Infectious Disease

Medical research on cytokine storm syndrome “is just beginning to scratch the surface”

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Fajgenbaum D. Cytokine Sturm: Where rheumatologists, oncologists and ID meet. Presented at: Biologic Therapies Summit IX; 21.-23. May 2021 (virtual meeting).

Disclosure:
Fajgenbaum reports on associations with Eusa Pharma and Pfizer.

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While COVID-19 brought cytokine storm syndrome to the forefront of medical research, there is still a lot to learn about these hyperactive immune events, according to a speaker at the Biologic Therapies Summit.

“A cytokine storm is an immune deficiency that causes collateral damage.” David Fajgenbaum, MD, MBA, MSc, Assistant Professor at the Perelman School of Medicine at the University of Pennsylvania said in his presentation.

“The bottom line of COVID-19 is that I believe the most severe cases will have a cytokine storm, but most cases won’t,” David Fajgenbaum, MD, MBA, MSC, told attendees. Source: Adobe Stock

The topic is personal for Fajgenbaum, who has battled cytokine storms due to idiopathic multicenter Castleman’s disease for much of his adult life. However, when the disease first appeared, there was little understanding of the condition and no diagnostic criteria.

The collateral damage he describes includes increased circulating cytokine levels, acute systemic symptoms of inflammation, and organ dysfunction as a result of inflammation that goes beyond a normal immune response.

Regarding clinical manifestations of cytokine storm syndrome, Fajgenbaum emphasized that these patients are at significant risk. “In the heart, it can affect every organ system in the body,” he said.

early detection

For clinicians who come across a patient with this syndrome, the first step, according to Fajgenbaum, is to identify the underlying disorder and rule out imitators. Therapy with chimeric antigen receptor T cells (CAR-T) can lead to a cytokine storm, as can hemophagocytic lymphohistiocytosis (HLH) and certain malignancies. “You can have cytokine storm and sepsis,” he added.

The next step is to set the severity level. “What’s the trajectory?” he said. “Some patients are seriously ill and keep getting worse. Sometimes you have to act quickly. “

While a cytokine panel can be a “sensible” tactic, the results may be less informative, according to Fajgenbaum. “It is often difficult to take actual steps because enough cytokine-disorder research has not been done to know which drugs will help,” he said.

Doctors eventually identified interleukin-6 as the main driver of these events. “We have known for years that most patients get better when you block IL-6,” said Fajgenbaum.

In patients who do not respond to IL-6 inhibition, however, the treatment paradigms remain unclear, according to Fajgenbaum.

Cytokine storm in COVID-19

All of this came to the fore when many patients with the most critical cases of COVID-19 suffered from cytokine storm-like syndrome. “You need your immune response to the virus, you just don’t need too much of your immune response,” he said. “They want the immune system to be heavily modulated.”

To achieve this modulation, doctors first resorted to the IL-6 inhibitor tocilizumab (Actemra, Genentech) to treat the virus. It has been used with varying degrees of efficiency. While the role of tocilizumab in COVID-19 by and large “remains unclear,” it appears to benefit some of the sickest patients, according to Fajgenbaum.

The problem is that IL-6 isn’t the only cytokine that is elevated during these events. IL-1 and interferon gamma are also most likely to be elevated. “That’s important because we have drugs that block them,” said Fajgenbaum. “If you block them, the patients will get better.”

However, Fajgenbaum offered the important caveat that in some cases blocking the elevated cytokine may not be the optimal therapeutic approach.

With this in mind, clinicians should also watch out for signaling pathways, including the Janus Kinase (JAK) transducer and Activator of Transcription (STAT).

For clinicians who encounter cytokine storm-like events in COVID-19 patients, Fajgenbaum noted that cytokine levels may not be as high as with cytokine storms from other causes.

“The bottom line of COVID-19 is that I believe the most severe cases will have a cytokine storm, but most of the cases will not,” said Fajgenbaum.

He suggested that the cytokine storm in COVID-19 can be put into “pretty simple framework” to understand.

“You have the virus, then you have the immune response,” he said. “The immune response can lead to symptoms.”

If symptoms appear, immunosuppressive therapy should be considered if the immune response appears to be overactive. However, if the immune response appears to be inadequate, a strengthening of the immune response can also be considered, according to Fajgenbaum. “You can also replace aspects of the immune response with monoclonal antibodies,” he said.

Regarding future directions for studying cytokine storm syndrome, Fajgenbaum urged exploration of the variety of underlying etiologies that drive these events. Exploratory modulation of the immune system can be a viable approach. “There is limited data on what biomarkers will drive therapeutic approaches,” he said, suggesting that this should be an area of ​​research as well.

Overall, rheumatology still has a long way to go to understand the cytokine storm. “We’re just starting to scratch the surface,” he said.

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