How are cytokine storm and the systemic inflammatory response characterized in coronavirus disease 2019 (COVID-19)?

Answer

Cytokine storm syndrome (CSS) is an accentuated immune response to triggers such as viral infections. Macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (sHLH) are two clinically similar CSSs. MAS is a CSS that is usually seen in the context of rheumatological diseases. HLH can be seen in patients with severe infection. It results from an excess of proinflammatory and inadequate anti-inflammatory stimuli. Some of the proinflammatory stimuli include foreign antigens, cytokines such as interleukin (IL)–1β, IL-2, IL-6, IL-7, IL-12, IL-18, tumor necrosis factor (TNF)–α, interferon (IFN)–γ, and granulocyte colony-stimulating factor (GCSF). Some of the anti-inflammatory stimuli include regulatory T cells, cytokines such as IL-10, transforming growth factor (TGF)–β, and IL-1ra.^[7]

Increased production of IFNγ by hematopoietic stem cells in response to viral infections is thought to trigger CSS. CSS is characterized by unremitting fever and multiorgan involvement, including acute respiratory distress syndrome (ARDS) and acute cardiac and renal injury. Laboratory abnormalities include cytopenias, increased ferritin, D-dimer, and increased serum levels of proinflammatory cytokines.

Evidence gathered to date shows that CSS is directly related to the severity of the disease process. Laboratory analysis of confirmed COVID-19 patients showed leukopenia and increased serum levels of proinflammatory cytokines such as IL-2, IL-6, IL-7, TNFα, IFNγ, and GCSF, similar to that observed in sHLH, suggesting a possible mechanism for tissue injury.^[8]

A retrospective multicenter study from Wuhan, China of COVID-19 patients showed statistically significant increased mortality in patients with elevated ferritin (>1200 ng/mL) and elevated IL-6 levels.^[9]

Data from China showed that about 80% of patients with COVID-19 had a mild infection. Among the remaining 20% of patients, a fraction of the patients developed severe disease with multiorgan failure necessitating ICU level of care. The pathogenesis behind this severe manifestation of disease appears to be related to overwhelming inflammatory response as seen in sHLH/CSS. The predilection to develop CSS is unclear and is thought to be related to host factors such as underlying immunodeficiency or genetic factors.

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