Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients

doi:10.1089/neu.2020.7332

Review

. 2021 Jan 1;38(1):1-43.

doi: 10.1089/neu.2020.7332. Epub 2020 Nov 11.

Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients

Steven T DeKosky¹, Patrick M Kochanek², Alex B Valadka³, Robert S B Clark⁴, Sherry H-Y Chou⁵, Alicia K Au⁶, Christopher Horvat⁷, Ruchira M Jha⁸, Rebekah Mannix⁹, Stephen R Wisniewski¹⁰, Max Wintermark¹¹, Susan E Rowell¹², Robert D Welch¹³, Lawrence Lewis¹⁴, Stacey House¹⁵, Rudolph E Tanzi¹⁶, Darci R Smith¹⁷, Amy Y Vittor¹⁸, Nancy D Denslow¹⁹, Michael D Davis²⁰, Olena Y Glushakova²¹, Ronald L Hayes²²

Affiliations

¹ McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida, USA.
² Department of Critical Care Medicine, Department of Anesthesiology, Pediatrics, Bioengineering, and Clinical and Translational Science, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
³ Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia, USA.
⁴ Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁵ Department of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁶ University of Pittsburgh, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁷ Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Division of Pediatric Critical Care, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁸ Departments of Critical Care Medicine, Neurology, Neurological Surgery, Clinical and Translational Science Institute, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁹ Department of Pediatrics and Emergency Medicine, Harvard Medical School, Department of Medicine, Division of Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
¹⁰ University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹¹ Department of Neuroradiology, Stanford University, Stanford, California, USA.
¹² Duke University School of Medicine, Durham, North Carolina, USA.
¹³ Department of Emergency Medicine, Wayne State University School of Medicine, Detroit Receiving Hospital/University Health Center, Detroit, Michigan, USA.
¹⁴ Department of Emergency Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
¹⁵ Department of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁶ Genetics and Aging Research Unit, Massachusetts General Hospital, McCance Center for Brain Health, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Department of Neurology (Research), Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Charlestown, Massachusetts, USA.
¹⁷ Immunodiagnostics Department, Naval Medical Research Center, Biological Defense Research Directorate, Fort Detrick, Maryland, USA.
¹⁸ Division of Infectious Disease and Global Medicine, University of Florida, Emerging Pathogens Institute, Gainesville, Florida, USA.
¹⁹ Departments of Physiological Sciences and Biochemistry and Molecular Biology, University of Florida, Center for Environmental and Human Toxicology, Gainesville, Florida.
²⁰ Department of Pediatrics, Wells Center for Pediatric Research/Pulmonology, Allergy, and Sleep Medicine, Riley Hospital for Children at Indiana University, Indianapolis, Indiana, USA.
²¹ University of Virginia Cancer Center, Charlottesville, Virginia, USA.
²² Banyan Biomarkers Inc., Alachua, Florida, USA.

PMID: 33115334
PMCID: PMC7757533
DOI: 10.1089/neu.2020.7332

Review

Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients

Steven T DeKosky et al. J Neurotrauma. 2021.

. 2021 Jan 1;38(1):1-43.

doi: 10.1089/neu.2020.7332. Epub 2020 Nov 11.

Authors

Affiliations

¹ McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida, USA.
² Department of Critical Care Medicine, Department of Anesthesiology, Pediatrics, Bioengineering, and Clinical and Translational Science, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
³ Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia, USA.
⁴ Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁵ Department of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁶ University of Pittsburgh, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁷ Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Division of Pediatric Critical Care, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁸ Departments of Critical Care Medicine, Neurology, Neurological Surgery, Clinical and Translational Science Institute, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁹ Department of Pediatrics and Emergency Medicine, Harvard Medical School, Department of Medicine, Division of Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
¹⁰ University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹¹ Department of Neuroradiology, Stanford University, Stanford, California, USA.
¹² Duke University School of Medicine, Durham, North Carolina, USA.
¹³ Department of Emergency Medicine, Wayne State University School of Medicine, Detroit Receiving Hospital/University Health Center, Detroit, Michigan, USA.
¹⁴ Department of Emergency Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
¹⁵ Department of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁶ Genetics and Aging Research Unit, Massachusetts General Hospital, McCance Center for Brain Health, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Department of Neurology (Research), Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Charlestown, Massachusetts, USA.
¹⁷ Immunodiagnostics Department, Naval Medical Research Center, Biological Defense Research Directorate, Fort Detrick, Maryland, USA.
¹⁸ Division of Infectious Disease and Global Medicine, University of Florida, Emerging Pathogens Institute, Gainesville, Florida, USA.
¹⁹ Departments of Physiological Sciences and Biochemistry and Molecular Biology, University of Florida, Center for Environmental and Human Toxicology, Gainesville, Florida.
²⁰ Department of Pediatrics, Wells Center for Pediatric Research/Pulmonology, Allergy, and Sleep Medicine, Riley Hospital for Children at Indiana University, Indianapolis, Indiana, USA.
²¹ University of Virginia Cancer Center, Charlottesville, Virginia, USA.
²² Banyan Biomarkers Inc., Alachua, Florida, USA.

