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The study covered in this summary was published in medRxiv.org as a preprint and has not yet been peer-reviewed.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