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

DOI: http://doi.org/10.1093/brain/awac321 Journal: Brain E-pub date: 21 Nov 2022 Authors: EJ Needham, AL Ren, RJ Digby, EJ Norton, S Ebrahimi, JG Outtrim, DA Chatfield, AE Manktelow, MM Leibowitz, VFJ Newcombe, R Doffinger, G Barcenas-Morales, C Fonseca, MJ Taussig, RM Burnstein, RJ Samanta, C Dunai, N Sithole, NJ Ashton, H Zetterberg, M Gisslén, A Edén, E Marklund, PJM Openshaw, J Dunning, MJ Griffiths, J Cavanagh, G Breen, SR Irani, A Elmer, N Kingston, C Summers, JR Bradley, LS Taams, BD Michael, ET Bullmore, KGC Smith, PA Lyons, AJ Coles, DK Menon, Cambridge NeuroCOVID Group, CITIID-NIHR COVID-19 BioResource Collaboration, Cambridge NIHR Clinical Research Facility

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

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.