenneth G. C. , Summers Charlotte , Thaventhiran James , Torok M. Estee , Toshner Mark R. , Weekes Michael P. , Alvio Gisele , Baker Sharon , Bermperi Areti , Brookes Karen , Bucke Ashlea , Calder Jo , Canna Laura , Crucusio Cherry , Cruz Isabel , Jesus Ranalie de , Dempsey Katie , Di Stephano Giovanni , Domingo Jason , Elmer Anne , Harris Julie , Hewitt Sarah , Jones Heather , Jose Sherly , Kennet Jane , King Yvonne , Kourampa Jenny , Li Emily , McMahon Caroline , Meadows Anne , Mendoza Vivien , O’Brien Criona , Ocaya Charmain , Pasquale Ciro , Perales Marlyn , Price Jane , Rastall Rebecca , Ribeiro Carla , Rowlands Jane , Ruffolo Valentina , Tordesillas Hugo , Vargas Phoebe , Vergese Bensi , Watson Laura , Worsley Jieniean , Zerrudo Julie-Ann , Bergamashi Laura , Betancourt Ariana , Bower Georgie , Bullman Ben , Cossetti Chiara , De Sa Aloka , Dunmore Benjamin J. , Epping Maddie , Fawke Stuart , Gräf Stefan , Grenfell Richard , Hinch Andrew , Hodgson Josh , Huang Christopher , Huhn Oisin , Hunter Kelvin , Jarvis Isobel , Jones Emma , Josipović Maša , Legchenko Ekaterina , Lewis Daniel , Marsden Joe , Martin Jennifer , Mescia Federica , O’Donnell Ciara , Omarjee Ommar , Perera Marianne , Pointon Linda , Pond Nicole , Richoz Nathan , Romashova Nika , Savoinykh Natalia , Sharma Rahul , Shih Joy , Strezlecki Mateusz , Sutcliffe Rachel , Tilly Tobias , Tong Zhen , Treacy Carmen , Turner Lori , Wood Jennifer , Wylot Marta , Allison John , Biggs Heather , Bradley John R. , Butcher Helen , Caputo Daniela , Chandler Matt , Chinnery Patrick , Clapham-Riley Debbie , Dewhurst Eleanor , Fernandez Christian , Furlong Anita , Graves Barbara , Gray Jennifer , Hein Sabine , Ivers Tasmin , Gresley Emma Le , Linger Rachel , Kasanicki Mary , King Rebecca , Kingston Nathalie , Meloy Sarah , Moulton Alexei , Muldoon Francesca , Ovington Nigel , Papadia Sofia , Penkett Christopher J. , Phelan Isabel , Ranganath Venkatesh , Paraschiv Roxana , Sage Abigail , Sambrook Jennifer , Scholtes Ingrid , Schon Katherine , Stark Hannah , Stirrups Kathleen E. , Townsend Paul , Walker Neil , Webster Jennifer , Selvan Mayurun , Polgarova Petra , Caddy Sarah L. , Caller Laura G. , Chaudhry Yasmin , Curran Martin D. , Feltwell Theresa , Fuller Stewart , Georgana Iliana , Hall Grant , Hamilton William L. , Hosmillo Myra , Houldcroft Charlotte J. , Izuagbe Rhys , Jahun Aminu S. , Khokhar Fahad A. , Kovalenko Anna G. , Meredith Luke W. , Parmar Surendra , Pinckert Malte L. , Yakovleva Anna , Horner Emily C. , Booth Lucy , Ferreira Alexander , Boston Rebecca , Hughes Robert , Puc Juan Carlos Yam , Beristain-Covarrubias Nonantzin , Rust Maria , Gurugama Thevinya , Gurugama Lihinya , Mulroney Thomas , Spencer Sarah , Hosseini Zhaleh , Williamson Kate 

TITLE=Levels of soluble complement regulators predict severity of COVID-19 symptoms

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1032331

DOI=10.3389/fimmu.2022.1032331

ISSN=1664-3224

ABSTRACT=<p>The SARS-CoV-2 virus continues to cause significant morbidity and mortality worldwide from COVID-19. One of the major challenges of patient management is the broad range of symptoms observed. While the majority of individuals experience relatively mild disease, a significant minority of patients require hospitalisation, with COVID-19 still proving fatal for some. As such, there remains a desperate need to better understand what drives this severe disease, both in terms of the underlying biology, but also to potentially predict at diagnosis which patients are likely to require further interventions, thus enabling better outcomes for both patients and healthcare systems. Several lines of evidence have pointed to dysregulation of the complement cascade as a major factor in severe COVID-19 outcomes. How this is underpinned mechanistically is not known. Here, we have focussed on the role of the soluble complement regulators Complement Factor H (FH), its splice variant Factor H-like 1 (FHL-1) and five Factor H-Related proteins (FHR1-5). Using a targeted mass spectrometry approach, we quantified these proteins in a cohort of 188 plasma samples from controls and SARS-CoV-2 patients taken at diagnosis. This analysis revealed significant elevations in all FHR proteins, but not FH, in patients with more severe disease, particularly FHR2 and FHR5 (FHR2: 1.97-fold, p&lt;0.0001; FHR5: 2.4-fold, p&lt;0.0001). Furthermore, for a subset of 77 SARS-CoV-2 +ve patients we also analysed time course samples taken approximately 28 days post-diagnosis. Here, we see complement regulator levels drop in all individuals with asymptomatic or mild disease, but regulators remain high in those with more severe outcomes, with elevations in FHR2 over baseline levels in this group. These data support the hypothesis that elevation of circulating levels of the FHR family of proteins could predict disease severity in COVID-19 patients, and that the duration of elevation (or lack of immune activation resolution) may be partly responsible for driving poor outcomes in COVID-19.</p>