Retrospective Analysis of Blood Biomarkers of Neurological Injury in Human Cases of Viral Infection and Bacterial Sepsis

Background. Blood biomarkers of neurological injury could provide a rapid diagnosis of central nervous system (CNS) injury caused by infections. An FDA-approved assay for mild traumatic brain injury (TBI) measures glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which signal astrocyte and neuronal injury, respectively. Here, we assessed the applicability of this biomarker assay for determining infection-induced brain injury. Methods. We measured serum levels of GFAP and UCH-L1 retrospectively in serum samples from three study populations: 1) human cases infected with Venezuelan equine encephalitis virus (VEEV) and Madariaga virus (MADV) (n=73), 2) human sepsis patients who were severely ill or diagnosed with encephalitis (n=66), and 3) sepsis cases that were subsequently evaluated for cognitive impairment (n=64). Results. In the virus infection group, we found elevated GFAP for VEEV (p=0.014) and MADV (p=0.011) infections, which correlated with seizures (p=0.006). In the bacterial sepsis group, GFAP was elevated in cases diagnosed with encephalitis (p=0.0007) and correlated with headaches (p=0.0002). In the bacterial sepsis cases with a later cognitive assessment, elevated GFAP (p=0.0057) at study enrollment was associated with cognitive impairment six months later with a positive prognostic capacity of 79% (CI: 66-95%; p=0.0068). Conclusions. GFAP and UCH-L1 levels measured using an FDA-approved assay for TBI may indicate brain injury resulting from viral or bacterial infections and could predict the development of neurological sequelae. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the Defense Threat Reduction Agency under project number CB10937 to DRS and grant number FID-2021-96 SENACYT to JPC. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The alphavirus studies were approved by the Panamanian Ministry of Health (protocol: 2077), the Gorgas Institutional Review Board (IRB) (protocol: 335/CBI/ICGES/21), and the University of Florida IRB (protocol: 201500292). Sera from suspected human sepsis cases were collected by the Naval Medical Research Command's Austere environments Consortium for Enhanced Sepsis Outcomes (ACESO) program during prospective observational studies in Cambodia and Ghana under IRB-approved protocols (protocols: NMRC.2013.0019 and NMRC.2016.0004-GHA) in compliance with all applicable U.S. Federal regulations governing the protection of human subjects. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.