Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

Authors: Benedict Michael, Cordelia Dunai, Edward Needham, Kukatharmini Tharmaratnam, Robyn Williams, Yun Huang, Sarah Boardman, Jordan J. Clark, Parul Sharma, Krishanthi Subramaniam, Greta K. Wood, Ceryce Collie, Richard Digby, Alexander Ren, Emma Norton, Maya Leibowitz, Soraya Ebrahimi, Andrew Fower, Hannah Fox, Esteban Tato, Mark Ellul, Geraint Sunderland, Marie Held, Claire Hetherington, Franklyn Egbe, Alish Palmos, Kathy Stirrups, Alexander Grundmann, Anne-Cécile Chiollaz, Jean‐Charles Sanchez, James P. Stewart, Michael J. Griffiths, Tom Solomon, Gerome Breen, Alasdair Coles, Nathalie Kingston, John R. Bradley, Patrick F. Chinnery, Jonathan Cavanagh, Sarosh R. Irani, Angela Vincent, J. Kenneth Baillie, Peter Openshaw, Malcolm G. Semple, ISARIC4C Investigators, J. Kenneth Baillie, Peter Openshaw, Malcolm G. Semple, Beatrice Alex, Petros Andrikopoulos, Benjamin Bach, William Barclay, Debby Bogaert, Meera Chand, Kanta Chechi, G Cooke, Ana da Silva, Thushan I. de Silva, Annemarie B Docherty, Gonçalo dos Santos, Marc‐Emmanuel Dumas, Jake Dunning, Tom Fletcher, Chris Green, William Greenhalf, Julian L. Griffin, Rishi K Gupta, Ewen M. Harrison, Antonia Y. Wai, Karl Holden, Peter Horby, Samreen Ijaz, Saye Khoo, Paul Klenerman, Andrew Law, Matthew R. Lewis, Sonia Liggi, Wei Shen Lim, Lynn Maslen, Alexander J. Mentzer, Laura Merson, Alison Meynert, Shona C. Moore, Mahdad Noursadeghi, Michael Olanipekun, Anthonia Osagie, Massimo Palmarini, Carlo Palmieri, William A. Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L. Robertson, Clark D Russell, Vanessa Sancho‐Shimizu, Caroline Sands, J. T. Scott, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David I. Stuart, Charlotte Summers, Olivia Swann, Zoltán Takáts, Panteleimon G. Takis, Richard S. Tedder, A. A. Roger Thompson, Emma C. Thomson, Ryan S. Thwaites, Lance Turtle, Maria Zambon, Thomas M Drake, Cameron J Fairfield, Stephen R Knight, Kenneth A McLean, Derek Murphy, Lisa Norman, Riinu Pius, Catherine A. Shaw, Marie Connor, Jo Ann Dalton, Carrol Gamble, Michelle Girvan, Sophie Halpin, Janet Harrison, Clare Jackson, James Lee, Laura Marsh, Daniel Plotkin, Stephanie Roberts, Egle Saviciute, Sara Clohisey, Ross Hendry, Susan Knight, Eva Lahnsteiner, Gary Leeming, Lucy Norris, James Scott-Brown, Sarah Tait, Murray Wham, Richard E. Clark, Audrey Coutts, Lorna Donnelly, Angie Fawkes, Tammy Gilchrist, Katarzyna Hafezi, Louise MacGillivray, Alan Maclean, Sarah McCafferty, Kirstie Morrice, Lee Murphy, Nicola Wrobel, Gail Carson, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. Aldera, Ana Alegria, Sam Allen, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, Sneha Basude, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John C. Berridge, Colin Berry, Nicola Best, Pieter Bothma, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, David Chadwick, Duncan Chambler, Nigel Chee, Jenny Child, Srikanth Chukkambotla, Tom Clark, Paul Collini, Catherine Cosgrove, Jason Cupitt, Maria-Teresa Cutino-Moguel, Paul Dark, Chris Dawson, Samir Dervisevic, Phil Donnison, Sam Douthwaite, Andrew Drummond, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Cariad Evans, Chi Eziefula, Chrisopher Fegan, Adam Finn, Duncan Fullerton, Sanjeev Garg, Atul Garg, Effrossyni Gkrania‐Klotsas, Jo Godden, Arthur Goldsmith, Clive Graham, Tassos Grammatikopoulos, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B. Hawcutt, Maria Hobrok, Luke Hodgson, Anil Hormis, Joanne Howard, Michael Jacobs, Susan Jain, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Jason Kendall, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, George Koshy, Shondipon Laha, Steven Laird, Susan Larkin, Tamás Leiner, Patrick Lillie, James Limb, Vanessa Linnett, Jeff Little, Mark D Lyttle, Michael MacMahon, Emily MacNaughton, Ravish Mankregod, Huw Masson, Elijah Matovu, Katherine McCullough, Ruth McEwen, Manjula Meda, Gary Mills, Jane Minton, Kavya Mohandas, Quen Mok, James Moon, Elinoor Moore, Patrick Morgan, Craig F. Morris, Katherine Mortimore, Samuel Moses, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Thapas Nagarajan, Megan Nagel, Mark Nelson, Lillian Norris, Matthew K. O’Shea, Marlies Ostermann, Igor Otahal, Mark Pais, Selva Panchatsharam, Danai Papakonstantinou, Padmasayee Papineni, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Tim Planche, Frank A. Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Bobby Ruge, Brendan Ryan, Taranprit Saluja, Matthias L. Schmid, Aarti Shah, Manu Shankar‐Hari, Prad Shanmuga, Anil Kumar Sharma, Anna Shawcross, Jagtur Singh Pooni, Jeremy Sizer, Richard Smith, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Richard Stewart, Pradeep Subudhi, Tamás Szakmány, Kate Tatham, J. Regan Thomas, Chris Thompson, Robert Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Nick Vallotton, Rama Vancheeswaran, Rachel Vincent, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Stephen Winchester, Martin Wiselka, Adam Wolverson, Dan Wootton, Andrew Workman, Bryan Yates, P. A. Young, Sarah E. McDonald, Victoria Shaw, Katie A. Ahmed, J. A. Armstrong, Milton Ashworth, Innocent G. Asiimwe, Siddharth Bakshi, Samantha L Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Nicola Carlucci, Emily Cass, Benjamin WA Catterall, Jordan J. Clark, Emily A Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Alejandra Doce Carracedo, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis WS Fisher, Lisa Flaherty, Terry Foster, Isabel García-Dorival, Philip Gunning, Catherine Hartley, Anthony Holmes, Rebecca L. Jensen, Christopher B. Jones, Trevor R. Jones, Shadia Khandaker, Katharine King, Robyn T. Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A Livoti, Maria Vittoria Mancini, Hannah Massey, Nicole Maziere, Sarah E. McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S Miah, Joanna Middleton, Joyce Mitchell, E. Gordon Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Will Reynolds, Paul Ridley, Debby Sales, Victoria Shaw, Rebecca K. Shears, Benjamin Small, Krishanthi Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock, J. E. Zhang, Seán Keating, Cara Donegan, Rebecca G. Spencer, Chloe Donohue, Fiona Griffiths, Hayley Hardwick, Wilna Oosthuyzen, Adam Hampshire, Adam Sieradzki, Adam Seed, Afagh Garjani, Akshay Gopinathan Nair, Alaisdair Coles, Alan Carson, Alastair Darby, Alex Berry, Alex Dregan, Alexander Grundmann, Alish Palmos, Ammar Al‐Chalabi, Andrew M. McIntosh, Angela E. Holland, Angela Roberts, Angela Vincent, Annalena Venneri, Anthony S. David, Arina Tamborska, Arvind H. Patel, Ava Easton, Benedict Michael, Bethan Blackledge, Bethany Facer, Bhagteshwar Singh, Brendan Sargent, Ceryce Collie, E. Charles Leek, Chérie Armour, Christopher M. Morris, Christopher Allen, Ciaran Mulholland, Claire MacIver, Cordelia Dunai, Craig J. Smith, Daniel J. van, Daniel Madarshahian, David Christmas, David Cousins, David Menon, David M. 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Harrison, Peter Jezzard, Peter M. Fernandes, Rachel Upthegrove, Rahul Batra, Rebecca Gregory, Rhys H. Thomas, Richard A. I. Bethlehem, Richard Francis, Ronan O’Malley, Rustam Al‐Shahi Salman, Ryan McIlwaine, Sandar Kyaw, Sarosh R. Irani, Savini Gunatilake, Scott Semple, Shahd Hamid, Sharon J. Peacock, Silvia Rota, Simon S. Keller, Sophie Pendered, Suzanne Barrett, Stella Hughes, Stella‐Maria Paddick, Stephen Sawcer, Stephen M. Smith, Steven Williams, Sui H. Wong, Sylviane Defres, Thomas Jackson, Thomas M. Jenkins, Thomas Pollak, Timothy R. Nicholson, Tonny Veenith, Victoria Grimbly, Virginia Newcombe, Leonie S. Taams, David Menon - Nature Communications 2023 cited by 41

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.