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.

COVID-19 Infection in Spinal Muscular Atrophy Associated with Multisystem Inflammatory Syndrome

“…The laboratory findings of CRS are lymphopenia and a rise in ferritin, C-reactive protein, creatinine, liver enzymes, and lactate dehydrogenase. A cytokine storm is defined as a severe immunological response resulting in a rapid release of cytokines (IFN- γ and TNF- α ), interleukins (IL-1, IL-2, IL-6, IL-10, and IL-18), and other immune mediators [ 10 , 32 , 33 ]. A variety of signs and symptoms have been reported as part of CRS ranging from nausea and fever to shock [ 34 , 35 ].…”

“…Multisystem inflammatory syndrome in children (MIS-C) is a more serious evolution of COVID-19 that manifests as an acute febrile illness with gastrointestinal symptoms and causes widespread inflammation resulting in hypotension, toxic shock, and multiorgan failure [7][8][9]. e outpouring of cytokines at the nadir of the acute phase has been described as a storm associated with PARDS that correlates with disease severity, morbidity, and mortality if not treated expeditiously [10]. e features of MIS-C are akin to those of Kawasaki disease with mucocutaneous involvement, cardiac complications that comprise arrhythmias, acute heart failure, coronary abnormalities, and myocardial and left ventricular dysfunction [11][12][13].…”

Case Report: Visceral Leishmaniasis and Hemophagocytic Lymphohistiocytosis: Three Clinical Cases, Three Different Pattern

“…[6][7][8] Currently, HLH and NK cell dysfunction have also been cited as possible clinical conditions in the context of COVID-19 infection, disease that has also been associated with a cytokine storm. 14,15 There was no availability of sCD25 (sIL-2Ra) in the reported cases, which would contribute significantly to the diagnostic confirmation of HLH. On the other hand, the information that patients with VL can express this marker 16 reinforces the need to evaluate them by including this analysis in their clinical approach.…”

Immunopathology and Immunopathogenesis of COVID-19, what we know and what we should learn

“…Activation of NF-κB by SARS-CoV-2 S and N proteins induces production of proinflammatory cytokines like IL-6 which shows positive correlation with disease severity. In fact, SARS-CoV-2-associated MIS-C can be a result of cytokine release syndrome (CRS) and these are tightly related due to their inflammatory basis ( Que et al, 2021 ).…”