COVID-19 and Kounis Syndrome: Deciphering Their Relationship

Abstract

Coronavirus infection is not a newly discovered condition. Currently, 7 coronaviruses that can cause human disease have been identified. Coronaviruses hCoV-HKU1, hCoV-OC43, hCoV-NL63, and hCoV-229E can principally cause asymptomatic or mild respiratory and gastrointestinal infections accounting for approximately 5-30% of common colds. These include the severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and the current new human coronavirus, SARS-CoV-2 that has rapidly spread from Wuhan in China to over 223 countries and regions in the world, causing a global pandemic affecting 114 million people with over 2.5 million deaths by March 1, 2021, with a case fatality ratio ranging from 1 to 3.5% in most countries. 2 Interestingly, these highly pathogenic human coronaviruses have evolutionarily acquired the ability to encode numerous proteins, allowing them to escape recognition and response by the immune system, while they can simultaneously enable inflammatory and immune cell overactivation inducing a cytokine storm. Severe systemic complications such as coagulopathy with thromboses, acute cardiac/coronary injury such as myocardial infarction and stent thrombosis, brain or liver injury, and multiple organ dysfunction have been associated with the cytokine storm and cytokine release syndrome, increasing the risk of mortality (Table Various types of cytokines have been associated with the cytokine storm, including interleukins, chemokines, interferons, tumor necrosis factors, and colony-stimulating factors. The cytokine storm can occur as a result of inappropriate recognition, for instance, in case of hypersensitivity or an ineffective response due to immune evasion. Indeed, a storm of proinflammatory cytokines that can lead to catastrophic events and to Kounis acute hypersensitivity-associated syndrome has been encountered in human anaphylaxis with profuse hypotension or hypoxemia. aphylaxis and Cytokines A Common Pathway Toward Kounis Syndrome In severe anaphylaxis accompanied by hypotension or hypoxemia, a range of mediators--similar to those of the cytokine storm in coronavirus disease 2019 (COVID-19) patients--are reported to increase in both animal models and in vitro cell stimulation studies. n immune-mediated anaphylaxis and in the COVID-19 cytokine storm, the implicated molecules are released from inflammatory cells and include IL-1, IL-1, IL-6, IL-10, IL-17A, IL-12 p70, IL-18, IFN, TNF, and an additional inflammatory cluster defined by thrombopoietin, IL-33, IL-16, IL-21, IL-23, IFN, eotaxin, and eotaxin-3, demonstrating an increased correlation with severe disease. 7 Furthermore, a marked increase in multiple type 2 effectors, namely interleukin-5 (IL-5), IL-13, immunoglobulin E (IgE), eosinophils, and type 2 antibody isotype IgE, was found in severe COVID-19 disease; the increase continued during the course of the disease. Eosinophils and basophils are activated by monocyte chemotactic protein 3, which is the most effective activating chemokine. 9 Dendritic cells may also initiate autoimmune responses and stimulate T cells, resulting in macrophage activation. Interactions between lymphocytes, monocytes, macrophages, and mast cells can increase vascular permeability, via release of TNF, IL-1, IL-6, CXCL8 (IL-8), macrophage migration inhibitory factor, CCL2 (also known as monocyte chemoattractant protein-1 (MCP-1)), high-mobility group box-1 protein, and matrix metalloproteinases. 11 The latter can promote plaque disruption or rupture, leading to myocardial infarction via activation of their zymogen forms such as interstitial collagenase, gelatinase, and stromelysin. 12 All types of inflammatory cells participate in an inflammatory vicious cycle in which they can activate each other, like a "ball of thread," via multidirectional signals (Figure For example, mast cells can activate macrophages and may enhance T-cell activation. Inducible macrophage protein 1a may activate mast cells, while

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