• Cytokines are proteins normally released by the immune system but, in some people, this reaction goes into overdrive, causing dangerous organ inflammation.
  • Cytokine storm is being increasingly reported in COVID-19 patients several weeks after the initial infection and is linked to many deaths.
  • Cytokine storm is similar to the immune response seen in people with Still's disease, a type of arthritis.
  • Several anti-inflammatory drugs used to treat arthritis are being investigated as possible treatments for COVID-19.

Video Transcript

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JOHN WHYTE: You're watching Coronavirus in Context. I'm Dr. John Whyte, Chief Medical Officer at WebMD. Today I'm joined by rheumatologist Dr. Maximilian Konig at Johns Hopkins School of Medicine, where he's going to talk about his interest in cytokine storm. Dr. Konig, thanks for joining me.

MAXIMILLIAN KONIG: Doctor Whyte, it's a pleasure to be here. Thank you so much for having me.

JOHN WHYTE: Now, you're a rheumatology fellow and you're studying cytokine storm. Tell us how that all happened.

MAXIMILLIAN KONIG: That's a very good question observation, you know? Most people who are in the field of r-- rheumatology probably do not study COVID-19 at the moment. Uh, for me, the path to actually being interested in cytokine storm is a little bit of a long-- is a longer one.

I started to be interested in cytokine storm in the context of patients with rheumatic disease that have a similar presentation at times that is referred to as macrophage activation syndrome, which has a lot of--

JOHN WHYTE: What would-- what would those conditions be? Rheumatoid arthritis, lupus, what would they be?

MAXIMILLIAN KONIG: Historically, it's most common in a condition called Still's disease, or adult onset Still's disease. Some patients with that condition develop a very fulminant immune response that has a lot of similarities to what we're currently seeing in COVID-19, but obviously has a lot of differences in the sense that it's not driven by a viral infection in most of the case.

I started working in a cancer lab at Johns Hopkins, being interested in diseases and mechanisms of disease related to cancer and immune responses in cancer. Particularly, I'm interested in studying how the immune system can be used to target cancer and treat the disease.

In that context, the lab that I joined, led by Dr. Vogelstein, Dr. Kingsley, and Dr. Bettegowda, is interested in using CAR T cell therapies to treat cancer. And I'm particularly interested in using a similar approach to treat cancer, but also potentially autoimmune rheumatic disease.

It turns out that our lab had an interest a couple of years ago in better understanding severe complications of CAR T cell therapy, including something that's called cytokine release syndrome. And in that context, we started to look particularly in immuno responses that are hyperactive, including ones that mimic cytokine storm. So that's kind of--

JOHN WHYTE: So what is cytokine-- what is cytokine storm? Can you explain that to a consumer audience?

MAXIMILLIAN KONIG: Absolutely. So cytokine storm is a concept that's actually pretty poorly defined. When physicians talk about cytokine storm, they often refer to a state of immune activation that's more than it should be.

So for example, when any of us has a viral infection, be it influenza, or in this case, SARS CoV-2, the cause of COVID-19, an appropriate immune response is necessary to clear the virus and protect from future infection.

What we're seeing in a subset of patients with COVID-19, unfortunately, is that this immune response becomes disregulated.

And in these patients, instead of, um, having an appropriate immune response that, afterwards, is lowered and resolves, we see that the immune response, a couple of weeks after initial infection, starts to ramp up. And that is associated with a lot of the disease's morbidity and mortality that we're seeing in this disease.

JOHN WHYTE: Several of the drugs that are being studied for COVID-19 are also drugs used for arthritis. Not just hydroxychloroquine, but there's a few others as well. Does that surprise you?

MAXIMILLIAN KONIG: Well, it doesn't surprise me in a sense that, given the similarities that we observed to diseases like macrophage activation syndrome and another condition called HLH, it is naturally that people would be thinking of applying a similar repertoire of medicines to treat the disease.

Hydroxychloroquine is not necessarily one of them, but many of the drugs that we currently use to treat rheumatoid arthritis and other autoimmune rheumatic diseases are currently being investigated as a treatment of people who have either severe or critical COVID-19.

And that includes drugs that target specific cytokines, inflammatory molecules, including IL-6, but also IL-1 and a plethora of other cytokines and immune, uh, cytokines and immune mediators that potentially, um, are associated with worsening disease and severe outcomes in COVID-19.

JOHN WHYTE: What are some of those other drugs that are being studied?

MAXIMILLIAN KONIG: So if you look at the moment, uh, it's almost an endless list of drugs. Anything that you can think of that probably has been used in the treatment of rheumatic disease is investigated in some form.

A lot of centers around the world have focused on drugs that target the IL-6 axis. IL-6 is an important cytokine, and has been found to be elevated in patients with COVID-19. Probably more importantly, IL-6 is elevated in patients early on who have poor outcomes.

So in a paper that was re-- reported early on from China, it said that if you looked at patients who have poor outcomes and eventually died, IL-6 levels were, early on, already elevated compared to those who survived.

