Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses
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, Cambridge NeuroCOVID Group, Fahim Anwar, Kieren Allinson, Junaid Bhatti, Edward T. Bullmore, Dorothy A Chatfield, David M. Christmas, Alasdair Coles, Jonathan P 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
Abstract
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.