Peripheral Inflammation May Explain Some Neurologic Symptoms in COVID-19

Abdullah Hashmi, MD, for Medscape

April 20, 2022

The study covered in this summary was published in as a preprint and has not yet been peer reviewed.

Key Takeaways

  • Use of molecular analysis to characterize immune response in the serum and cerebrospinal fluid (CSF) of patients with COVID-19 revealed that neurologic sequelae are likely due to a buildup of extrathecal proteins with a distinct response of the brain to peripheral inflammation rather than an intrathecal antiviral immune response.

  • Proteomics revealed an almost similar but much less pronounced CSF protein profile in COVID-19 patients compared to patients with herpes simplex viral encephalitis (HSVE)with or without bacterial superinfection.

  • Levels of inflammatory markers were higher in serum and CSF of patients with bacterial superinfections compared to those without bacterial superinfections.

  • RNA sequencing found linear mRNA, micro RNAs, and t-RNA fragments differentially expressed in COVID-19 patients compared to patients with HSVE or control group patients.

Why This Matters

  • There are few data on evidence for direct brain damage and inflammatory mediators within the CSF of patients with COVID-19.

  • Studies to this point have not determined whether COVID-19 patients with and those without bacterial superinfection have neurologic sequelae with changes in inflammatory markers.

  • The results of this study allow for further investigation into blood-derived mediators of inflammation in CSF for neurologic symptoms after SARS-CoV-2 infection.

Study Design

  • This retrospective study enrolled 38 patients with COVID-19, 10 patients with herpes simplex virus encephalitis (HSVE), and 28 patients with noninflammatory and nonneurodegenerative diseases.

  • Patients with other neuroimmunologic diseases, such as viral meningitis, a history of multiple sclerosis, or HIV, were excluded.

  • Cytokine array, ELISA, and mass spectrometry were used to analyze inflammatory markers from CSF and serum samples.

Key Results

  • Several proteins are regulated in response to COVID-19, either stronger or in different directions than in HSVE. Moreover, in COVID-19 patients, some proteins found in the CSF, such as LRG1 of the Serpin family, are not known to be produced in CSF.

  • Downregulation of apolipoproteins and other regulatory proteins, such as NPTXR and CACNA2D1, and upregulation of complement proteins and fibrinogen proteins were found in COVID-19 patients and were different from those in patients with HSVE.

  • Bacterial superinfection was associated with increased levels of inflammation-related proteins but did not affect the protein pattern itself.

  • Elevated levels of cytokines and progranulin were found in patients with COVID-19 compared to control patients, but levels were lower than in patients with HSVE neuroinflammatory disease. Only levels of IL-16 were higher in patients with COVID-19 compared to HSVE patients.

  • No pathologic autoantibodies were found in the COVID-19 group.

  • Patients with severe COVID-19 had linear and circular RNA profiles differentially expressed in comparison with healthy control persons and patients with other neurologic diseases.


  • Limitations of this study were not discussed by the authors.

This is a summary of a preprint research study, "The Brain Reacting to COVID-19: Analysis of the Cerebrospinal Fluid and Serum Proteome, Transcriptome and Inflammatory Proteins," written by researchers at the Otto-von-Guericke University, Institute of Molecular and Clinical Immunology, Magdeburg, Germany and Universitadsmedizin Berlin, Department Neurology, Berlin Germany on medRxiv provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on

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