Changes in neuroinflammatory biomarkers correlate with disease severity and neuroimaging alterations in patients with COVID-19 neurological complications.
Author:
Barros-Aragão Fernanda G. Q.1ORCID, Pinto Talita P.1, Carregari Victor C.1, Rezende Nathane B. S.1, Pinheiro Thaís L.1, Reis-de-Oliveira Guilherme2, Cabral-Castro Mauro J.3, Queiroz Daniel C.4, Fonseca Paula L. C.4, Gonçalves Alessandro L.4, de Freitas Gabriel R.1, Sudo Felipe K.1, Mattos Paulo1, Bozza Fernando A.1, Rodrigues Erika C.1, Aguiar Renato S.4, Rodrigues Rosana S.1, Brandão Carlos O.5, Souza Andrea S.1, Martins-de-Souza Daniel2, De Felice Fernanda G.6, Tovar-Moll Fernanda F.1
Affiliation:
1. D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil 2. Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP); Campinas, Brazil. 3. Institute of Microbiology Paulo de Goés, Federal University of Rio de Janeiro (UFRJ), Brazil 4. Department of Genetics, Ecology, and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais; Belo Horizonte, Brazil. 5. Neurolife Laboratories, Rio de Janeiro, Brazil 6. Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences & Department of Psychiatry, Queen’s University, Kingston; Ontario, Canada.
Abstract
Abstract
COVID-19 induces acute and persistent neurological symptoms in mild and severe cases. Proposed concomitant mechanisms include direct viral infection and strain, coagulopathy, hypoxia, and neuroinflammation. However, underlying molecular alterations associated with multiple neurological outcomes in both mild and severe cases are majorly unexplored. To illuminate possible mechanisms leading to COVID-19 neurological disease, we retrospectively investigated in detail a cohort of 35 COVID-19 mild and severe hospitalized patients presenting neurological alterations subject to clinically indicated cerebrospinal fluid (CSF) sampling. Clinical and neurological investigation, brain imaging, viral sequencing, and cerebrospinal CSF analyses were carried out. We found that COVID-19 patients presented heterogeneous neurological symptoms dissociated from lung burden. Nasal swab viral sequencing revealed a dominant strain at the time of the study, and we could not detect traces of SARS-CoV-2’s spike protein in patients’ CSF by multiple reaction monitoring analysis. Patients presented ubiquitous systemic hyper-inflammation and broad alterations in CSF proteomics related to inflammation, innate immunity, and hemostasis, irrespective of COVID-19 severity or neuroimaging alterations. Elevated CSF interleukin-6 (IL6) correlated with disease severity (sex-, age-, and comorbidity-adjusted mean Severe 24.5 pg/ml, 95% confidence interval (CI) 9.62–62.23 vs. Mild 3.91 pg/mL CI 1.5–10.3 patients, p = 0.019). CSF tumor necrosis factor-alpha (TNFα) and IL6 levels were higher in patients presenting pronounced neuroimaging alterations compared to those who did not (sex-, age-, and comorbidity-adjusted mean TNFα Pronounced 3.4, CI 2.4–4.4 vs. Non-Pronounced 2.0, CI 1.4–2.5, p = 0.022; IL6 Pronounced 33.11, CI 8.89-123.31 vs Non-Pronounced 6.22, CI 2.9-13.34, p = 0.046). Collectively, our findings put neuroinflammation as a possible driver of COVID-19 acute neurological disease in mild and severe cases.
Publisher
Springer Science and Business Media LLC
Reference68 articles.
1. Alvim RG, Lima TM, Rodrigues DAS, Marsili FF, Bozza VBT, Higa LM, Monteiro FL, Leitão IC, Carvalho RS, Galliez RM, Castineiras TMPP, Nobrega A, Travassos LH, Ferreira OC Jr, Tanuri A, Vale AM, Castilho LR (2020) An affordable anti-SARS-COV-2 spike protein ELISA test for early detection of IgG seroconversion suited for large-scale surveillance studies in low-income countries. medRxiv (Preprint) https://doi.org/10.1101/2020.07.13.20152884 [Accessed June 22, 2021] 2. Angriman F, Ferreyo B, Burry L, Fan E (2021) Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context. Lancet Respir Med 9:655–664 https://pubmed.ncbi.nlm.nih.gov/33930329/ [Accessed August 16, 2021] 3. Interleukin-6 trans-signaling in the senescent mouse brain is involved in infection-related deficits in contextual fear conditioning;Burton MD;Brain Behav Immun,2012 4. Candido DS et al (2020) Evolution and epidemic spread of SARS-CoV-2 in Brazil. Science (1979) 369:1255–1260 https://pubmed.ncbi.nlm.nih.gov/32703910/ [Accessed April 24, 2022] 5. Chou SH-Y, Beghi E, Helbok R, Moro E, Sampson J, Altamirano V, Mainali S, Bassetti C, Suarez JI, McNett M, GCS-NeuroCOVID Consortium and ENERGY Consortium (2021) Global Incidence of Neurological Manifestations Among Patients Hospitalized With COVID-19-A Report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium. JAMA Neurol 4:e2112131 http://www.ncbi.nlm.nih.gov/pubmed/33974053 [Accessed May 16, 2021]
|
|