Neurovascular injury during COVID-19 infection is likely triggered by antibody-mediated cytotoxicity directed at endothelial cells. These findings were published in Brain.

Severe COVID-19 infection can lead to encephalopathy attributed to hypoxia or multiorgan dysfunction. The pathophysiology of this neurovascular injury remains unclear especially because viral cells have rarely been detected in cerebrospinal fluid.

Researchers at the National Institutes of Health in the United States sought to explore possible mechanisms of neural damage from SARS-CoV-2. Patients (n=9) who had died early in the pandemic, between March and July 2020, were examined and compared with 10 individuals who died from pulmonary infections.


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The patients with COVID-19 were aged 24-73 years, 7 were men, 2 had diabetes, 2 had a substance use disorder, 1 had hypertension, and 1 had hypertension and diabetes. Five patients died suddenly, and the others died days to weeks after symptom onset. The cohort of control individuals was aged 43-74 years, 9 were men, and there were no significant demographic differences compared with the COVID-19 cohort.

All COVID-19 patients had microvascular abnormalities on postmortem magnetic resonance imaging (MRI).

The COVID-19 cases had strong diffuse immunostaining in perivascular regions while the non-COVID cases had minimal or no immunostaining (all P ≤.0011). The proportion of areas involved among the COVID-19 cohort ranged between 5%-65% and immunostaining patterns did not differ between brain regions, except that there was more weak staining in the hindbrain (mean, 26.87% vs 15.75%; P =.04).

The olfactory bulb of 1 patient showed strong fibrinogen staining in 22% of the area, indicating blood-brain barrier interruption.

Platelet aggregates were observed in all COVID-19 cases but were rare in control individuals (mean, 16 vs 0.3 vessels with aggregates/mm2; P <.0001). In COVID-19 cases, more aggregates were observed in the hindbrain (mean, 20 vs 14 vessels with aggregates/mm2; P =.04).

They were also found to have immune complex deposits in all regions of the brain, predominantly in the extracellular matrix and some glial cells and neurons.

CD68+ macrophages were observed in all COVID-19 cases and at greater numbers compared with control individuals (mean, 289.55 vs 71.70 cells/mm2; P <.0001). Among the cases, these macrophages were more concentrated in the hindbrain (mean, 376.00 vs 219.25 cells/mm2; P =.0007). The pattern of T cell infiltration was similar to the macrophages, but at lower concentrations (mean, 14.00 vs 289.55 cells/mm2; P <.0001).

In COVID-19, fibrinogen deposition was correlated with the amount of CD68+ cells (r, 0.63; P <.0001) as well as CD3+ (r, 0.55; P <.0001), CD8+ (r, 0.43; P =.0031), and transmembrane 119 (TMEM119)+ (r, 0.41; P =.0034) cells. Platelet aggregates were correlated with CD68+ (r, 0.49; P =.0003) and CD3+ (r, 0.35; P =.0109) cells. Similarly, fibrinogen and platelet deposits were correlated (r, 0.37; P =.0084).

The major limitation of this study was that 5 of the COVID-19 cases were found dead in their homes or on the subway and there was a lack of data about medical history and postmortem interval.

“Cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury,” the researchers concluded.

Reference

Lee M-H, Perl DP, Steiner J, et al. Neurovascular injury with complement activation and inflammation in COVID-19. Brain. Published online July 5, 2022. doi:10.1093/brain/awac151



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