Multidisciplinary Team Studies Cytokine Storms Brewing in COVID-19

Cytokine storms occur when the immune system, typically the body’s first responders, flares out of control.

By Jillian Rose Lim

A healthy immune system works as our body’s best first responders, rallying to keep potential infections and invaders at bay when it senses we’re sick, injured, or exposed to something harmful. For a subgroup of patients with severe cases of COVID-19, however, this carefully coordinated response appears to go haywire. Confused about which cells in the body to protect and which to attack, the immune system flares out of control, resulting in hyperinflammation, organ failure, and sometimes, death.

Ed Behrens, MD, has been studying this overzealous immune reaction, known as a cytokine storm, for the majority of his research career. As chief of the Division of Rheumatology at Children’s Hospital of Philadelphia, Dr. Behrens treats and investigates a variety of conditions that cause cytokine storms, from autoimmune diseases to genetic disorders. Now, alongside a multidisciplinary team within the Immune Dysregulation Frontier Program at CHOP, he’s working hard to understand the role cytokine storms play in COVID-19 and effective ways to treat the life-threatening reaction.

“A cytokine ‘storm’ implies the force of a hurricane or a tornado, or some type of extreme outpouring of immune activity, such that a number of organs in the body are failing all at the same time because the immune system is confused,” Dr. Behrens, who is also faculty in the Perelman School of Medicine at the University of Pennsylvania, said.

By collecting biospecimens from pediatric patients who tested positive for COVID-19, he hopes to learn more about how cytokine storms contribute to outcomes and answer a number of key questions: Why do some patients’ immune systems respond differently than others? How is the immune system responding in severe cases of COVID-19? Why do adult cases often appear more serious than children? The answers could yield significant clinical impact for both children and adults infected with the virus, according to Dr. Behrens.

“If we can understand what's uniquely happening in children’s immune systems and how they respond to COVID-19, then maybe we can figure out why adults getting so sick,” Dr. Behrens said.

Cytokine Storms in COVID-19: How Does it Work?

Dr. Behrens describes cytokines as a kind of “communicator” molecule produced by the immune system. In healthy individuals, a controlled number of cytokines populate the immune system and send messages between cells that instruct them how to act. But in patients who experience cytokine storms, this number of cytokines becomes elevated. With so many communicators speaking at once, the immune system turns to confusion and chaos, much like a military command gone amiss.

“If you had one general commanding you to go here and do this, the army knows what to do,” Dr. Behrens said. “But if you have a thousand generals all screaming at the same time, the immune system doesn't know what to do. And so, everybody just runs around crazy, doing damage without a lot of organization and direction.”

In the body, this can lead to rogue cytokines wreaking havoc on a patient’s tissues and organs, often causing life-threatening damage.

But what triggers a cytokine storm to begin with? Dr. Behrens said the reasons differ depending on various diseases or conditions. In hemophagocytic lymphohistiocytosis (HLH), for example, genetic mutations can spur cytokine storms. But certain viral infections and pathogens can cause a cytokine storm to brew, too, and this is an area that he and other members of the Frontier program were already discussing as early as last year.

“A lot of us think about Ebola or dengue being cytokine storm syndromes,” Dr. Behrens said. “Right now, there’s a lot of people who believe COVID-19 is another kind of virus that causes a cytokine storm, and that’s why people are getting so ill as opposed to the common cold. What makes you so sick with COVID-19 is perhaps in part the virus, but also in part your immune system’s response to the virus – a response that’s overactive and not productive.”

Pathways of Discovery

To understand why, and in which patients, such a reaction occurs, Dr. Behrens and colleagues in the Frontier Program moved quickly to put together an IRB-approved study where they could analyze biospecimen samples from COVID-19 cases at CHOP. Members of the Frontier program span multiple departments including oncology, immunology, intensive care, and hematology, and together, the team will use these samples to examine cytokine storms in cases of COVID-19 from nearly every angle.

“We're going to completely characterize the immune landscape of children infected with COVID-19 to understand what it is their immune systems are doing,” Dr. Behrens said. “So, we’ll look at the kind of antibody response children make. We’ll look at the cytokines they produce. And we’ll conduct tests that allow us to look at what each individual cell in the blood is doing at any moment in time.”

On top of that, the team will study each patients’ genetics to learn whether certain genetic predispositions can make a patient either more resistant or susceptible to COVID-19.

“By looking at all these things, we’re asking, ‘Can we learn something new about what makes people sick that can lead us to better therapies, earlier diagnosis, and new treatments to prevent or reverse COVID- 19 when it occurs?” Dr. Behrens said.

Studying COVID-19 in children will address questions such as why children who get infected don’t get the serious pulmonary syndrome that contributes to deaths in adults, and why some children do in fact get seriously ill, but others don’t.

Though collection of the samples and lab research is ongoing, Dr. Behrens and the Frontier team are already using their combined expertise and experience in cytokine storms and immune dysregulation to help guide current clinical cases in real time. One of the things Dr. Behrens may look out for, for example, are elevated levels of a certain cytokine called interleukin-6 (IL-6).

COVID-19 patients show moderately high levels of IL-6, similar to those with cytokine release syndrome (CRS). CRS is a type of cytokine storm commonly observed in patients who receive CAR T-cell (CAR-T) immunotherapy. These patients often experience severe pneumonia or acute respiratory distress syndrome. Since physician-researchers at CHOP have successfully treated pediatric patients who develop CRS after immunotherapy with a drug that blocks IL-6, Dr. Behrens speculates such a drug may help COVID-19 patients with higher amounts of IL-6 cytokines as well. Thus, he works alongside David Teachey, MD, his co-leader in the Immune Dysregulation Frontier Program, who led studies on IL-6 in acute lymphoblastic leukemia.

"CHOP and the University of Pennsylvania pioneered the concept of blocking IL6 to treat patients who became critically ill after CAR T-cell therapy,” Dr. Teachey, who is also a physician in the Cancer Center and faculty in the Perelman School of Medicine at Penn, said. “This work led to the FDA approval of tocilizumab for cytokine release syndrome after CAR-T. We hope that we will find cytokine blockers, including tocilizumab, will help other children who develop cytokine storm in other situations, such as COVID-19. We believe our unique multidisciplinary approach in will improve our chance of making a significant impact."

On top of that, the team has also developed a rapid cytokine assay that can measure the number and type of cytokines in a patient’s system and produce results in less than a day. Such an assay can help guide the kind of treatment decisions a clinician makes. For example, if a patient shows elevated levels of IL-6, a clinician may be inclined to administer a treatment that blocks that cytokine type.

“The idea would be is that we're delivering precision therapy to the patient,” Dr. Behrens said. “We’re only giving them a drug that blocks what is elevated.”

Much more exciting findings are to come, but for now, Dr. Behrens said the team is balancing their ability to provide guidance for current COVID-19 patients with thorough research and science.

“We’re trying to help [patients] in the moment as best we can, using the latest technology to figure out what's going on with their immune systems so we can help guide clinical decision,” Dr. Behrens said. “But good science still takes time. It’s to be done carefully, and not rushed.”