PMID: 33115334
PMCID: PMC7757533
DOI: 10.1089/neu.2020.7332

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus attacks multiple organs of coronavirus disease 2019 (COVID-19) patients, including the brain. There are worldwide descriptions of neurological deficits in COVID-19 patients. Central nervous system (CNS) symptoms can be present early in the course of the disease. As many as 55% of hospitalized COVID-19 patients have been reported to have neurological disturbances three months after infection by SARS-CoV-2. The mutability of the SARS-COV-2 virus and its potential to directly affect the CNS highlight the urgency of developing technology to diagnose, manage, and treat brain injury in COVID-19 patients. The pathobiology of CNS infection by SARS-CoV-2 and the associated neurological sequelae of this infection remain poorly understood. In this review, we outline the rationale for the use of blood biomarkers (BBs) for diagnosis of brain injury in COVID-19 patients, the research needed to incorporate their use into clinical practice, and the improvements in patient management and outcomes that can result. BBs of brain injury could potentially provide tools for detection of brain injury in COVID-19 patients. Elevations of BBs have been reported in cerebrospinal fluid (CSF) and blood of COVID-19 patients. BB proteins have been analyzed in CSF to detect CNS involvement in patients with infectious diseases, including human immunodeficiency virus and tuberculous meningitis. BBs are approved by the U.S. Food and Drug Administration for diagnosis of mild versus moderate traumatic brain injury and have identified brain injury after stroke, cardiac arrest, hypoxia, and epilepsy. BBs, integrated with other diagnostic tools, could enhance understanding of viral mechanisms of brain injury, predict severity of neurological deficits, guide triage of patients and assignment to appropriate medical pathways, and assess efficacy of therapeutic interventions in COVID-19 patients.

Keywords: CNS injury; COVID-19; GFAP, SARS-CoV-2; UCH-L1; blood biomarkers.

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Conflict of interest statement

Ronald L. Hayes owns stock in, receives compensation from, and is an executive officer of Banyan Biomarkers, Inc. and as such may benefit financially as a result of the outcomes of this research or work reported in this publication. Nancy D. Denslow was a founder of the company and currently serves on the Board of Directors of Banyan Biomarkers, Inc. that has developed assays for biomarkers for traumatic brain injury. These biomarkers may be of interest to identify brain damage from COVID-19. Steven DeKosky chairs medical advisory boards for Acumen Pharmaceuticals and Cognition Therapeutics and chairs the Drug Safety Monitoring Boards for Biogen, Prevail Pharmaceuticals, and Vaccinex, Inc. He is editor of the Section on Dementia for Up-To-Date, a point of care electronic textbook, and Associate Editor of Neurotherapeutics, the journal of the American Society for Experimental Neurotherapeutics. None of them have any conflicts with the manuscript or its contents. Michael D. Davis is a Co-Founder of Airbase Breathing Company. Ruchira M. Jha is a paid consultant/on the Advisory Board for Biogen. Robert D. Welch will be doing a seminar for Abbott Labs, Inc. regarding a point-of-care test for GFAP and UCH-L1 and he previously (not since 2017) received contract research funding from Banyan Biomarkers, Inc.

Figures

**FIG. 1.**
Generalized schematic of a clinical research study of BBs of CNS Injury in COVID-19 patients. BBs, blood biomarkers; CNS, central nervous system; COVID-19, coronavirus disease 2019; EHR, electronic health record; FDA, U.S. Food and Drug Administration; ICU, intensive care unit; IRB, institutional review board.

