Severe Covid-19 is associated with a high inflammatory state similar to that seen in cytokine release syndrome (CRS) in adults with secondary hemophagocytic lymphohistiocytosis (sHLH) which is often due to viral infections.1,2
sHLH is characterized by unremitting fever, pulmonary involvement (including ARDS), pancytopenias, and high serum levels of ferritin, C-reactive protein (CRP) and many inflammatory cytokines, such as Interleukin (IL)-6. These features are also often seen in severe Covid-19 disease. In fact, elevated serum IL-6 has been shown to be associated with respiratory failure, ARDS, adverse clinical outcomes, and death in Covid-19.1,2
Why CRS in Covid-19? It all begins with SARS-CoV2 activation of monocytes, macrophages and dendritic cells leading to IL-6 release. IL-6 in turn activates B and T lymphocytes as well as the innate immune system. In addition, IL-6 has a profound effect on endothelial cells resulting in vascular permeability, neutrophil recruitment and further increase in IL-6 production, setting the stage for a “perfect cytokine storm.” IL-6 also induces the liver to synthesize CRP and ferritin.
The importance of IL-6 in severe Covid-19 is further highlighted by the excitement surrounding drugs that block its action, potentially improving morbidity and mortality in this disease. Tocilizumab, a monoclonal antibody against IL-6 receptor used in the treatment of certain rheumatological diseases and CRS in CAR T cell therapy, looks promising.3
Bonus Pearl: Did you know that IL-6 was formally called B-cell stimulatory factor-2 because it induced B cells to produce immunoglobulins?
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- Moore JB, June CH. Cytokine release syndrome in severe Covid-19. Science 2020;368:473-4. doi:10.1126/science.abb8925
- Mehta P, McAuley DF, Brown M, et al. Covid-19:consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext
- Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19. J Transl Med 2020;18:164. https://translational-medicine.biomedcentral.com/track/pdf/10.1186/s12967-020-02339-3
- Kishimoto T. IL-6: From its discovery to clinical applications. Int Immunol 2010;22:347-52. https://pubmed.ncbi.nlm.nih.gov/20410258/
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