dcyphr | Cytokine release syndrome in severe COVID-19



    Severe acute respiratory syndrome-coronavirus-2 SARS-CoV-2 was declared to have emerged from Wuhan china in December 2019. SARS-CoV-2 is the third coronavirus to have caused respiratory illness in humans. Coronavirus disease 2019 (COVID-19) was recognized as a global pandemic in March 2020 and has had an deleterious effect on the economy and global health. 20% of COVID-19 cases experience pneumonia and fever which cause acute respiratory distress syndrome (ARDS). This is similar to the cytokine release syndrome (CRS) that induced (ARDS) and secondary hemophagocytic lymphocytosis (sHLH) that was observed in SARS-Cov, MERS-CoV, and leukemia patients receiving engineering T-Cells. These past experiences have shown that treatment of inflammation is important in reduction and infection severity. Thus, mediations like tocilizumab have become of recent importance. 

    SARS-CoV-2 is a betacoronavirus that is most closely related to SARS-Cov. Both viruses use angiotensin-converting enzyme-related carboxypeptidase (ACE2) receptor to gain entry into the cell. This receptor is mainly produced in the cardiopulmonary tissues and hematopoietic cells such as monocytes and macrophages. Low white blood cell count correlates with SARS-CoV-2 infection severity. However, low white blood cell counts are not unique to COVID-19 as it was seen with H1N1 infection. 

    Cytokine release syndrome (CRS) was a major cause of death in the SARS-CoV and MERS-CoV infections. Elevated levels of proinflammatory marker cytokine interleukin-6 (IL-6) and other biomarkers are indicative of severe MERS-CoV infections. Similarly, (CRS) is common in patients with COVID-19 infection. Higher levels of (IL-6) are associated with the development of acute respiratory distress failure (ARDS) and poor clinical outcomes. (IL-6) promotes the production of the protein C-reactive protein (CRP) which is a marker of severe betacoronavirus infection. 

    Infection of the body's monocytes, macrophages, and dendritic cells will result in activation. This will cause a secretion in (IL-6) and other inflammatory cytokines. (IL-6) can signal through two main pathways cis and trans.

CIS signaling pathway 

 In cis signaling (IL-6) will bind to membrane-bound (IL-6) receptor (mIL-6R) in a complex with gp130. Later the signaling pathway is mediated by JAKs (Janus kinases) and STAT3 (signal transducer and activator of transcription 3). The membrane bound gp130 receptor is produced throughout the body, but mIL-6R is restricted to immune cells. This activation of the cis pathway results an activation of the adaptive immune system (T and B cells) and the innate immune system (Neutrophils, macrophages, and natural killer [NK] cells). The activation of these pathways will result in CRS. 

Trans signaling pathway 

In trans signaling high levels of plasma IL-6 will bind to the soluble form of IL-6R (sIL-6R). This will form a complex with gp130 on potentially all cellular surfaces as gp130 is expressed everywhere. This results in a IL-6-sIL-6R-JAK-STAT3 complex that will activate downstream signaling in cells that do not express the mIL-6R receptor, specifically endothelial cells. This will result in a systematic “cytokine storm” from the resultant secretions of the endothelial cells. These activated cells secrete vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1),  IL-8, and additional IL-6, and reduced E-cadherin expression on endothelial cells. VEGF and reduced E-cadherin work in conjunction to contribute to vascular permeability and leakage. This participates in hypotension and the pulmonary issues seen in acute respiratory distress failure (ARDS). 

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a hyper inflammatory condition marked by CRS, low blood cell count, and multiorgan failure. This can be seen in leukemia patients receiving T-cell treatments or those with multiple viral infections. Similarly, higher levels of cytokines and ferritin are notable biomarkers. Cells that express CD163 are important as a source of ferritin. Therefore (sHLH) is also known as macrophage activation. Higher levels of ferritin and IL-6 was associated with patient death. 

    Patients receiving chimeric antigen receptor (CAR) T cell therapy can develop CRS and sHLH. The first patient to receive engineered T-cells to treat leukemia resulted in extreme inflammation in the form of developing CRS and sHLH. This led to ARDS with accompanied multiorgan failure and hypotension. There were incredibly high levels of IL-6 present so the researchers treated this patient with tocilizumab, and IL-6 antagonist. At the time it was used to treat rheumatic conditions. The patients recovered rapidly. 

    The efficacy of IL-6-IL-6R antagonists for CRS and sHLH treatment shows the role of IL-6 signaling in hyperinflammatory conditions. Therefore severe conditions of COVID-19 may benefit from IL-6 pathway dependent inhibition. A Chinese study of 21 patients using tocilizumab shows that fever reduced within the first day and the oxygen requirements of the patients decreased in 75% of participants. Early tests are promising, but additional research must be done on IL-6 or IL-6R antagonists. IL-6 inhibitors prevent both cis and trans pathways. However, IL-6R inhibitors prevent cis, trans, and trans presentation pathways. 

    Recently corticosteroids were used for SARS and MARS patients to reduce systemic inflammation. However, it resulted in delayed clearance of the virus and thus the WHO advises to avoid using corticosteroids on COVID-19 patients currently. Long term treatments of IL-6 inhibitors result in complications, but one or two doses are unlikely to cause issues. It is possible that IL-6 therapies could be used in future pandemics.