Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses
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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.
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SciScore for 10.1101/2021.12.03.21266112: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: 20 Written consent was gained from either patients themselves, or from their legal representatives where they lacked capacity to consent.
IRB: This study was approved by the Swedish Ethical Review Authority (2020–01771) and the East of England – Cambridge Central Research Ethics Committee (17/EE/0025); via the Cambridge Biomedical Research Centre).Sex as a biological variable not detected. Randomization Samples from healthy controls and patients with COVID-19 were randomly distributed across the slides to mitigate against experimental variation. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources Protein microarray autoantibody profiling: … SciScore for 10.1101/2021.12.03.21266112: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: 20 Written consent was gained from either patients themselves, or from their legal representatives where they lacked capacity to consent.
IRB: This study was approved by the Swedish Ethical Review Authority (2020–01771) and the East of England – Cambridge Central Research Ethics Committee (17/EE/0025); via the Cambridge Biomedical Research Centre).Sex as a biological variable not detected. Randomization Samples from healthy controls and patients with COVID-19 were randomly distributed across the slides to mitigate against experimental variation. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources Protein microarray autoantibody profiling: Autoantibody screening was performed using a custom central nervous system protein microarray based on the HuProt™ (version 4.0) platform.22,23 The microarray was devised in collaboration with Cambridge Protein Arrays Ltd. (Cambridge, UK) and CDI laboratories (Puerto Rico) to detect autoantibodies predominantly directed against central nervous system antigens (n = 51), but also to a number of blood-brain barrier (n = 5) and other tissue-specific (n = 94, covering organ systems including lung, heart and coagulation) antigens, as well as spike and nucleocapsid antigens (full antigen list detailed in Supplemental Figure 1). antigens , as well as spike and nucleocapsid antigens ( full antigen list detailed in Supplemental Figure 1suggested: NoneThe slides were washed again, incubated at room temperature for two hours with fluorophore-conjugated goat anti-human IgM-μ chain-Alexa488 (Invitrogen, Carlsbad, CA, USA, Cat. No. A21215) and goat anti-human IgG-Fc-DyLight550 (Invitrogen Cat. No. SA5-10135) secondary antibodies, washed, and then scanned using a Tecan LS400 scanner and GenePix Pro v4 software, with the output being median fluorescence value of the quadruplicate spots for each protein. anti-human IgM-μsuggested: Noneanti-human IgG-Fc-DyLight550suggested: NoneSoftware and Algorithms Sentences Resources All analyses were performed using GraphPad Prism Version 9.2.0 GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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