Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses
Authors: Michael Benedict D. , Dunai Cordelia , Needham Edward J. , Tharmaratnam Kukatharmini , Williams Robyn , Huang Yun , Boardman Sarah A. , Clark Jordan , Sharma Parul , Subramaniam Krishanthi , Wood Greta K. , Collie Ceryce , Digby Richard , Ren Alexander , Norton Emma , Leibowitz Maya , Ebrahimi Soraya , Fower Andrew , Fox Hannah , Tato Esteban , Ellul Mark , Sunderland Geraint , Held Marie , Hetherington Claire , Nkongho Franklyn , Palmos Alish , Grundmann Alexander , Stewart James P. , Griffiths Michael , Solomon Tom , Breen Gerome , Coles Alasdair , Cavanagh Jonathan , Irani Sarosh R. , Vincent Angela , Taams Leonie , Menon David K. 
Published: April 2023

We measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants with COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided subacute/convalescent sera (6-76 weeks post-admission). Compared to 60 controls, brain injury biomarkers (Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in patients with altered consciousness. Tau and NfL remained elevated in convalescent sera, particularly following cerebrovascular and neuroinflammatory disorders. Acutely, inflammatory mediators (including IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) were higher in participants with altered consciousness, and correlated with brain injury biomarker levels. Inflammatory mediators were lower than acute levels in convalescent sera, but levels of CCL2, CCL7, IL-1RA, IL-2Rα, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with Tau levels even at this late time point. When compared to acute COVID-19 patients with a normal GCS, network analysis showed significantly altered immune responses in patients with acute alteration of consciousness, and in convalescent patients who had suffered an acute neurological complication. The frequency and range of autoantibodies did not associate with neurological disorders. However, autoantibodies against specific antigens were more frequent in patients with altered consciousness in the acute phase (including MYL7, UCH-L1, GRIN3B, and DDR2), and in patients with neurological complications in the convalescent phase (including MYL7, GNRHR, and HLA antigens). In a novel low-inoculum mouse model of SARS-CoV-2, while viral replication was only consistently seen in mouse lungs, inflammatory responses were seen in both brain and lungs, with significant increases in CCL4, IFNγ, IL-17A, and microglial reactivity in the brain. Neurological injury is common in the acute phase and persists late after COVID-19, and may be driven by a para-infectious process involving a dysregulated host response.

Graphical abstract

(a) The acute cohort (days 1-11 post-hospitilisation) showed elevated pro-inflammatory cytokines, brain injury markers, and autoantibodies. The sub-acute/convalescent cohort (weeks to months post-COVID+ve test) retained elevated brain injury markers but lower proinflammatory cytokines and autoantibodies.

(b) The mouse model of para-infectious brain with no active viral replication, had increased cytokines (IFNγ and IL-17A) and microglia reactivity (increased Iba1 expression).

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