Published reports indicate that approximately 20% of COVID-19 patients tend to have severe or critical disease, with a mortality rate of 50% or more in critical cases
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17. According to various reports, COVID-19 mortality has been predicted by factors such as decreased hemoglobin, elevated cytokines, D-dimer, cardiac and/or renal injury, leukocytosis, and elevation of neutrophil : lymphocyte ratio (NLR)
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17. One possible explanatory aspect for these factors contributing to severe COVID-19 cases is an inappropriately exaggerated immune response previously described as a “cytokine storm,” which results in the formation of reactive oxygen species (ROS)
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20. Such an acute severe immunological response in similar viral infections is known to release a cascade of inflammatory mediators, including various interleukins, tumor necrosis factor (TNF α) and other chemokines. Interleukin-6 (IL-6), which is capable of signaling through both membrane-bound receptors (IL-6R) and soluble receptors, is one of the most important
21. The IL-6 pathway involves increased vascular permeability and immune cell recruitment through modulation of endothelial activation and dysfunction
21. Furthermore, infiltrating neutrophils, a hallmark of COVID-19, can release myeloperoxidase (MPO), which can activate several pathways that lead to elevated cytokines and production of ROS such as hypochlorous acid (HOCl), superoxide (O2•-), and hydrogen peroxide (H2O2)
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24. Notably, HOCl can both compete with O2 at hemoglobin heme binding sites and also cause heme degradation and subsequent release of free iron (Fe2+). Free iron can then undergo the Fenton reaction to produce an array of ROS, including the highly reactive hydroxyl radical (•OH)
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27. Another possible facet of the observed pathophysiology in critical cases of COVID-19 is a decline in nitric oxide (NO), a key mediator of vasodilation
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29. Vasodilation mediated by NO deficiency combined with the effect of excessive ROS on the structure and function of hemoglobin (Hb) could impact pulmonary and peripheral circulation, possibly eventually leading to critical or fatal hypoxia. Therefore, connection of these pathways establishes a multi-hit model that relates simultaneous activation of ROS-mediated mechanisms to key features of critically ill COVID-19 patients. Understanding these pathways will provide multiple clues to develop therapeutic strategies that will prevent severe morbidity and mortality related to COVID 19.