Elevation of Neuronal Injury Markers in Patients with Neurologic Sequelae after Hospitalization for SARS-CoV-2 Infection: A Biomarker Pilot Study

Abstract

Background: Patients with SARS-CoV-2 infection (COVID-19) risk developing long-term neurologic symptoms after infection, though risk factors and mechanisms for this phenomenon remain largely unknown. This study seeks to identify biomarkers associated with neurologic sequelae in patients after hospitalization for SARS-CoV-2 infection.

Methods: Plasma samples, sociodemographic information, clinical outcome data, and baseline laboratory information were retrospectively analyzed from an observational cohort study conducted from 3/19/20 to 3/20/2021. Three neuronal injury markers; Glial fibrillary astrocytic protein (GFAP), Neurofilament light chain (NF-L) and Tau, and two inflammatory plasma protein markers; Monocyte Chemoattractant Protein-4 (MCP-4) and T-cell Immunoglobulin and Mucin domain protein-3 (TIM-3), were measured. SARS-CoV-2 positive patients were followed for one-year after hospitalization using post-SARS-CoV-2 online questionnaires and virtual visits. Sixty-one adults with SARS-CoV-2 infection were included. Sixty hospitalized adults from the pre-SARS-CoV-2 era were matched according to age, sex, ICU duration, and qSOFA scores and served as historical controls.

Findings: Sixty-one patients with confirmed SARS-CoV-2 infection were included (53 for outcomes) of which 21 (40%) developed neurologic symptoms during one year of recovery. In the historical control cohort, from forty-seven patients that were followed, 7 (14%) developed persisting neurological symptoms. COVID-19 Patients with neurologic sequalae were older, had more severe disease, including hepatic injury, decreased renal function, leukocytosis, and higher levels of inflammatory markers. COVID-19 was associated with an additional risk for neurological sequelae compared to controls. Glial fibrillary astrocytic protein (GFAP) and Neurofilament light chain (NF-L) were significantly elevated in SARS-CoV-2 infection compared to control patients. After adjusting for age, sex, and disease severity, GFAP and NF-L remained significantly associated with longer-term neurological symptoms in patients with SARS-CoV-2 infection.

Interpretation: A significant proportion of patients recovered from acute COVID-19 infection develop neurological sequelae in the year after hospitalization. Compared to historical controls, patients with SARS-CoV-2 infection were more likely to have neurological symptoms during one year of follow-up after hospitalization. Plasma GFAP and NF-L levels are higher in patients hospitalized for SARS-CoV-2 infection relative to control patients and are associated with neurological symptoms. GFAP and NF-L warrant exploration as biomarkers for long-term neurologic complications after SARS-CoV-2 infection.

Funding Information: S.D is funded by NIH UG3 TR002878. M.S is funded by the John S. Latsis Public Benefit Foundation. H.I.L is a recipient of the John S. LaDue Memorial Fellowship at Harvard Medical School.

Declaration of Interests: S.D is a founder for LQTT and Switch Therapeutics that had no role in this study. D.R is an employee of Meso Scale Diagnostics. S.S is a former employee of Meso Scale Diagnostics. R.N is a former employee of Meso Scale Diagnostics P.B is an employee of Meso Scale Diagnostics.G.S is the Chief Scientific Officer of Meso Scale Diagnostics. All other authors have nothing to disclose.

Ethics Approval Statement: This study has ethical approval by the institutional review board (IRB) at Massachusetts General Hospital.