Medical research ‘just starting to scratch the surface’ on cytokine storm syndrome
Fajgenbaum D. Cytokine storm: Where rheumatologists, oncologists, and ID meet. Presented at: Biologic Therapies Summit IX; May 21-23, 2021 (virtual meeting).
Fajgenbaum reports associations with Eusa Pharma and Pfizer.
While COVID-19 launched cytokine storm syndrome to the forefront of medical research, there is still much to be learned about these hyperactive immune events, according to a presenter at the Biologic Therapies Summit.
“A cytokine storm is an immune dysregulation 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 topic is personal to Fajgenbaum, who has battled cytokine storms due to idiopathic multicentric Castleman disease for much of his adult life. However, when the disease first onset, there was little understanding of this condition and no diagnostic criteria.
That collateral damage he described includes elevated circulating cytokine levels, acute systemic inflammatory symptoms and organ dysfunction secondary to inflammation beyond a normal immune response.
Regarding clinical manifestations of cytokine storm syndrome, Fajgenbaum stressed that these patients are at considerable risk. “At its heart it can affect every organ system within the body,” he said.
For clinicians who encounter a patient with this syndrome, the first step is to identify the underlying disorder and rule out mimickers, according to Fajgenbaum. Chimeric antigen receptor T-cell (CAR-T) therapy 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 establish severity. “What is the trajectory?” he said. “Some patients are critically ill and getting worse. Sometimes you have to act quickly.”
While a cytokine panel can be a “reasonable” tactic, the results may be less than informative, according to Fajgenbaum. “It is often hard to take actual steps around because not enough research has been done across cytokine disorders to know which drugs will be helpful,” he said.
That said, clinicians eventually identified interleukin-6 as a key driver of these events. “We have known for years that if you block IL-6, most patients get better,” Fajgenbaum said.
However, in patients who fail to respond to IL-6 inhibition, treatment paradigms remain unclear, according to Fajgenbaum.
Cytokine storm in COVID-19
All of this came to the forefront when many patients with the most critical cases of COVID-19 were experiencing a cytokine storm-like syndrome. “You need your immune response against the virus, you just don’t need too much of your immune response” he said. “You want the immune system to be tightly modulated.”
To achieve that modulation, clinicians initially reached for IL-6 inhibitor tocilizumab (Actemra, Genentech) as a treatment for the virus. It has been used with varying degrees of efficacy. While the role of tocilizumab in COVID-19, in the big picture, “remains unclear,” it does seem to benefit some of the sickest patients, according to Fajgenbaum.
The issue is that IL-6 is not the only cytokine elevated in these events. IL-1 and interferon-gamma are also most likely to be elevated. “This is important because we have drugs that block them,” Fajgenbaum said. “When you block them, patients get better.”
However, Fajgenbaum offered the important caveat that, in some cases, blocking the cytokine that is elevated may not be the optimal therapeutic approach.
With that in mind, clinicians should also pay attention to signaling pathways, including the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway.
For clinicians encountering cytokine storm-like events in COVID-19 patients, Fajgenbaum noted that cytokine levels may not be as elevated as they are in cytokine storms of other etiologies.
“The bottom line for COVID-19 is that I believe most severe cases are experiencing cytokine storm, but the majority of cases are not,” Fajgenbaum said.
He suggested that cytokine storm in COVID-19 can be put into “a fairly simple framework” to understand.
“You have virus, then you have the immune response,” he said. “The immune response can lead to symptoms.”
When the symptoms emerge, immunosuppressive therapies should be considered if it appears as though the immune response is overactive. However, if the immune response appears insufficient, boosting the immune response may also be considered, according to Fajgenbaum. “You can also replace aspects of the immune response with monoclonal antibodies,” he said.
As far as future directions for study of cytokine storm syndrome are concerned, Fajgenbaum urged investigation of the variety of underlying etiologies that drive these events. Exploratory modulation of the immune system may be a viable approach. “Limited data exist for what biomarkers will drive therapeutic approaches,” he said, and suggested that this should also be an area of research.
Overall, the rheumatology community still has a long way to go in understanding the cytokine storm. “We are just starting to scratch the surface,” he said.