Brain injury markers associated with dysregulated immunological responses in COVID-19

The coronavirus disease 2019 (COVID-10) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to over 265 million documented COVID-19 cases and over 5.26 million deaths so far. In many cases, it has been found to be associated with neurological complications including stroke, delirium, Guillain-Barré syndrome, and autoimmune encephalitis. A new preprint describes the presence of inflammatory markers and autoantibodies in COVID-19 patients, and their correlation with brain injury. Study: Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity. Image Credit: Dusan Petkovic/Shutterstock

Background

Many patients with COVID-19 have neurological presentations, while a prolonged neuropsychiatric post-viral syndrome is also known to occur in up to a third of cases, even without very severe disease. While the actual incidence remains unknown, dysregulated inflammation appears to be a key aspect of severe COVID-19, and could be related to the neurological damage in this condition.

The current study, which appears on the medRxiv* preprint server, explores the changing status of serum markers of neurological damage and abnormal autoinflammatory/autoimmune responses in patients with COVID-19 The former includes neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau. In the second category are proinflammatory cytokines and autoimmune antibodies.

What did the study show?

We have demonstrated that markers of brain injury are associated with dysregulated immunological responses in COVID-19, and that there may be a separate late process irrespective of initial disease severity which is characterised by elevated serum total Tau concentrations and the presence of IgM autoantibodies.”

The researchers found that in patients hospitalized with COVID-19, both Nfl and GFAP were raised in proportion to the severity of illness. Even when examined four months later, patients continued to show evidence of continuing dysregulated immune responses, with Nfl levels still higher than normal, though reduced in magnitude compared to the acute stage of illness.  

High levels of these markers were linked to higher pro-inflammatory cytokine measurements, as well as the presence of autoantibodies.

Besides this, another process of brain injury seems to have been set in motion, with total Tau protein levels being raised even in patients without initially severe COVID-19 or high levels of pro-inflammatory cytokines. Autoantibodies, mainly immunoglobulin M (IgM) to a number of targets were also observed, including the lung surfactant protein A1 and myelin-associated glycoprotein.

The latter was directed chiefly against lung surfactant and certain brain proteins like myelin-associated glycoprotein, but autoantibodies were also detected against a number of other antigens. Moreover, serum total Tau was found to be elevated in patients at follow-up, perhaps reflecting an ongoing neurological process. This did not correlate with disease severity in the initial COVID-19 episode, nor to the levels of GFAP or Nfl.

What are the implications?

The study observed a link between brain injury biomarkers and dysregulated innate and immune responses. When coupled with the fact that the most effective treatments for COVID-19 are those that target the inflammatory or immune response, the findings seem to be indicative of an underlying inflammatory-immune mechanism for neurologic damage, rather than direct brain invasion by the virus.

In fact, there is little experimental proof of such neuroinvasion. In contrast, the inflammatory damage hypothesis would be in agreement with the postulate that severe COVID-19 is due to uncontrolled inflammation and the resulting multi-system injury, rather than direct viral damage. The inflammation could be directed against the neurons themselves or against the cerebrovascular bed, the latter being associated with microvascular ischemic brain injury.

It seems that as the number of autoantibodies rises, it indicates a more general type of underlying immune activation. Furthermore, brain injury is related in the degree to the extent of immune activation rather than to the presence of specific brain tissue targets.

Of the various autoantibodies found in this condition, both polyreactive and specific antibodies have been identified, including those often associated with rheumatological disorders and the much more recently identified anti-interferon antibodies. The researchers suggest that in many cases they may be the result of tissue damage and may be involved in debris clearance. However, anti-interferon antibodies may also drive severe disease, while the formation of immune complexes could trigger a cascade of secondary cellular immune responses in COVID-19.

Conclusions

Blood Nfl levels were found to be correlated with the severity of acute COVID-19, and therefore predict a poorer outcome. An earlier study involving some of the same researchers showed that the Nfl and GFAP levels return to normal by six months, which may indicate that the raised levels of Nfl observed at four months in the current study were captured at the fag-end of this period of active brain injury.

The study observed, for the first time, an elevation in Tau protein level during the follow-up period. This protein is found to be raised in Alzheimer’s disease and frontotemporal dementia, and the degree of rise correlates with cognitive impairment in such patients. This finding needs to be confirmed by larger studies.

The most interesting part of this observation is its occurrence irrespective of the initial severity of the disease, which may indicate its potential as an easily measured biomarker of risk for the long-term neuropsychiatric syndromes of long COVID-19.

The late Tau protein elevation and the presence of IgM autoantibodies could mark a persistent abnormality of the immune response that is responsible for brain injury, especially directed against the neuronal dendrites and axons – since Tau is a protein found in these processes.

Finally, it is possible that the neurologic injury and immune-inflammatory markers observed here are not specific to COVID-19, but occur in all severe illnesses.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.