Diagnosing and Managing Cytokine Storm Syndrome in Hospitalized Patients

Jump To Section

• Cytokine Storm Diagnostic Challenge
• Occam's Razor Limitations
• Common Triggers and Conditions
• Ferritin Testing and Screening
• Early Identification and Treatment
• Full Transcript

Cytokine Storm Diagnostic Challenge

Dr. Randy Cron, MD, addresses the significant risk of cytokine storm syndromes like macrophage activation syndrome in hospitalized febrile patients. He notes that these dangerous hyperinflammatory states often go unrecognized. This lack of recognition is a major problem because cytokine storms can complicate a patient's primary diagnosis. Dr. Randy Cron, MD, explains that a cytokine storm is not a standalone diagnosis but a severe complication that makes patients much sicker.

Occam's Razor Limitations

Dr. Randy Cron, MD, discusses the principle of Occam's razor in medical diagnosis. This principle suggests finding one diagnosis to explain all of a patient's symptoms. However, Dr. Randy Cron, MD, highlights a critical exception with cytokine storms. He states, "With cytokine storms, it's really the opposite." A patient can have a primary condition like sepsis and then develop a secondary cytokine storm syndrome. This complexity means physicians must think beyond a single unifying diagnosis in critically ill patients.

Common Triggers and Conditions

Dr. Cron details the wide array of conditions that can trigger a cytokine storm. Infections are very common triggers, particularly from intracellular pathogens like viruses. The herpes virus family, including Epstein-Barr virus, is notoriously associated with cytokine storms. Hemorrhagic fever viruses like Dengue and Ebola are also known triggers. Beyond infections, certain blood cancers like leukemias and lymphomas can initiate a storm.

In the rheumatologic world, systemic juvenile idiopathic arthritis and its adult counterpart, adult-onset Still's disease, are highly associated with cytokine storms. Systemic lupus erythematosus (lupus) is another common trigger, especially at the time of initial diagnosis. Dr. Randy Cron, MD, emphasizes that cytokine storms can occur with almost all rheumatologic conditions.

Ferritin Testing and Screening

Dr. Randy Cron, MD, strongly advocates for serum ferritin testing as a crucial screening tool. He calls it a "simple, cheap, relatively fast turnaround test." For a hospitalized patient with a fever, he believes checking ferritin is essential. While not highly specific at moderate levels, it becomes very specific at extremely high values. Dr. Randy Cron, MD, states, "If your ferritin is over 10,000... you probably have a cytokine storm."

He recommends this test even when the primary reason for hospitalization is known. A normal ferritin level can help rule out a cytokine storm, while a high level mandates further investigation. This simple step is a key part of the diagnostic workup for a critically ill patient.

Early Identification and Treatment

The central theme from Dr. Cron is the vital importance of early recognition. He stresses that "the earlier you treat cytokine storm and identify it and treat it, the better patients are going to do." Identifying the storm allows clinicians to treat this specific complication. Treatment must also address the underlying trigger, such as an infection or cancer, if it can be identified.

Dr. Randy Cron, MD, concludes that this proactive approach is a matter of patient safety. Using an available and global test like ferritin can dramatically improve outcomes for the sickest patients in the intensive care unit. This strategy can save lives by preventing a fatal hyperinflammatory response.

Full Transcript

Dr. Anton Titov, MD: You wrote in one of your papers that patients were in the hospital with fever, a particular risk for me is macrophage activation syndrome, a cytokine storm. Why is that?

Dr. Randy Cron, MD: They're not necessarily at risk, so I look at it like this. There are a lot of people who get cytokine storms again, but they go unrecognized.

Like a lot of things in medicine, we try to come up with one underlying diagnosis, and there's this thing called Occam's razor. So if you have three or four different systems or lab findings or image findings, you want to come up with one diagnosis to explain why that person is sick.

Now that's not to say you can't have a cold and break your toe, right? You can break this razor, but it's not perfect.

Dr. Randy Cron, MD: But it is a pretty good way because if you know someone comes in and they're coughing up blood and their kidneys are failing, you don't want to come up with two different diagnoses. You want to figure out okay, maybe they have inflammation of their blood vessels leading to inflammation in their lungs and their kidneys, right? Because then you'll come up with a diagnosis. Otherwise, you're gonna come up with multiple wrong diagnoses.

