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Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses

2022; Oxford University Press; Volume: 145; Issue: 11 Linguagem: Inglês

10.1093/brain/awac321

1460-2156

Edward Needham, Alexander Ren, Richard Digby, Emma Norton, Soraya Ebrahimi, Joanne Outtrim, Doris A. Chatfield, Anne E. Manktelow, Maya Leibowitz, Virginia Newcombe, Rainer Döffinger, Gabriela Barcenas‐Morales, Cláudia Fonseca, Michael Taussig, Rowan Burnstein, Romit Samanta, Cordelia Dunai, Nyaradzai Sithole, Nicholas J. Ashton, Henrik Zetterberg, Magnus Gisslén, Arvid Edén, Emelie Marklund, Peter Openshaw, Jake Dunning, Michael J. Griffiths, Jonathan Cavanagh, Gerome Breen, Sarosh R. Irani, Anne Elmer, Nathalie Kingston, Charlotte Summers, John R. Bradley, Leonie S. Taams, Benedict Michael, Edward T. Bullmore, Kenneth G. C. Smith, Paul Lyons, Alasdair Coles, David Menon, Fahim Anwar, Kieren Allinson, Junaid Bhatti, Edward T. Bullmore, Dorothy A Chatfield, David M. Christmas, Alasdair Coles, Alasdair Coles, Marta Correia, Tilak Das, Paul C. Fletcher, Alasdair Jubb, Victoria Lupson, Anne E. Manktelow, David Menon, Andrew W. Michell, Edward Needham, Virginia Newcombe, Joanne Outtrim, Linda Pointon, Christopher T. Rodgers, James B. Rowe, Catarina Rua, Nyaradzai Sithole, Lennart R. B. Spindler, Emmanuel A. Stamatakis, Jonathan M. Taylor, Fernanda Valério, Barry Widmer, Guy Williams, Patrick F. Chinnery, John Allison, Gisele Alvio, Ali Ansaripour, Sharon F. Baker, Stephen Baker, Laura Bergamaschi, Areti Bermperi, Ariana Betancourt, Heather Biggs, Sze-How Bong, Georgie Bower, John R. Bradley, Karen Brookes, Ashlea Bucke, Ben Bullman, Katherine Bunclark, Helen Butcher, Sarah Caddy, Jo Calder, Laura Caller, Laura Canna, Daniela Caputo, Matt Chandler, Yasmin Chaudhry, Patrick F. Chinnery, Debbie Clapham-Riley, Daniel Cooper, Chiara Cossetti, Cherry Crucusio, Isabel Cruz, Martin D. Curran, Jérôme D. Coudert, Eckart M. D. D. De Bie, Rnalie De Jesus, Aloka De, Anne-Maree Dean, Katie Dempsey, Eleanor Dewhurst, Giovanni Di Stefano, Jason Domingo, Gordon Dougan, Benjamin J. Dunmore, Anne Elmer, Madeline Epping, Codie Fahey, Stuart Fawke, Theresa Feltwell, Christian Fernandez, Stewart Fuller, Anita Furlong, Iliana Georgana, Anne George, Nick Gleadall, Ian Goodfellow, Stefan Gräf, Barbara Graves, Jennifer L. Gray, Richard Grenfell, Ravindra K. Gupta, Grant Hall, William L. Hamilton, Julie Harris, Sabine Hein, Christoph Hess, Sarah H. Hewitt, Andrew Hinch, Josh Hodgson, Myra Hosmillo, Elaine Holmes, Charlotte J. Houldcroft, Christopher Huang, Oisín Huhn, Kelvin Hunter, Tasmin Ivers, Aminu S. Jahun, Sarah Jackson, Isobel Jarvis, Emma Jones, Heather Jones, Sherly Jose, Maša Josipović, Mary Kasanicki, Jane Kennet, Fahad Khokhar, Y. King, Nathalie Kingston, Jenny Kourampa, Emma Le Gresley, Elisa Laurenti, Ekaterina Legchenko, Paul J. Lehner, Daniel J. Lewis, Emily Li, Rachel Linger, Paul Lyons, Michael Mackay, John C. Marioni, Jimmy Marsden, Jennifer Martin, Cecilia Matara, Nicholas J. Matheson, Caroline McMahon, Anne Meadows, Sarah Meloy, Vivien Mendoza, Luke Meredith, Nicole Mende, Federica Mescia, Alice Michael, Alexei Moulton, Rachel Michel, Lucy Mwaura, Francesca Muldoon, Francesca Nice, Criona O’Brien, Charmain Ocaya, Ciara O’Donnell, Georgina Okecha, Ommar Omarjee, Nigel Ovington, Willem H. Owehand, Sofia Papadia, Roxana Paraschiv, Surendra Parmar, Ciro Pascuale, Caroline Patterson, Christopher J. Penkett, Marlyn Perales, Marianne Perera, Isabel Phelan, Malte L. Pinckert, Linda Pointon, Petra Polgarova, Gary Polwarth, Nicole Pond, Jane Price, Venkatesh-Prasad Ranganath, Cherry Publico, Rebecca Rastall, Carla Ribeiro, Nathan Richoz, Veronika Romashova, Sabrina Rossi, Jane Rowlands, Valentina Ruffolo, Jennifer Sambrook, Caroline Saunders, Natalia Savinykh Yarkoni, Katherine Schon, Mayurun Selvan, Rahul Sharma, Joy Shih, Kenneth G. C. Smith, Sarah Spencer, Luca Stefanucci, Hannah Stark, Jonathan Stephens, Kathleen Stirrups, Mateusz Strezlecki, Charlotte Summers, Rachel Sutcliffe, James Thaventhiran, Tobias Tilly, Zhen Tong, Hugo Tordesillas, Carmen Treacy, Mark Toshner, Paul Townsend, Carmen Treacy, Lori Turner, Phoebe Vargas, Bensi Vergese, Julie von Ziegenweidt, Neil Walker, Laura Watson, Jennifer Webster, Michael P. Weekes, Nicola K. Wilson, Jennifer Wood, Jieniean Worsley, Marta Wylot, Anna Yakovleva, Cissy Yong and Julie-Anne Zerrudo, Caroline Saunders, Anne Elmer,

Vagus Nerve Stimulation Research

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.