Penn Medicine is leading the quest to understand and treat a deadly cytokine condition.

By Scott Harris

An image of a person in a white doctor’s coat holding an umbrella to protect themselves from a “storm” of red and blue cytokine molecules.

In the distance, the storm appears relatively benign: fatigue and abdominal pain. Then come the night sweats and fevers. As the storm gains strength, the pain and fatigue become unbearable. The lymph nodes enlarge. In its full fury, the storm wreaks havoc on everything it touches. 

It’s the chilling reality of a cytokine storm, the powerful and mysterious autoimmune condition with several known causes and precious few treatment options. In a functional immune system, the cytokine protein promotes healthy inflammation in response to infection, trauma, cancer, and similar problems in the body. But in a cytokine storm, also known as cytokine release syndrome, the body floods itself with an extreme amount of these molecules, leading to a wide range of symptoms, serious organ damage and, if left untreated, death. 

Once considered uncommon, cytokine storms gained new notoriety as a deadly complication of COVID-19. As a result, interest in cytokine storms has increased. Penn Medicine has emerged as a leader in cytokine storm research. 

“It feels like the worst flu you’ve ever had, and on top of that, your organs start to shut down,” said David Fajgenbaum, MD’13, MBA’15, MSc, a nationally renowned cytokine storm researcher and an assistant professor of Translational Medicine and Human Genetics at the Perelman School of Medicine at the University of Pennsylvania. “Your liver, kidneys, heart, and lungs all can shut down, because your immune system is out of control. You either die or you hit the immune system with the right drug at the right time to stop it. Relatively speaking, we really don’t know very much about them.” 

Fajgenbaum knows of what he speaks. In 2010, he was diagnosed with idiopathic multicentric Castleman disease, a rare affliction that causes cytokine storms. Fajgenbaum has been admitted to the ICU five times for the condition.

Breakthrough discoveries from Penn Medicine have advanced scientific and clinical knowledge of cytokine storms. Most recently, a study led by Fajgenbaum and published in Nature Communications revealed that a protein called CXCL13 could serve as a biomarker to help better predict a patient’s response — or dangerous lack thereof — to siltuximab, one of the few Castleman treatments on the market today. 

David Fajgenbaum sits at his desk and stares at a computer screen with the city skyline in the window behind him

“I hope this research helps clinicians treat patients like me more effectively,” Fajgenbaum said. “This test could lead to more effective treatment approaches. We’re helping improve the speed and accuracy of diagnosis and uncover new treatment approaches that save lives.”

Penn Medicine’s history with cytokine storm research traces back more than a decade. In 2012, a cytokine storm nearly killed 6-year-old Emily Whitehead, the first pediatric participant in a trial investigating CAR T-cell therapy developed at Penn Medicine and Children’s Hospital of Philadelphia. It was thanks to quick thinking by CAR-T pioneer Carl June, MD, that doctors saved her life using the arthritis drug tocilizumab. That drug was subsequently approved by the U.S. Food and Drug Administration for treating cytokine storms in people undergoing CAR T-cell therapy, along with the landmark approval of the CAR-T therapy itself, in 2017. 

Fast forward to the COVID-19 pandemic, when many infected patients experienced cytokine storms to devastating effects. Fajgenbaum and June developed a unifying definition of cytokine storm to guide clinicians, published in the New England Journal of Medicine in December 2020. A 2022 literature review in the journal Virology concluded that cytokine storms are “one of the possible events for the progressive and severe forms of COVID-19 and its mortality,” and that “management of the cytokine release syndrome…may be an intriguing approach for COVID-19 therapy.” 

This is a driving factor behind the work underway at Penn’s Center for Cytokine Storm Treatment and Laboratory, which Fajgenbaum founded. Fajgenbaum also founded the Castleman Disease Collaborative Network, which connects thousands of Castleman clinicians, researchers, and patients around the country. 

The next big goal of Penn Medicine’s cytokine storm research: more diagnostics advances. The ultimate objective is safe harbor for everyone at risk.  

“We need to implement the biomarker test to inform personalized treatment of patients,” Fajgenbaum said. “We have a lot more work to do.”

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