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

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.