What Is A Cytokine Storm?

The news cycle is heavily saturated with information about COVID-19 and its variants, but one of the most worrying aspects so far has been the huge disparity in the way the virus presents itself: Why do some people have no symptoms (or only mild ones), while others are so sick they become hospitalized and may require ventilation?

The Centers for Disease Control and Prevention (CDC) continues to study and learn more about the underlying conditions that are associated with severe illness from COVID-19. While there isn't a definitive answer, having a serious medical condition has been associated with more severe COVID-19 outcomes.

Lack of oxygen in the blood and systemic inflammation may lead to high levels of cytokines—or cytokine storm syndrome (known more broadly as a cytokine storm). Although no one knows for sure how many COVID-19 patients are becoming very ill as a result of the cytokine storm from an escalated immune response, it's reasonable to assume that the condition is responsible for at least some of the COVID-19-related fatalities we've seen. Here's everything you need to know.

What Is a Cytokine Storm?

Whenever a healthy body is fighting an infection, there's a natural immune system response that occurs. According to Carl Fichtenbaum, MD, professor in the division of infectious diseases at the University of Cincinnati College of Medicine, part of this response involves releasing cytokines, biological chemicals that stimulate cell pathways and allow for communication between cells. These cytokines, according to the American Cancer Society, essentially signal the immune system to start doing its job.

Again, that's normal—unless this outpouring of cytokines suddenly becomes accelerated. "Normally, cytokines are meant to be helpful to us in moderation," explained Dr. Fichtenbaum, "but when a certain pathway is engaged [too much] the immune system starts causing damage to the patient."

Dr. Fichtenbaum said that "when most people hear the term 'storm,' they think of a raining downpour, but that's not the most accurate way to explain a cytokine storm."

Clinically speaking, a cytokine storm means a cell pathway has been turned on, leading to the production of a number of biological mediators (which are kind of like signal transmitters) that cause changes to the body and interfere with normal cell function. Commonly, this means an excessive number of cytokines are released, which create high levels of inflammation in the area of the body being flooded—so much inflammation, even, that it can be fatal.

"Imagine that you put your foot on the accelerator and it gets glued to it," Dr. Fichtenbaum said. "You can't get your foot off the gas to slow down your car." Essentially, these storms can be more deadly than the original virus the body is fighting.

Do These Storms Occur in Patients With COVID-19?

Yes, and clinicians aren't surprised: Cytokine storms can be instigated by a number of infections, including influenza, pneumonia, and sepsis. This heightened immune response doesn't happen in all patients with severe infections, but according to a 2021 article in Clinical Microbiology Review, most critically ill COVID-19 patients had a preexisting condition, such as high blood pressure, diabetes, heart disease, or respiratory disease—conditions that are known to disturb the levels of cytokines.

This means that some patients get very sick, very quickly.

"We're seeing people across the course of this illness respond in a hyper-inflammatory way," said Deepa Gotur, MD, a critical care physician at Houston Methodist Hospital. "It's a cascade of cytokines affecting the patient's lungs, heart, kidneys. The extent [to which their bodies are overreacting] is similar to how cancer patients respond to infection."

"Most of the COVID-19 patients experiencing cytokine storms are presenting with fevers and shortness of breath, then having so much difficulty breathing they eventually require ventilation," said Dr. Gotur. This typically occurs about six or seven days after the onset of illness.

How Are Cytokine Storms Detected and Treated?

There's no way to test whether or not someone is experiencing a cytokine storm, though bloodwork may give clinicians clues that a hyper-inflammatory response is happening. "Some clinicians and investigators have been suggesting that we do certain blood tests upon hospital admission for warning signs that this might be an impending problem, but that's a theoretical idea that hasn't been proven," explained Dr. Fichtenbaum.

Otherwise, doctors are looking at how individual patients are presenting, such as if they are continuing to have breathing difficulty despite receiving oxygen. That might mean their bodies are being flooded with cytokines. There may also be biomarkers that doctors can test for to indicate the potential for a cytokine storm.

As far as treatment, there are several interventions, like ventilator intubation and extracorporeal membrane oxygenation (ECMO). Doctors are also paying close attention to how patients are responding to some of the treatments being used, like antibody plasma infusions, protein binding medications, and stem cell therapies.

Dr. Fichtenbaum said "some clinicians may be using a medication that blocks interleukin-6 (IL-6), one of the key biological mediators responsible for cytokine storms." However, the National Institutes of Health (NIH) recommends against using this therapy and it is not a well-studied treatment.

What Are the Outcomes for Patients Who Experience a Cytokine Storm?

There isn't much data available on how many patients recover from cytokine storms, especially ones caused by COVID-19, though Dr. Fichtenbaum said "the fatality rate is higher for patients who experience this heightened inflammatory response."

What's more, Dr. Gotur said that "since many people are already experiencing a storm by the time they get to a hospital, it's often difficult to avoid serious interventions like life support and ECMO."

Dr. Gotur's team has been working hard to prevent patients from ever reaching the storm phase. At Houston Methodist, clinicians have mobilized to determine how to treat every patient in every stage of the disease, using all their resources—from experimental medications to oxygen treatments—in hopes of avoiding the kind of hyper-inflammatory response that requires more serious interventions or, ultimately, can lead to fatalities.

"We quickly realized we needed to start utilizing our resources earlier to prevent patients from being intubated or going on life support," Dr. Gotur said. "Our mortality is low because we have a set algorithm and approach for every stage of this disease process. We have instances where we feel we have prevented the patient from needing a ventilator or ECMO support."

Moving forward, Dr. Fichtenbaum said it will be important for experts to perform controlled studies to answer a few key questions if we want to have better outcomes for patients regarding cytokine storms:

• Who is at most risk, and is there a way we can predict a storm before it happens?
• Can preemptive strategies and therapies be successful?
• Once a storm happens, can we treat it effectively with mediator blockers or other medications that interfere with the cytokine storm pathway?

We don't have that research, but clinical trials are ongoing in the midst of the pandemic, with clinicians tracking and reporting on all of the medications, therapies, and strategies they're using to treat COVID-19 patients. With more answers, we could hopefully see more patient recoveries and success stories, too.

The information in this story is accurate as of press time. However, as the situation surrounding COVID-19 continues to evolve, it's possible that some data have changed since publication. While Health is trying to keep our stories as up-to-date as possible, we also encourage readers to stay informed on news and recommendations for their own communities by using the CDC, WHO, and their local public health department as resources.