The Epidemiological and Mechanistic Understanding of the Neurological Manifestations of COVID-19: A Comprehensive Meta-Analysis and a Network Medicine Observation

Abstract

Background and Purpose: The clinical characteristics and biological effects on the nervous system of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain poorly understood. The aim of this study is to advance epidemiological and mechanistic understanding of the neurological manifestations of coronavirus disease 2019 (COVID-19) using stroke as a case study.Methods: We performed a meta-analysis of clinical studies reporting stroke history, intensive inflammatory response and procoagulant state (C-reactive protein (CRP), Procalcitonin (PCT) and coagulation indicator (D-dimer)) in patients with COVID-19. Via network-based analysis of SARS-CoV-2 host genes and stroke-associated genes in the human protein-protein interactome, we inspected the underlying inflammatory endophenotypes between COVID-19 and stroke. Finally, we further verified the network medicine-based findings using large-scale single-cell RNA-sequencing data generated from the lymphocytic choriomeningitis virus (LCMV) infected mouse model.Results: The overall pooled prevalence of stroke history was 2.98% (95% CI, 1.89 - 4.68; I2=69.2%) in the COVID-19 population. Notably, the severe group had a higher prevalence of stroke (6.06%; 95% CI 3.80 - 9.52; I2 = 42.6%) compare to the non-severe group (1.1%, 95% CI 0.72 - 1.71; I2 = 0.0%). In addition, there were increased CRP, PCT and D-dimer in severe illness, and the pooled mean difference was 40.7mg/L (95% CI, 24.3 - 57.1), 0.07mg/L (95% CI, 0.04 - 0.10) and 0.63mg/L (95% CI, 0.28 - 0.97) respectively. Vascular cell adhesion molecule 1 (VCAM-1), dimethylarginine dimethylaminohydrolase-1 (DDAH-1), CD59 and NOTCH-3 were selected from the results of the protein-protein interactome (PPI) network analysis. Among them, VCAM-1, one of the leukocyte adhesion molecules, is suspected to play a vital role in a holistic perspective. Even though the verification using LCMV data revealed no significant change could be observed in part of virus-host genes and stroke-associated genes, suggesting the relative importance of inflammatory responses in SARS-CoV-2 infection-associated neurological manifestations.Conclusion: In this study, we identified increased vulnerability of those with a history of stroke to severe COVID-19, suggesting monotonic relationships, thus implicating causality. Some candidates underlying inflammatory responses (i.e., VCAM-1) and procoagulant pathways were preliminarily identified for neurologists in caring COVID-19 patients with cerebrovascular disease, which requires future clinical and functional validation studies.Funding Statement: This work was supported by the National Heart, Lung, and Blood Institute (R00HL138272) and the National Institute of Aging (R01AG066707).Declaration of Interests: The authors declare that they have no conflict of interest.