Cytokine release syndrome in severe COVID-19

21 Apr, 2020

SARS-CoV-2 is a betacoronavirus that is most closely related to SARS-CoV. Both viruses use the angiotensin-converting enzyme–related carboxypeptidase (ACE2) receptor to gain entry to cells. This receptor is widely expressed in cardiopulmonary tissues but also in some hematopoietic cells, including monocytes and macrophages. A key feature of COVID-19 infection is lymphopenia (low blood lymphocyte count), which correlates with clinical severity. SARS-CoV efficiently infects primary human monocytes and dendritic cells, whereas MERS-CoV infects monocytes and T cells via dipeptidyl peptidase 4 (DPP4). It is possible that SARS-CoV-2 also infects dendritic cells. T cell apoptosis and exhaustion resulting from defective activation due to dendritic cell dysfunction might contribute to the immunopathology of COVID-19. However, lymphopenia as a biomarker of poor prognosis for COVID-19 is not specific because it was also a biomarker that correlated with fatality in the 2009 influenza A (H1N1) pandemic.

CRS was found to be the major cause of morbidity in patients infected with SARS-CoV and MERS-CoV. Elevated serum concentrations of the cytokine interleukin-6 (IL-6) and other inflammatory cytokines are hallmarks of severe MERS-CoV infections. CRS is common in patients with COVID-19, and elevated serum IL-6 correlates with respiratory failure, ARDS, and adverse clinical outcomes. Elevated serum C-reactive protein (CRP), a protein whose expression is driven by IL-6, is also a biomarker of severe betacoronavirus infection.

There are a number of caveats to consider, given the global urgency of mitigating the COVID-19 pandemic. In sepsis-associated ARDS, corticosteroids are often administered. However, corticosteroid use in SARS and MERS patients did not improve mortality and resulted in delayed viral clearance. As a result, the expert consensus from infectious disease authorities and the WHO is to avoid systemic corticosteroids in COVID-19 patients at present. A theoretical possibility is that the suppression of inflammation by IL-6 antagonism might delay viral clearance. However, IL-6 blockade also results in rapid reduction of serum IL-10, an immunosuppressive cytokine secreted by macrophages, which may mitigate concerns about prolonging viral clearance.Moreover, one or two doses of an IL-6 antagonist are unlikely to result in complications, such as fungal infections or osteonecrosis of the jaw, which occur in patients dosed monthly on these drugs for chronic conditions such as rheumatoid arthritis. It is notable that tocilizumab was first approved for rheumatic conditions, then for CRS in patients receiving CAR T cell therapy, and is now being further repurposed for the COVID-19 pandemic. It is possible that IL-6 directed therapies will be used in future pandemics involving other viruses such as influenza and Ebola.


On the right, you can visualize a schematic of the pathways leading to cytokine release syndrome, extracted from the original article.