Trending Clinical Topic: Cytokine Storm

Ryan Syrek


September 18, 2020

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Unexpected findings regarding an immune system overactivation known as a "cytokine storm" resulted in this week's top trending clinical topic. In contrast to some previous reports, a new study published in JAMA found that cytokine storm did not play a role in more severe COVID-19 outcomes in a small group of patients. Researchers compared cytokine levels in critically ill patients with COVID-19 with those in patients who had bacterial sepsis, trauma, or cardiac arrest. They found that the circulating cytokine concentrations were lower compared with those seen in patients with the other diseases (see Infographic below).

Exactly what constitutes a cytokine storm remains ill defined, according to many experts. In a discussion of immune responses to COVID-19, Akiko Iwasaki, PhD, told Eric J. Topol, MD, and Abraham Verghese, MD, that the typical cytokine storm previously reported in patients with COVID-19 includes interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF). In a study published in Nature , Iwasaki and colleagues found that cytokines belonging to type II and type III immune responses were also involved. As she explained to Topol and Verghese, "In severe cases, the immune system kind of looks confused and disoriented, generating all types of cytokines that are also causing some sort of storm. I think COVID disease may start with the typical cytokine storm but then extend to different types of tornados and hurricanes and all kinds of misdirected immune responses."

Although the JAMA study suggests that COVID-19 may not be characterized by cytokine storm, the small sample size and single-center study design are recognized as important limitations. A separate study published online in PNAS also found lower levels of certain cytokines in patients with COVID-19 compared with patients who had bacterial acute respiratory distress syndrome or sepsis. One of that study's authors, Tadamitsu Kishimoto, MD, PhD, suggested that the difference may be that SARS-CoV-2 directly infects and activates endothelial cells rather than macrophages, as occurs in sepsis. In responding to the JAMA findings, Kishimoto explained, "SARS-CoV-2 infection causes critical illness and severe dysfunction in respiratory organs and induces a cytokine storm," even in the setting of lower but still elevated serum IL-6 levels.

Although the exact nature of the cytokine response to COVID-19 is still under investigation, anticytokine therapies are currently being explored. Biovista, a company that has used artificial intelligence to find possible COVID-19 treatments, announced that it has identified the antifibrinolytic agent aprotinin and the angiotensin II receptor blocker irbesartan as potentially reducing the effects of cytokine storm. Elsewhere, an outpatient trial of fluvoxamine, routinely prescribed for depression, found that the drug may prevent an overactive immune response or cytokine storm.

Given the critical role of immune response in patients with COVID-19, further findings regarding mechanisms and potential treatments are likely to be met with the same degree of interest that made cytokine storm this week's top trending clinical topic.

Read a comprehensive roundup of clinical information about COVID-19.


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