New study explores the role of the immune response in severe COVID-19 and whether immunotherapy might be used to treat COVID-19 patients.
The body’s immune response is largely controlled by signalling molecules known as cytokines. In the presence of an infection, pro-inflammatory cytokines encourage the accumulation of defensive cells at the site of infection. This can often lead to inflammation at the infection site. However, in some disease states, including COVID-19, the immune response generated becomes too great. A condition known as cytokine release syndrome (CRS) has been documented in many COVID-19 patients but also in other disease states such as sepsis. In this scenario, extremely high levels of cytokines have led to a hyperimmune response. This response can be extremely damaging, in some cases leading to coagulation problems, leakage of vascular fluid, and even death.
Finding an effective therapy for tackling CRS could greatly improve patient outcomes in a variety of disease, including some of the more severe COVID-19 patients. A new study published by the Proceeding of the National Academy of Sciences examines in detail the mechanisms by which CRS occurs and causes harm (1). It also explores the impact of tocilizumab, an immunotherapy drug, on CRS, and potentially to treat COVID-19.
The study recruited patients from a variety of disease states (sepsis, acute respiratory distress syndrome and burns) as well as healthy control patients. Apart from the healthy controls, all patients had been diagnosed with CRS. The research team collected and analysed serum samples from all participants. They discovered a number of interesting CRS features across the different disease states. Cytokines in general were elevated in all patients, but the specific cytokines varied slightly between the disease states. However, certain cytokines such as IL-6, IL-8 and IL-10 were elevated in all CRS patients. Furthermore, levels of a particular protein called plasminogen activator inhibitor (PAI-1) corresponded to the clinical severity of systemic inflammation. Elevated levels of PAI-1 have previously been found in numerous disease states and are known to increase the risk of blood clot formation. PAI-1 was found to be elevating in CRS but in patients with chronic auto-inflammatory disorders such as rheumatoid arthritis. As a result, PAI-1 could represent a useful and selective marker of CRS progression.
Similarly, serum levels of IL-6 in CRS patients were positively correlated with a number of other cytokines (and also PAI-1), meaning as IL-6 levels increase, so too do levels of these other molecules. A further experiment revealed that IL-6 does in fact increase levels of PAI-1, but only in the presence of a protein known as soluble IL-6 receptor (sIL-6R), a process known as trans-signalling. This finding suggests that IL-6, through the trans-signalling process, forms an inflammatory circuit in endothelial cells. In this circuit, elevated levels of IL-6 (due to infection/sepsis etc.) leads to the production of PAI-1 in the endothelial cells which line the inside of blood vessels. In turn, this causes inflammation in these cells producing more IL-6.
As a result, IL-6 represents a promising target for therapy in CRS. The researchers explored the effects of using an IL-6 receptor inhibiting drug called tocilizumab. Seven patients with severe COVID-19 infections were recruited and each received tocilizumab injections. All seven patients made significant improvements after receiving the injection. Furthermore, tocilizumab was shown to reduce levels of PAI-1 in these patients as well as reducing levels of IL-10.
The findings of this study are of immediate relevance as they suggest that PAI-1 may be responsible for the coagulation complications observed in many COVID-19 patients. It suggests that elevated PAI-1 is caused by the IL-6 cytokine and that blocking the action of IL-6 through the use of tocilizumab immunotherapy may be of clinical benefit to treat COVID-19.
It should be noted that the study is relying on a very small sample size and although it demonstrates a link between IL-6 and PAI-1 it fails to explain this link. Further research is needed to explore and replicate the findings of this study.
Written by Michael McCarthy
1. Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y, et al. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proceedings of the National Academy of Sciences. 2020:202010229.
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