Mixed storm in SARS-CoV-2 infection: A narrative review and new term in the Covid-19 era

Abstract

Coronavirus disease 2019 (Covid-19) is caused by a novel severe acute respiratory syndrome coronavirus virus type 2 (SARS-CoV-2) leading to the global pandemic worldwide. Systemic complications in Covid-19 are mainly related to the direct SARS-CoV-2 cytopathic effects, associated hyperinflammation, hypercytokinemia, and the development of cytokine storm (CS). As well, Covid-19 complications are developed due to the propagation of oxidative and thrombotic events which may progress to a severe state called oxidative storm and thrombotic storm (TS), respectively. In addition, inflammatory and lipid storms are also developed in Covid-19 due to the activation of inflammatory cells and the release of bioactive lipids correspondingly. Therefore, the present narrative review aimed to elucidate the interrelated relationship between different storm types in Covid-19 and the development of the mixed storm (MS). In conclusion, SARS-CoV-2 infection induces various storm types including CS, inflammatory storm, lipid storm, TS and oxidative storm. These storms are not developing alone since there is a close relationship between them. Therefore, the MS seems to be more appropriate to be related to severe Covid-19 than CS, since it develops in Covid-19 due to the intricate interface between reactive oxygen species, proinflammatory cytokines, complement activation, coagulation disorders, and activated inflammatory signaling pathway.

Keywords: Covid-19; cytokine storm; inflammatory storm; lipid storm; mixed storm; oxidative storm.

Figure 1

Cytokine storm in Covid‐19: Binding of SARS‐CoV‐2 to the angiotensin‐converting enzyme 2 (ACE2) in association with transmembrane protein protease serine 2 (TMPPSS2) induces the release of damage‐associated molecular patterns (DAMPs) which induce immune cells to release proinflammatory cytokines and activates several inflammatory signaling pathways like nuclear factor kappa B (NF‐κB), nod‐like receptor pyrin 3 (NLRP3) inflammasome and a disintegrin and metalloprotease 17 (ADAM17) with subsequent release of proinflammatory cytokines. SARS‐CoV‐2 activates neutrophils to form the neutrophil extracellular traps (NETs) with further release of proinflammatory cytokines. A huge amount of proinflammatory cytokines trigger the development of cytokine storm which causes disseminated intravascular coagulopathy (DIC) and multiorgan failure (MOF) and acute respiratory distress syndrome (ARDS). Covid‐19, coronavirus disease 2019; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus virus type 2.

Figure 2

Prostaglandin metabolites in Covid‐19: Phospholipase A2 (PLA2) activates the conversion of membrane phospholipid to arachidonic acid (AA) which is converted by cyclooxygenase (COX) to thromboxane A2 (TXA2), prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). TXA2 induces thrombosis and PGD2 activates the immune cells while PGE2 has an anti‐inflammatory effect and reduces the development of acute respiratory distress syndrome (ARDS). Prostaglandin D2 (PGD2) induces airway inflammation by activating the recruitment of inflammatory cells. SARS‐CoV‐2 activates phospholipid, AA, and COX.

Figure 3

Leukotriene metabolites in Covid‐19: Phospholipase A2 (PLA2) activates the conversion of membrane phospholipid to arachidonic acid (AA) which is converted by 5‐lipooxygenase (5‐LOX) to leukotriene A4 (LTA4) which converted to LTB4 and cysteinyl LTs leading to activation of nuclear factor kappa B (NF‐κB) and development of lipid storm and release of proinflammatory cytokines. In turn, proinflammatory cytokines induce the development of acute respiratory distress syndrome (ARDS). As well, proinflammatory cytokines stimulate the expression of PLA2 and 5‐LOX. Zileuton and PF‐4191834 are 5‐LO inhibitors while hydroxamic acid is an inhibitor of LTA4 hydrolase. Covid‐19, coronavirus disease 2019; LT, leukotriene.

Figure 4

Oxidative stress in Covid‐19: SARS‐CoV‐2 infection lead to hypoxia, dysregulation of renin‐angiotensin system (RAS), overproduction of reactive oxygen species (ROS)/reactive nitrogen species (RNS), and inhibition of endogenous antioxidant system with subsequent oxidative storm formation. Covid‐19, coronavirus disease 2019; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus virus type 2.

Figure 5

Inflammatory cells in Covid‐19: SARS‐CoV‐2 triggers activation of neutrophils and other blood inflammatory cells leading to eosnipenia, basopenia, lymphopenia, and monocytopenia with neutrophilia and development of neutrophil extracellular traps (NETs). NETs inhibit interferon‐gamma (INF‐γ) production with attenuation of T cell proliferation. Covid‐19, coronavirus disease 2019; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus virus type 2.

Figure 6

Thrombotic storm in Covid‐19: SARS‐CoV‐2 infection triggers activation of the coagulation system and platelet activation with inhibition of fibrinolytic and endogenous anticoagulant systems. These changes provoke the development of thrombosis which stimulate thrombotic cascades and the release of proinflammatory cytokines leading to the propagation of a thrombotic storm. Covid‐19, coronavirus disease 2019; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus virus type 2.

Figure 7

Mixed storm in Covid‐19: SARS‐CoV‐2 activates the release of prostaglandins (PGs) and leukotrienes (LTs) with the development of lipid storm (LS). Stimulation release of proinflammatory cytokines (PIC) and reactive oxygen species (ROS)/reactive nitrogen species (RNS) provoke the development of cytokine storm (CS) and oxidative storm (OS). As well, SARS‐CoV‐2 stimulates T helper cells (Th1) causing inflammatory storm (IS), and activation of clotting factors induces the development of thrombotic storm (TS). The interrelated storms propagate the development of mixed storm with the progression of acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and multiorgan injury (MOI). Covid‐19, coronavirus disease 2019; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus virus type 2.