Hyperinflammatory States Associated With Brain Injury in COVID-19

The study covered in this summary was published in medRxiv.org as a preprint and has not yet been peer-reviewed.

Key Takeaway

  • Well-established blood biomarkers of brain injury (neurofilament light [NfL] and glial fibrillary acidic protein [GFAP]) are elevated in hospitalized patients with COVID-19 in a severity-dependent manner, and are still detectable at postdischarge follow up.

  • These markers of brain injury are higher in patients with evidence of exaggerated inflammatory responses (measured by the presence of autoantibodies and pro-inflammatory cytokines), suggesting that the brain injury may be the result of this excess inflammation.

  • A second, separate phenomenon, characterized by elevations of serum total tau and IgM autoantibodies, is seen at postdischarge follow-up, and appears to be independent of initial disease severity and global upregulated inflammation.

Why This Matters

  • Survivors of COVID-19 often experience protracted neuropsychiatric symptoms. The reason why such symptoms should occur following a respiratory infection are unclear.

  • To improve long-term outcomes from COVID-19, scientists need to understand the mechanisms that lead to persisting symptomatology, so that targeted interventions can be used. 

  • This study suggests that brain injury occurs universally in patients hospitalized with COVID-19, and appears to be the result of exaggerated inflammatory responses. In principle, modulation of the inflammatory response might mitigate against brain injury.

Study design

  • 250 serum samples from 175 patients hospitalized with COVID-19 at up to three timepoints (median timings: day 7 post-admission, day 31 post-admission, and 4 months at post-discharge follow-up).

  • Blood was assayed for brain-injury biomarkers (NfL, GFAP and total tau; using Quanterix Simoa HDx Neuro 4-PLEX), autoantibodies (against 150 antigens, using a custom protein microarray based on the CDI Labs HuProt Platform), and cytokines (IL-1β, IL-6, IL-10, TNF-α and IFN-γ ).

  • Patients were stratified by COVID-19 severity according to whether they needed a) no supplemental oxygen, b) supplemental oxygen by facemask, or c) mechanical ventilation.

Key results

  • Blood levels of NfL and GFAP were significantly elevated in patients with COVID-19, particularly in those with severe COVID-19, and the magnitude of elevation was comparable to that seen in moderate to severe traumatic brain injury in some patients.

  • Autoantibodies against a multitude of antigens were frequently seen in patients with COVID-19, most commonly against lung surfactant protein A1, and myelin-associated glycoprotein (a protein expressed in the brain and peripheral nerves). Autoantibodies were more frequently detected in patients with severe COVID-19 and, alongside elevations of pro-inflammatory cytokines, were associated with serum levels of brain-injury biomarkers.

  • Whereas the levels of NfL and GFAP fell with time, NfL remained elevated compared with controls at postdischarge follow-up. Intriguingly, serum total tau levels, which were not elevated during hospitalization, rose by the postdischarge follow-up timepoint, and were associated with a discrete immunological profile characterized by the presence of IgM antibodies.


  • The study does not answer whether this phenomenon is specific to COVID-19, or whether similar findings occur in infectious diseases more broadly.

  • The paper does not report clinical correlations of the blood biomarkers of brain injury, such as neuropsychometric testing.

  • The study reports the association between brain injury and inflammation, but does not prove causality between the two.


  • The study was largely funded by the NIHR Cambridge Biomedical Centre and by NIHR funding to the NIHR BioResource (RG94028 & RG85445); full funding details are available in the preprint.

  • The authors disclose conflicts of interest in the preprint; none are directly relevant to the study.

This is a summary of a preprint research study written by Edward Needham, PhD, from the University of Cambridge, United Kingdom, 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 Medrxiv.org.

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