Cytokine storm syndrome in coronavirus disease 2019: A narrative review

Abstract

Cytokine storm syndrome (CSS) is a critical clinical condition induced by a cascade of cytokine activation, characterized by overwhelming systemic inflammation, hyperferritinaemia, haemodynamic instability and multiple organ failure (MOF). At the end of 2019, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, and rapidly developed into a global pandemic. More and more evidence shows that there is a dramatic increase of inflammatory cytokines in patients with COVID-19, suggesting the existence of cytokine storm in some critical illness patients. Here, we summarize the pathogenesis, clinical manifestation of CSS, and highlight the current understanding about the recognition and potential therapeutic options of CSS in COVID-19.

Keywords: COVID-19; SARS-CoV-2; cytokine storm syndrome; recognition; treatment.

Fig. 1

Proposed pathogenesis of CSS. In the setting of CAR T‐cell therapy, CAR T cells can recognize target cells (tumour cells) and induce the lysis of target cells, along with the activation of CAR T cells and T cell, causing a consecutive release of cytokines including IFN‐γ or TNF‐α. These cytokines trigger a cascade reaction by activation of innate immune cells including macrophages, DCs and endothelial cells with further cytokine releasing, which finally leads to a cytokine storm. In the setting of HLH, mutations in perforin coding gene or genes essential for perforin transport will cause a failure of normal cytolytic function and inability to clear the antigenic stimulus, leading to the persistent activation of macrophages and T cells by the infected cells, accompanied by excessive secretion of proinflammatory cytokines, which finally leads to a cytokine storm. Abbreviations: CSS: cytokine storm syndrome; CAR: chimeric antigen receptor; IFN‐γ: interferon‐gamma; TNF‐α: tumour necrosis factor‐alpha; IL: interleukin; CTL: cytotoxic T lymphocytes; NK cell: natural killer cell; and DC: dendritic cell.

Fig. 2

Possible mechanisms of cytokine storms in COVID‐19. SARS‐CoV‐2 transmitted by air droplets reaches the lungs. On the one hand, the S protein on the surface of the virus binds to the ACE2 receptor in alveolar epithelial cells, resulting in the down‐regulation of ACE2 expression and an increase of angiotensin level, which leads to increased pulmonary capillary permeability and pulmonary oedema. On the other hand, SARS‐CoV‐2 reaches the lungs again through blood circulation and interacts with ACE2 receptors on the surface of alveolar capillary endothelial cells, making the alveolar capillary endothelium the target of attack by the immune system, thus inducing a series of immune responses and aggravating lung injury. The imbalance of lymphocyte subsets characterized by the decrease of CD4⁺, CD8⁺ T cells, the increase of the number of proinflammatory Th17 cells and the increase of CD8⁺ cytotoxic particles, aggravated the disorder of host immune system. Inflammatory monocytes amplify cytokines production. In addition, many kinds of cytokines are released in patients with COVID‐19, which contribute to the formation of a cytokine storm. Abbreviations: ACE2: angiotensin‐converting enzyme 2 and NK cell: natural killer cell.