Cytokine Storm Syndrome: Causes, Diagnosis, and Treatment Advances

Jump To Section

• COVID-19 Cytokine Storm
• Inflammatory Markers and Diagnosis
• CAR T-Cell Therapy Link
• Interleukin-6 Targeted Treatment
• Other Cytokine Targets
• Pandemic Research Advances
• Full Transcript

COVID-19 Cytokine Storm

Dr. Randy Cron, MD, explains that the COVID-19 pandemic served a crucial role in raising awareness about cytokine storm syndrome. He notes that this increased recognition is vital for proper diagnosis and treatment. Dr. Randy Cron, MD, emphasizes that cytokine storm often leads to poor outcomes when undiagnosed.

The COVID-19 cytokine storm presents unique characteristics compared to other respiratory infections. Even severe influenza strains like H1N1 (swine flu) can trigger cytokine storms. However, Dr. Randy Cron, MD, describes the COVID-19 version as "relatively unique" in its presentation and laboratory findings.

Inflammatory Markers and Diagnosis

Ferritin serves as a sensitive and broad marker for cytokine storm syndrome. Dr. Randy Cron, MD, explains that elevated ferritin appears in almost every cytokine storm case. Typical cytokine storms show ferritin levels in the thousands, tens of thousands, or even hundreds of thousands.

COVID-19 patients with cytokine storm features typically show ferritin levels in the 1,000-3,000 range. Other important inflammatory markers include C-reactive protein (CRP) and interleukin-6. These laboratory findings help physicians diagnose and monitor cytokine storm syndrome severity.

CAR T-Cell Therapy Link

Dr. Randy Cron, MD, describes cytokine release syndrome as an iatrogenic problem originating from cancer treatments. This syndrome occurs in patients with refractory leukemias and lymphomas who have failed multiple chemotherapy protocols. CAR T-cell therapy represents a novel approach that saves lives but carries this significant risk.

Approximately 20-30% of patients receiving CAR T-cell therapy develop cytokine release syndrome. This connection provided crucial early insights into cytokine storm mechanisms. The research from oncology treatments informed early approaches to COVID-19 cytokine storm management.

Interleukin-6 Targeted Treatment

Interleukin-6 received early attention during the COVID-19 pandemic for several reasons. Chinese researchers could easily measure this pro-inflammatory cytokine compared to others like interleukin-1. China also had available reagents to block interleukin-6 signaling through monoclonal antibodies.

These drugs target the interleukin-6 receptor, preventing immune system signaling. The US FDA had already approved this approach for cytokine release syndrome in CAR T-cell therapy patients. Early COVID-19 studies involved case series rather than controlled trials, producing mixed results.

Meta-analyses of multiple studies suggest interleukin-6 blockade probably improved survival. However, Dr. Randy Cron, MD, notes the benefit appears less dramatic than in other cytokine storm syndromes. The unique nature of COVID-19 cytokine storm likely contributed to these variable outcomes.

Other Cytokine Targets

Researchers explored multiple cytokine targets beyond interleukin-6 during the pandemic. Interleukin-1 received some investigation, though less extensively than interleukin-6. Studies produced conflicting results regarding its effectiveness for COVID-19 cytokine storm.

Other investigated cytokines included GM-CSF (granulocyte-macrophage colony-stimulating factor). Various studies examined this target with similarly mixed results. Researchers also explored additional interesting cytokines as potential therapeutic targets.

Pandemic Research Advances

The global scale of the COVID-19 pandemic enabled unprecedented research into cytokine storms. Dr. Randy Cron, MD, emphasizes that worldwide studies provided massive data collection opportunities. Researchers conducted numerous trials exploring various therapeutic approaches.

This extensive research effort advanced understanding of cytokine storm syndromes broadly. The pandemic created opportunities for large randomized double-blinded placebo-controlled trials. These gold standard studies provided more reliable data than earlier observational reports.

Dr. Anton Titov, MD, facilitates this discussion by asking about changes in cytokine storm knowledge since the pandemic began. The conversation with Dr. Randy Cron, MD, highlights how COVID-19 accelerated cytokine storm research and clinical recognition.

Full Transcript

Dr. Anton Titov, MD: COVID-19 brings cytokine storm syndrome into common knowledge. What do we know about cytokine storm syndrome today that we did not know before the COVID-19 pandemic?

Dr. Randy Cron, MD: I think we briefly talked about this a couple of years ago. One of the silver linings for me with this pandemic is getting the concept of cytokine storm out there. If you're not aware of it, you're not going to diagnose it. If you don't diagnose and treat it, things often don't go well.

Because there were similar features with COVID infection and other cytokine storms, that umbrella term has captured COVID for the sickest of the sick—those hospitalized and often requiring intensive care.

But COVID is a pretty unique cytokine storm, even compared to other respiratory infections. For example, bad strains of influenza-like H1N1 can kill a lot of people and can have a cytokine storm associated with bad swine flu. But the COVID cytokine storm is relatively unique.

Markers of inflammation in the sickest of the sick—for example, ferritin—is a really sensitive, broad, all-encompassing marker that we can measure in the blood. We see it elevated in almost every cytokine storm.

In most typical cytokine storms, this is in the thousands, tens of thousands, even hundreds of thousands. For the most part, patients with severe COVID-19 who have features of a cytokine storm may be in the one to two to three thousand range. So even that in itself is kind of funny.

Other markers do go up, like C-reactive protein and interleukin-6. This is a protein that is a circulating inflammatory protein of the immune system that signals throughout immune system cells that have receptors for it.

Interleukin-6 got a lot of attention early on because in China, where cases were first reported, interleukin-6 is a relatively easy pro-inflammatory cytokine to measure compared to some others like interleukin-1, which are much more difficult to measure.

For whatever reason, in China they have reagents that can block interleukin-6 but don't for the most part have many available agents to block other pro-inflammatory cytokines, like interleukin-1 or IL-1.

We knew from a different type of cytokine storm called cytokine release syndrome, which is an iatrogenic problem. This occurs in patients with refractory leukemias and lymphomas—cancers of white blood cells that have gone through multiple chemotherapeutic protocols and the cancer keeps coming back.

There are some fabulous novel therapies now where they can give you modified T cells back. One type is called CAR T-cell therapy. It's great because it has saved lives of people who would otherwise die from these refractory leukemias.

However, when they first started using these therapies, about 20 to 30% of the patients got a cytokine storm labeled cytokine release syndrome. As part of that, interleukin-6 was very elevated.

They targeted that with monoclonal antibodies that bind the receptor for interleukin-6, which stops the signaling. That's actually US FDA-approved treatment for that now.

Early during the pandemic, because those drugs were available and they could measure interleukin-6, that was something tried early on. The early studies were more like case series—did this help 100 people or not—but they weren't well-controlled, randomized, double-blinded clinical trials.

We didn't have the time to do it initially. Unfortunately, this virus and its cytokine storm syndrome is relatively unique. So the data have been all over the map.

Drug therapies like blocking interleukin-6, either the cytokine itself or the receptor—some have shown benefit for some severe COVID patients, some have not.

When you do meta-analysis and gather all the data from randomized double-blinded placebo-controlled trials or large open-label studies where patients are randomized, it looks like if you receive those therapies, it probably did improve survival some, but not to the degree we've seen in other cytokine storm syndromes.

This pandemic has affected so many people worldwide that people have done study after study around the world to explore what can potentially help these individuals.

Interleukin-1 has been studied not nearly as much as interleukin-6, for example. Some studies have shown benefit, others have not.

People have looked at another cytokine called GM-CSF. Again, some have shown benefits, some have not. Other interesting cytokines have been explored as well.