Cytokine release syndrome in COVID-19: a major mechanism of morbidity and mortality

Abstract

The coronavirus disease 2019 (COVID-19) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) erupted in Hubei Province of China in December 2019 and has become a pandemic. Severe COVID-19 patients who suffer from acute respiratory distress syndrome (ARDS) and multi-organ dysfunction have high mortality. Several studies have shown that this is closely related to the cytokine release syndrome (CRS), often loosely referred to as cytokine storm. IL-6 is one of the key factors and its level is positively correlated with the severity of the disease. The molecular mechanisms for CRS in COVID-19 are related to the effects of the S-protein and N-protein of the virus and its ability to trigger NF-κB activation by disabling the inhibitory component IκB. This leads to activation of immune cells and the secretion of proinflammatory cytokines such as IL-6 and TNF-α. Other mechanisms related to IL-6 include its interaction with GM-CSF and interferon responses. The pivotal role of IL-6 makes it a target for therapeutic agents and studies on tocilizumab are already ongoing. Other possible targets of treating CRS in COVID-19 include IL-1β and TNF-α. Recently, reports of a CRS like illness called multisystem inflammatory syndrome in children (MIS-C) in children have surfaced, with a variable presentation which in some cases resembles Kawasaki disease. It is likely that the immunological derangement and cytokine release occurring in COVID-19 cases is variable, or on a spectrum, that can potentially be governed by genetic factors. Currently, there are no approved biological modulators for the treatment of COVID-19, but the urgency of the pandemic has led to numerous clinical trials worldwide. Ultimately, there is great promise that an anti-inflammatory modulator targeting a cytokine storm effect may prove to be very beneficial in reducing morbidity and mortality in COVID-19 patients.

Keywords: COVID-19; IL-6; Kawasaki disease; NF-κB; SARS-CoV-2; cytokine release syndrome; hemophagocytic lymphohistiocytosis (HLH); multisystem inflammatory syndrome in children (MIS-C).

Figure 1.

IL-6 and GM-CSF in NF-?B pathways. A. The N and S protein of SARS-CoV-2 interact with the NF-?B complex, leading to phosphorylation and degradation of I?B, and to the release of NF-?B dimers and translocation from the cytoplasm to the nucleus. The NF-?B dimers further bind to DNA binding sites and upregulate the expression of target genes such as IL-6, TNF-? and GM-CSF. B. GM-CSF further stimulates CD14 + CD16+ monocytes to produce higher levels of IL-6 and other inflammatory cytokines. C. By promoting the production of other cytokines and chemokines, differentiation of monocyte and macrophage, attraction of other immune cells and inhibiting Treg cells, IL-6 may play an important role in apoptosis of T cells and development of CRS.

Figure 2.

IMMs are induced to accumulate and produce large quantities of cytokines and chemokines after infection, resulting in the apoptosis of T cells together with a delayed IFN-?/? response. The T cell apoptosis further blocks the clearance of viruses and induces proinflammatory cytokine release, which may further aggravate a cytokine storm.

Figure 3.

An illustration showing that cytokine release syndrome, cytokine storm, MIS-C, and a Kawasaki disease like syndrome seen in COVID-19 patients and hemophagocytic lymphohistiocytosis are all variations of a hyperactive inflammatory disorder associated with infection. The manifestation of these syndromes or lack thereof is highly dependent on the immune system responses specific for each individual infected host and there may be both genetic (inherent) and environmental (external) factors that lead to the variability in the response. CRS = Cytokine release syndrome, MIS-C = multisystem inflammatory syndrome in children, HLH = Hemophagocytic lymphohistiocytosis, KD (COVID-19) = Kawasaki disease seen in COVID-19 patients. A, B and C show symptoms in COVID-19 patients that may also be present in related inflammatory conditions.