Cytokine Storm: The Primary Determinant for the Pathophysiological Evolution of COVID-19 Deterioration

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing major threat to global health and has posed significant challenges for the treatment of severely ill COVID-19 patients. Several studies have reported that cytokine storms are an important cause of disease deterioration and death in COVID-19 patients. Consequently, it is important to understand the specific pathophysiological processes underlying how cytokine storms promote the deterioration of COVID-19. Here, we outline the pathophysiological processes through which cytokine storms contribute to the deterioration of SARS-CoV-2 infection and describe the interaction between SARS-CoV-2 and the immune system, as well as the pathophysiology of immune response dysfunction that leads to acute respiratory distress syndrome (ARDS), multi-organ dysfunction syndrome (MODS), and coagulation impairment. Treatments based on inhibiting cytokine storm-induced deterioration and occurrence are also described.

Keywords: acute respiratory distress syndrome (ARDS); coronavirus disease 2019 (COVID-19); cytokine storms; multi-organ dysfunction syndrome (MODS); severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Figure 1

The activation of inflammation during SARS-CoV-2 infection. The virus enters the host cell by interacting with the ACE2 receptor and the cellular serine protease TMPRSS2 through its spike protein. ACE2 internalization weakens the anti-inflammatory ACE2/Ang-(17)/MAS receptor axis maintained by ACE2. At low SARS-CoV-2 viral load, cells do not initiate the interferon response; however, upregulation of Ang II stimulates its receptor AT1R and promotes the transcription of several inflammatory cytokine-related genes through proinflammatory pathways such as the NF-κB and MAPK signaling pathways. Proinflammatory cytokines activate and recruit a variety of immune cells to migrate to the site of infection, and the activated immune cells will secrete more inflammatory cytokines. In this stage, the inflammation leads to an increase in capillary permeability and consequent liquid exudation. PRR, pattern recognition receptor; PAMPs, Pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns.

Figure 2

A dysfunctional immune response induces cytokine storms. SARS-CoV-2 may invade T cells that are attracted to the site of infection and replicates inside them. At the later stage of COVID-19, T cells become depleted and the expression of PD-1 and Tim-3 increases, while the high IL-10, TNF, and IL-6 concentration affect T cell survival or proliferation. The number of B cells also decreases in patients with severe disease. The dysfunction of adaptive immunity results in the magnification of innate immunity and establishes an inflammatory feedback loop. High concentrations of IFN-α2 and IFN-γ may upregulate the expression of ACE2 during the cytokine storm. Additionally, as ACE2 is an ISG, its internalization will further induce ACE2 expression and eventually provide more receptors for virus invasion and aggravate the infection, thus intensify the inflammation. In this stage, capillary permeability is further increased and the capillary and alveolar epithelia become damaged, causing the leakage of a large amount of protein-rich liquid into the lung interstitium and limiting gas exchange. ISG, interferon-stimulating gene.

Figure 3

The pathophysiological outcome of the cytokine storm in SARS-CoV-2 infection. The excess filtration of immune cells and accumulation of cytokines at infected sites results in acute respiratory distress syndrome (ARDS); non-cardiogenic pulmonary edema and hyaline membrane formation; severe lung tissue damage; and destruction of the blood–blood barrier. SARS-CoV-2 can infect vascular endothelial cells that also express ACE2 and enter the blood circulation to infect other ACE2-expressing tissues. The occurrence of an inflammatory storm in other organs may lead to MODS. PAMPs, DAMPs and cytokines trigger monocyte activation and induce the membrane expression of TF on monocytes and endothelial cells. Endothelial damage can also expose TF. Under the action of cytokines (mainly IL-6), endothelial cells recruit TF-expressing inflammatory monocytes, while TF can also promote the conversion of prothrombin to thrombin, forming a fibrin-based blood clot. Recruited by activated endothelial cells, neutrophils release NETs, which activate the contact activation pathway of coagulation and platelets, thereby amplifying blood clotting. MODS, multi-organ dysfunction syndrome; TF, tissue factor; TLR, Toll-like receptor; NETs, neutrophil extracellular traps.