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Key Event Title
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Dysregulated fibrinolysis/bradykinin leading to hyperinflammation||AdverseOutcome||Penny Nymark (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
Hyperinflammation can be defined as an uncontrolled and self-perpetuating inflammatory process that results in tissue damage. The state of hyperinflammation is also observed in cytokine storm syndrome, cytokine release syndrome, haemophagocytic lymphohistiocytosis, macrophage activation syndrome and in conditions of sepsis; however, it is not a frequent observation. For example, in COVID-19 infection, hyperinflammation plays a critical role in driving the disease severity. Although high viral titre initiates the cascade, the disease severity itself is dependent on the severity of the inflammatory state.
Clinically, the hallmarks of hyperinflammation state include excessive serum levels of pro-inflammatory mediator C-reactive protein, reduced or absence of lymphocytes (lymphopenia), high levels of ferritin and D-dimer, and increased lactate dehydrogenase. Higher neutrophil to lymphocyte ratio is another clinical marker. Some research studies have also associated high serum levels of IL-6 protein and accumulation of neutrophils to be causal and indicative of hyperinflammation. While the total serum levels of these markers is important, more critically, how fast the levels increase in serum is taken into consideration in judging the severity (https://doi.org/10.1101/2021.01.11.20248765 ). The number of studies that have reported on the various markers of hyperinflammation is listed in Table-1.
Although the initiation and promotion of inflammation involves several cell types including epithelial cells, alveolar macrophages, type I and II pneumocytes and dendritic cells, the cell types that play role on inducing hyperinflammatory state may include macrophages, dendritic cells and neutrophils. Lack of neutrophil plays an important role in slowing the viral clearance and thus perpetuating the condition. Hyperferritinaemia is associated with high macrophage activation.
How It Is Measured or Detected
Domain of Applicability
Evidence for Perturbation by Stressor
Regulatory Significance of the Adverse Outcome
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2. Channappanavar et al., Cell Host Microbe 19 (2) (2016) 181–193,
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5. Chu H, et al., Clin Infect Dis. 2020;71(6):1400-1409.
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8. Jin J-M et al., Front. Public Health, 29 April 2020 | https://doi.org/10.3389/fpubh.2020.00152
9. Hadjadj et al., Science doi: 10.1126/science.abc6027
10. Henry B et al., Acta Biomed. 2020;91(3):e2020008. doi:10.23750/abm.v91i3.10217
11. Lazear H.M et al., Immunity. 2019;50:907–923.
13. Mojtabavi, H., et al., Eur Cytokine Netw 31, 44–49 (2020). https://doi.org/10.1684/ecn.2020.0448
14. Zhang B, Zhou X, Qiu Y, et al. Clinical characteristics of 82 death cases with COVID‐19. medRxiv. 2020.