See this image and copyright information in PMC

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References

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1. Desforges M., Le Coupanec A., Dubeau P., Bourgouin A., Lajoie L., Dube M., and Talbot P.J. (2019). Human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system? Viruses 12, 14 - PMC - PubMed
1. Mao L., Jin H., Wang M., Hu Y., Chen S., He Q., Chang J., Hong C., Zhou Y., Wang D., Miao X., Li Y., and Hu B. (2020). Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 77, 683–690 - PMC - PubMed
1. Varatharaj A., Thomas N., Ellul M.A., Davies N.W.S., Pollak T.A., Tenorio E.L., Sultan M., Easton A., Breen G., Zandi M., Coles J.P., Manji H., Al-Shahi Salman R., Menon D.K., Nicholson T.R., Benjamin L.A., Carson A., Smith C., Turner M.R., Solomon T., Kneen R., Pett S.L., Galea I., Thomas R.H., and Michael B.D.; CoroNerve Study Group. (2020). Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry 7, 875–882 - PMC - PubMed

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[1] McKibbin W.J., and Fernando R. (2020). Global Macroeconomic Scenarios of the COVID-19 Pandemic (June 25, 2020). CAMA Working Paper No 62/2020. https://ssrn.com/abstract=3635103 or 10.2139/ssrn.3635103 (Last accessed November6, 2020) - DOI

[2] McKibbin W.J., and Fernando R. (2020). Global Macroeconomic Scenarios of the COVID-19 Pandemic (June 25, 2020). CAMA Working Paper No 62/2020. https://ssrn.com/abstract=3635103 or 10.2139/ssrn.3635103 (Last accessed November6, 2020) - DOI

[3] Tenforde M.W., Kim S.S., Rose E.B., Shapiro N.I., Files D.C., Gibbs K.W., Erickson H.L., Steingrub J.S., Smithline H.A., Gong M.N., Aboodi M.S., Exline M.C., Henning D.J., Wilson J.G., Khan A., Qadir N., Brown S.M., Peltan I.D., Rice T.W., Hager D.N., Ginde A.A., Stubblefield W.B., Patel M.M., Self W.H., and Feldstein L.R.; IVY Network Investigators; CDC COVID-19 Response Team. (2020). Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020. MMWR Morb. Mortal. Wkly. Rep. 69, 993–998 - PMC - PubMed

[4] Tenforde M.W., Kim S.S., Rose E.B., Shapiro N.I., Files D.C., Gibbs K.W., Erickson H.L., Steingrub J.S., Smithline H.A., Gong M.N., Aboodi M.S., Exline M.C., Henning D.J., Wilson J.G., Khan A., Qadir N., Brown S.M., Peltan I.D., Rice T.W., Hager D.N., Ginde A.A., Stubblefield W.B., Patel M.M., Self W.H., and Feldstein L.R.; IVY Network Investigators; CDC COVID-19 Response Team. (2020). Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020. MMWR Morb. Mortal. Wkly. Rep. 69, 993–998 - PMC - PubMed

[5] Desforges M., Le Coupanec A., Dubeau P., Bourgouin A., Lajoie L., Dube M., and Talbot P.J. (2019). Human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system? Viruses 12, 14 - PMC - PubMed

[6] Desforges M., Le Coupanec A., Dubeau P., Bourgouin A., Lajoie L., Dube M., and Talbot P.J. (2019). Human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system? Viruses 12, 14 - PMC - PubMed

[7] Mao L., Jin H., Wang M., Hu Y., Chen S., He Q., Chang J., Hong C., Zhou Y., Wang D., Miao X., Li Y., and Hu B. (2020). Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 77, 683–690 - PMC - PubMed

[8] Mao L., Jin H., Wang M., Hu Y., Chen S., He Q., Chang J., Hong C., Zhou Y., Wang D., Miao X., Li Y., and Hu B. (2020). Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 77, 683–690 - PMC - PubMed

[9] Varatharaj A., Thomas N., Ellul M.A., Davies N.W.S., Pollak T.A., Tenorio E.L., Sultan M., Easton A., Breen G., Zandi M., Coles J.P., Manji H., Al-Shahi Salman R., Menon D.K., Nicholson T.R., Benjamin L.A., Carson A., Smith C., Turner M.R., Solomon T., Kneen R., Pett S.L., Galea I., Thomas R.H., and Michael B.D.; CoroNerve Study Group. (2020). Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry 7, 875–882 - PMC - PubMed

[10] Varatharaj A., Thomas N., Ellul M.A., Davies N.W.S., Pollak T.A., Tenorio E.L., Sultan M., Easton A., Breen G., Zandi M., Coles J.P., Manji H., Al-Shahi Salman R., Menon D.K., Nicholson T.R., Benjamin L.A., Carson A., Smith C., Turner M.R., Solomon T., Kneen R., Pett S.L., Galea I., Thomas R.H., and Michael B.D.; CoroNerve Study Group. (2020). Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry 7, 875–882 - PMC - PubMed

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Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients

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Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients

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Conflict of interest statement

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