Cytokine Storm in COVID-19: Immunopathogenesis and Therapy

Abstract

A cytokine storm is a hyperinflammatory state secondary to the excessive production of cytokines by a deregulated immune system. It manifests clinically as an influenza-like syndrome, which can be complicated by multi-organ failure and coagulopathy, leading, in the most severe cases, even to death. The term cytokine storm was first used in 1993 to describe the graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. It was then reused to define the adverse syndromes secondary to the administration of immunostimulating agents, such as anti-CD28 antibodies or bioengineered immune cells, i.e., CAR T-cell therapy. Currently, the concept of cytokine storm has been better elucidated and extended to the pathogenesis of many other conditions, such as sepsis, autoinflammatory disease, primary and secondary hemophagocytic lymphohistiocytosis, and multicentric Castleman disease. Moreover, cytokine storm has recently emerged as a key aspect in the novel Coronavirus disease 2019, as affected patients show high levels of several key pro-inflammatory cytokines, such as IL-1, IL-2, IL-6, TNF-α, IFN-γ, IP-10, GM-CSF, MCP-1, and IL-10, some of which also correlate with disease severity. Therefore, since the onset of the pandemic, numerous agents have been tested in the effort to mitigate the cytokine storm in COVID-19 patients, some of which are effective in reducing mortality, especially in critically ill patients, and are now becoming standards of care, such as glucocorticoids or some cytokine inhibitors. However, the challenge is still far from being met, and other therapeutic strategies are being tested in the hope that we can eventually overcome the disease.

Keywords: COVID-19; JAK inhibitors; anakinra; cytokine storm; glucocorticoids; methylene blue; plasmapheresis; tocilizumab.

Figure 1

Schematic diagram of the effects of the RAAS system during SARS-CoV-2 infection and the proposed treatment. (1) Renin secreted by the kidney cleaves angiotensinogen, produced by the liver, to form AT1; (2) AT1 is converted to AT2 by pulmonary ACE. (3) AT2 binds to AT2R1 (angiotensin II receptors 1). The excess of AT2 through AT2R1 hyperactivation causes vasoconstriction, sodium retention (by aldosterone release), hypertension, inflammatory, IL-6, hypertrophy, fibrosis, and thrombosis. (4) SARS-CoV-2 binds to ACE2 to enter the host cell; however, the cellular protective response leads to ACE2 shedding. (5) ADAM17-regulated ectodomain shedding of ACE2 results in an increased amount of soluble and active ACE2 (sACE2). (6) AT1 and AT2 can also bind to sACE2. (7) They are then metabolized by ACE2 into Ag 1–9 and Ag 1–7, respectively. (8) The excess of Ag 1–9 and Ag 1–7 signaling via AT2R2 and MasR can induce vasodilatation, natriuresis, hypotension, anti-inflammatory effects, IL-10, lymphopenia, apoptosis, and thrombosis. (9) These events, in turn, produce a compensatory upregulation of both renin secretion and ACE activity, which establish the onset of a positive feedback loop. In the black boxes, drugs that can potentially stop the positive feedback loop by inhibiting enzymes of the RAAS are indicated. Dashed arrows indicate enzymatic activity, full arrows indicate non-enzymatic passage, and dashed blue arrows represent the positive feedback loop. Created in Bio-render.com. Reprinted from Ref. [42].