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
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Needham, E., Ren, A., Digby, R., Norton, E., Ebrahimi, S., Outtrim, J., Chatfield, D., Manktelow, A., Leibowitz, M., Newcombe, V., Doffinger, R., Barcenas-Morales, G., Fonseca, C., Taussig, M., Burnstein, R., Samanta, R., Dunai, C., Sithole, N., Ashton, N., Zetterberg, H., Gisslén, M., Edén, A., Marklund, E., Openshaw, P., Dunning, J., Griffiths, M., Cavanagh, J., Breen, G., Irani, S., Elmer, A., Kingston, N., Summers, C., Bradley, J., Taams, L., Michael, B., Bullmore, E., Smith, K., Lyons, P., Coles, A. & Menon, D. 2022, 'Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses', Brain, article no: awac321. https://doi.org/10.1093/brain/awac321