Neurovascular injury with complement activation and inflammation in COVID-19

This study, titled “Neurovascular injury with complement activation and inflammation in COVID-19,” explores the neuropathological changes in patients with COVID-19, focusing on vascular pathology, neuroinflammatory changes, and cellular and humoral immune responses. Conducted during the first wave of the pandemic (March to July 2020), it examines brain tissues from deceased patients, including various brain regions, using immunohistochemistry​​​​.

Key Findings:

  1. Patient Demographics: The study included nine patients (seven males and two females, aged 24–73 years) with comorbidities like diabetes and hypertension. Most died suddenly, with evidence of lung involvement​​.
  2. Microvascular Injury and Endothelial Cell Activation: There was significant fibrinogen leakage in COVID-19 cases, indicating microvascular damage and endothelial cell activation. Fibrinogen, which normally doesn’t cross the blood-brain barrier, was found in high concentrations around blood vessels and diffusely throughout the brain​​.
  3. Complement Activation and Immune Complexes: Complement components (C1q, C4d) and immune complexes (IgG, IgM) were present on endothelial cells and platelets, more pronounced in COVID-19 cases than controls. This suggests complement activation playing a role in the pathology​​.
  4. Inflammatory Infiltrates: There was a marked increase in CD68+ macrophages and CD8+ T cells, indicating significant perivascular inflammatory infiltration in COVID-19 cases. Fewer CD4+ T cells and CD20+ B cells were observed​​.
  5. Microglial Activation and Neuronal Injury: Microglia clusters, associated with neuronal cell loss, were prominent in the cerebellum and brainstem nuclei. There was a noticeable loss of Purkinje cells and neuronophagia (microglia engulfing neurons), especially in the hindbrain​​.
  6. Reactive Astrocytosis: Intense astrocyte activation was noted in perivascular regions and walls of blood vessels, with diffuse astrocytosis in the white matter of the brain​​.
  7. Spatial Transcriptomics: The study analyzed brainstem transcriptomics, revealing differences in gene expression between COVID-19 patients and controls. This helped identify genes and pathways potentially involved in COVID-19 neuropathology​​.
  8. Correlation Between Fibrinogen Leakage and Inflammatory Infiltrates: A positive correlation was found between fibrinogen deposition and CD68+ cells, TMEM119+ cells, CD3+ cells, and CD8+ cells. Platelet aggregates also correlated with inflammatory markers​​.
  9. Viral Detection Efforts: Despite using multiple techniques, including PCR and RNA in situ hybridization, the study failed to detect SARS-CoV-2 in the brain, even in areas with inflammation​​.
  10. Discussion on Vascular Pathology: The study discusses the potential mechanisms of vascular compromise in COVID-19, including endothelial cell dysfunction and the role of activated platelets in thrombosis formation​​.

In summary, the study provides comprehensive insights into the neurovascular and inflammatory changes in COVID-19 patients, highlighting the complex interplay of immune response, vascular injury, and neuronal damage. This research contributes to our understanding of the neurological impacts of COVID-19.

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