Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses
Authors: Needham Edward J , Ren Alexander L , Digby Richard J , Norton Emma J , Ebrahimi Soraya , Outtrim Joanne G , Chatfield Doris A , Manktelow Anne E , Leibowitz Maya M , Newcombe Virginia F J , Doffinger Rainer , Barcenas-Morales Gabriela , Fonseca Claudia , Taussig Michael J , Burnstein Rowan M , Samanta Romit J , Dunai Cordelia , Sithole Nyarie , Ashton Nicholas J , Zetterberg Henrik , Gisslén Magnus , Edén Arvid , Marklund Emelie , Openshaw Peter J M , Dunning Jake , Griffiths Michael J , Cavanagh Jonathan , Breen Gerome , Irani Sarosh R , Elmer Anne , Kingston Nathalie , Summers Charlotte , Bradley John R , Taams Leonie S , Michael Benedict D , Bullmore Edward T , Smith Kenneth G C , Lyons Paul A , Coles Alasdair J , Menon David K ,   Cambridge NeuroCOVID Group, Anwar Fahim , Allinson Kieren , Bhatti Junaid , Bullmore Edward T , Chatfield Dorothy A , Christmas David , Coles Alasdair J , Coles Jonathan P , Correia Marta , Das Tilak , Fletcher Paul C , Jubb Alasdair W , Lupson Victoria C , Manktelow Anne E , Menon David K , Michell Andrew , Needham Edward J , Newcombe Virginia F J , Outtrim Joanne G , Pointon Linda , Rodgers Christopher T , Rowe James B , Rua Catarina , Sithole Nyarie , Spindler Lennart R B , Stamatakis Emmanuel A , Taylor Jonathan , Valerio Fernanda , Widmer Barry , Williams Guy B , Chinnery Patrick F ,   CITIID-NIHR COVID-19 BioResource Collaboration, Allison John , Alvio Gisele , Ansaripour Ali , Baker Sharon , Baker Stephen , Bergamaschi Laura , Bermperi Areti , Betancourt Ariana , Biggs Heather , Bong Sze-How , Bower Georgie , Bradley John R , Brookes Karen , Bucke Ashlea , Bullman Ben , Bunclark Katherine , Butcher Helen , Caddy Sarah , Calder Jo , Caller Laura , Canna Laura , Caputo Daniela , Chandler Matt , Chaudhry Yasmin , Chinnery Patrick , Clapham-Riley Debbie , Cooper Daniel , Cossetti Chiara , Crucusio Cherry , Cruz Isabel , Curran Martin , Coudert Jerome D , Bie Eckart M D D De , Jesus Rnalie De , Sa Aloka De , Dean Anne-Maree , Dempsey Katie , Dewhurst Eleanor , Stefano Giovanni di , Domingo Jason , Dougan Gordon , Dunmore Benjamin J , Elmer Anne , Epping Madeline , Fahey Codie , Fawke Stuart , Feltwell Theresa , Fernandez Christian , Fuller Stewart , Furlong Anita , Georgana Iliana , George Anne , Gleadall Nick , Goodfellow Ian G , Gräf Stefan , Graves Barbara , Gray Jennifer , Grenfell Richard , Gupta Ravindra K , Hall Grant , Hamilton William , Harris Julie , Hein Sabine , Hess Christoph , Hewitt Sarah , Hinch Andrew , Hodgson Josh , Hosmillo Myra , Holmes Elaine , Houldcroft Charlotte , Huang Christopher , Huhn Oisín , Hunter Kelvin , Ivers Tasmin , Jahun Aminu , Jackson Sarah , Jarvis Isobel , Jones Emma , Jones Heather , Jose Sherly , Josipović Maša , Kasanicki Mary , Kennet Jane , Khokhar Fahad , King Yvonne , Kingston Nathalie , Kourampa Jenny , Gresley Emma Le , Laurenti Elisa , Legchenko Ekaterina , Lehner Paul J , Lewis Daniel , Li Emily , Linger Rachel , Lyons Paul A , Mackay Michael , Marioni John C , Marsden Jimmy , Martin Jennifer , Matara Cecilia , Matheson Nicholas J , McMahon Caroline , Meadows Anne , Meloy Sarah , Mendoza Vivien , Meredith Luke , Mende Nicole , Mescia Federica , Michael Alice , Moulton Alexei , Michel Rachel , Mwaura Lucy , Muldoon Francesca , Nice Francesca , O’Brien Criona , Ocaya Charmain , O’Donnell Ciara , Okecha Georgina , Omarjee Ommar , Ovington Nigel , Owehand Willem H , Papadia Sofia , Paraschiv Roxana , Parmar Surendra , Pascuale Ciro , Patterson Caroline , Penkett Christopher , Perales Marlyn , Perera Marianne , Phelan Isabel , Pinckert Malte , Pointon Linda , Polgarova Petra , Polwarth Gary , Pond Nicole , Price Jane , Ranganath Venkatesh , Publico Cherry , Rastall Rebecca , Ribeiro Carla , Richoz Nathan , Romashova Veronika , Rossi Sabrina , Rowlands Jane , Ruffolo Valentina , Sambrook Jennifer , Saunders Caroline , Yarkoni Natalia Savinykh , Schon Katherine , Selvan Mayurun , Sharma Rahul , Shih Joy , Smith Kenneth G C , Spencer Sarah , Stefanucci Luca , Stark Hannah , Stephens Jonathan , Stirrups Kathleen E , Strezlecki Mateusz , Summers Charlotte , Sutcliffe Rachel , Thaventhiran James E D , Tilly Tobias , Tong Zhen , Tordesillas Hugo , Treacy Carmen , Toshner Mark , Townsend Paul , Treacy Carmen , Turner Lori , Vargas Phoebe , Vergese Bensi , Ziegenweidt Julie von , Walker Neil , Watson Laura , Webster Jennifer , Weekes Michael P , Wilson Nicola K , Wood Jennifer , Worsley Jieniean , Wylot Marta , Yakovleva Anna , Zerrudo Cissy Yong and Julie-Anne ,   Cambridge NIHR Clinical Research Facility, Saunders Caroline , Elmer Anne 
Published: September 2022

AbstractCOVID-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.