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

Edward J Needham, Alexander L Ren, Richard J Digby, Emma J Norton, Soraya Ebrahimi, Joanne G Outtrim, Doris A Chatfield, Anne E Manktelow, Maya M Leibowitz, Virginia F J Newcombe, Rainer Doffinger, Gabriela Barcenas-Morales, Claudia Fonseca, Michael J Taussig, Rowan M Burnstein, Romit J Samanta, Cordelia Dunai, Nyarie Sithole, Nicholas J Ashton, Henrik ZetterbergMagnus Gisslén, Arden Edén, Emelie Marklund, Peter J M 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 D Michael, Edward T Bullmore, Kenneth G C Smith, Paul A Lyons, Alasdair J Coles, David K Menon

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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 hospitalisation, 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 characterised 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.
Original languageEnglish
Pages (from-to)awac321
JournalBrain research
Publication statusPublished - 1 Sept 2022


  • Autoantibodies
  • Brain injury
  • neuroinflammation
  • Covid-19


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