Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses
Authors: Michael Benedict , Dunai Cordelia , Needham Edward , Tharmaratnam Kukatharamini , Williams Robyn , Huang Yun , Boardman Sarah , Clark Jordan , Sharma Parul , Subramaniam Krishanti , Wood Greta , 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 , Egbe Franklyn , Palmos Alish , Stirrups Kathleen , Grundmann Alexander , Stewart James , Griffiths Michael , Solomon Tom , Breen Gerome , Coles Alasdair , Cavanagh Jonathan , Irani Sarosh , Vincent Angela , Baillie J , Openshaw Peter , Semple Malcolm ,   ISARIC-4C Investigators, corsortium COVID-CNS , Taams Leonie , Menon David 
Published: May 2023

Abstract

Neurological complications occur in a significant proportion of COVID-19 cases. In order to identify key biomarkers, we measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants admitted to hospital for management of COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided convalescent sera (up to76 weeks post admission). Compared to 60 controls, brain injury biomarkers (total-Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in participants with altered consciousness. Total-Tau (tTau) 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 in convalescent sera than acute sera. Levels of CCL2, CCL7, IL-1RA, IL-2Rα, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with tTau levels even at later time points. When compared to acute COVID-19 patients with a normal Glasgow Coma Scale score (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 of COVID-19 and we found brain injury markers persist during convalescence and may be driven by a para-infectious process involving a dysregulated host response.