With cytokine storms, it's really the opposite. And that is you can have a bad infection like sepsis. You are growing bacteria in your blood. That puts you in the intensive care unit, and a subset of those patients, and we don't know exactly how many, but a subset of those patients will have a cytokine storm syndrome.

And again, maybe there's a genetic predisposition to why some people develop that and others do not. So it's not like its own diagnosis. It's just kind of an entity that can occur, just like sepsis itself is an entity that can occur if you get a bacterial infection.

And so if we think of it as something that can complicate a variety of conditions and make you sicker than you typically would be with that condition, and you recognize it, then you have to treat that aspect. Again, it's important to treat the underlying trigger, if you can figure out what that is. Sometimes you can't.

Dr. Randy Cron, MD: But you also have to treat the cytokine storm, if just treating the trigger doesn't resolve it. And so the common places that we see this type of occurrence often is in the intensive care unit, because they're often sicker than you normally would be with whatever condition it is.

Dr. Randy Cron, MD: But the diseases that we see it in are a whole slew of infectious diseases, particularly intracellular pathogens or bugs that go inside your cells, mostly viruses.

Dr. Randy Cron, MD: But there are other types of bugs that can do that too. And there are certain viruses that tend to do it more than others. And we're not exactly sure why that is.

The herpes virus family, including things like Epstein Barr Virus, which can cause mononucleosis, among other things, is kind of one of the most notorious viruses for cytokine storm. There are things called hemorrhagic fever viruses like Ebola, or Dengue, which can infect up to 100 million people annually. It's in parts of Southeast Asia in particular. It's an incredibly common infection, and a subset of those patients do get very, very sick and probably develop a cytokine storm syndrome as well.

So infections are a very common trigger of cytokine storms, as are certain blood cancers like leukemias and lymphomas in addition to the treatment for that which can cause cytokine release syndrome if they have a refractory one, but even just the cancer itself can trigger it.

And then in the rheumatologic world, the most notorious again in children is systemic juvenile arthritis and the adult counterpart of that as adult-onset Still's disease. On the adult side, because adult onset Still's disease is pretty rare, lupus or systemic lupus erythematosus is common.

Dr. Randy Cron, MD: But you can see this with almost all the rheumatologic conditions, there are case reports or cases, but lupus has been a pretty common one, particularly at the time of diagnosis. That's where cytokine storm syndrome is most likely to be seen.

That can be very confusing, because as part of cytokine storms, often your cell lines will go down, your platelet count, your white counts, your red blood cell counts, they often go down.

Dr. Randy Cron, MD: But that can happen with bad lupus itself. If you're not thinking about it, you may miss cytokine storm syndrome, particularly in the most severe patients who are often in the intensive care unit.

So there's a long way to get into your question.

Dr. Randy Cron, MD: But so in my opinion, because ferritin is such a simple, cheap, relatively fast turnaround test, and is a good screen, right? It's not highly specific until you get to very high levels, then it actually becomes very specific. Like if you're over 10,000. And you are in the setting of a fever, for example.

And you don't have underlying liver disease or have received multiple blood cell transfusions, which can also drive up your serum ferritin. If your ferritin is over 10,000, and have a fever and are sick enough to be in the hospital, you probably have a cytokine storm, very slim chance you don't.

Dr. Randy Cron, MD: But nevertheless, I think if you're sick enough to be hospitalized, for whatever condition you have, and you have a fever, those two things, I think you're worthy of a serum ferritin. Again, it's cheap, it's an easy screen, if it's low, great. Maybe you can take it off your radar, check it again in a couple of days at the patient's getting worse.

For example, if it's high, then you need to start thinking about it. Because again, the earlier you treat cytokine storm and identify it and treat it, the better patients are going to do. So that's my extreme position.

Because that's where I live, but it's a simple test. It's a test. It's available pretty much throughout the world. It usually does not take a long time to come back.

And if you're sick enough to be in the hospital and you have a fever even if you know why you're there because again, this can be a complication of a whole slew of conditions, check ferritin. And if it's normal, great. If it's not, then you need to start working it up, maybe getting some other tests that may help confirm or deny the cytokine storm diagnosis.

At that time, you have to decide, do I want to start treating this and then that's a whole separate avenue of exploration.