There are a couple of other cytokines that follow a similar pattern, and that has guided, I think, initial interests in-- in investigating drugs that could be potentially interfering with that up regulation of inflammatory markers.

In that context, there are drugs that are used, for example, for rheumatoid arthritis, but also sometimes used in Still's disease that I mentioned earlier, which has this phenotype of macrophage activation syndrome.

One of them is called tocilizumab. It's an antibody that blocks IL-6 receptor. But there are similar drugs in that same--

JOHN WHYTE: That also has anti-inflammatory properties as well, does it not?

MAXIMILLIAN KONIG: It-- it has, right? So the antibody is neutralizing to IL-6 in a sense that it binds the IL-6 receptor, and therefore IL-6 cannot signal anymore. So it's a potent anti-inflammatory drug.

And usually when we use it, we see a rapid decline in inflammatory markers in patients who get the drugs as early as one or two days after administration.

JOHN WHYTE: But those drugs also have significant risks as well. And this is the challenge, is it not, in terms of targeting drugs that impact cytokine storm, specifically IL-6 and some of the others?

MAXIMILLIAN KONIG: It-- it's an absolutely important observation that you're making. And I cannot stress enough that, at the moment, we know very little to what degree using these drugs, be it IL-6 inhibitors, IL-6 in-- receptor inhibitors, or other potent immunosuppressive drugs, is going to be helpful or harmful depending when they're given and to what patient they are given.

So that's why it is so important that we're currently pursuing clinical trials around the world to help figure out what the risk benefit ratio is. There are encouraging early results that suggests that some patients may get benefit, but it's probably not the case across the board.

So it's going to be very important to differentiate at what point you should be giving that drugs and to what patient population. The risks that you mentioned is potentially important to consider.

We know that patients who have severe COVID-19, and those are patients that end up being in the hospital, often intubated, and often in the ICU where they are at high risk of secondary infection, would be getting these drugs.

And due to the long half life of many of these agents, including, for example, tocilizumab, it is possible that we would be giving a drug to a patient who could have significant side effects from being immunosuppressed for prolonged period of time.

In that same context, it's important to consider that we're giving the drug to somebody who doesn't have sterile inflammation. What I mean by that is that we're giving the drug to a patient who doesn't have rheumatoid arthritis or other forms of inflammation that's driven by your own immune system in the context of being overactive, not necessarily in the context of fighting a virus or a bacterial infection.

JOHN WHYTE: What that relates to, is there any belief that COVID-19 could have some element of auto immune disease?

MAXIMILLIAN KONIG: I-- I think at the moment, we have no evidence of that. But it's important to realize that for some reason that we still poorly understand, the immune system starts to become into overdrive.

There are very few data that I could think of that would suggest that there's any mechanism underlying this that's autoimmune in nature, but we know too little to really understand for sure.

JOHN WHYTE: With the release of all these cytokines, and it's a, you know, which cames first, their underlying condition or the overreaction of the body. But obviously, cytokine storm is-- is a contributor in and of itself to-- to someone's, um, condition, is it not?

MAXIMILLIAN KONIG: Yes. So that's actually what we think is going on. If you look at the trajectory of patients get admitted to the hospital for severe COVID-19, what we often see that patients in the first week or 1 and 1/2 weeks of disease have symptoms, but they're not critically ill.

And somewhere within the second and third week in a subset of patients, and we don't fully understand what subset that is and what influences that risks, the immune system becomes overactive and then leads to all the complications that we think are associated with poor outcomes in COVID-19.

JOHN WHYTE: Is that unusual for a virus?

MAXIMILLIAN KONIG: It has been reported with other viruses. So if we look back in-- in the literature, there are reports of patients with influenza, um, specifically influenza like the H1N1 epidemic, um, several years back, where similar presentations had been reported.

Patients that would have severe disease to the degree that would-- they would be in a kind of cytokine storm. And it's actually known from prior coronavirus diseases, including SARS and MERS, prior illnesses that were described within the last 10 years, where we saw similar, um, manifestations of cytokine storm after infection.

JOHN WHYTE: What do you hope to know six months from now that you don't know today?

MAXIMILLIAN KONIG: That's a great question. So first of all, at the moment, a lot of the efforts are focused on treating patients that already have severe disease. I think it's very important to understand better what the right drugs will be to interfere with-- in the process.

And it's going to be incredibly important to understand when these drugs need to be given in the disease course. If we give it too late, the concern is that patients will not have the appropriate benefit anymore, because there is already enough organ damage.

If we give it too early, the hypothetical risk is that we interfere with the body's ability to actually interfere, clear, and fight the virus. So timing is going to be important. And at the moment, I don't understand where the right window of opportunity is.

The second thing that I would really like to understand, thinking about cytokine storm, is how we can prevent cytokine storm from happening in the first place. And that's where a lot of research efforts that I'm interested are currently going.

Ideally, we would be able to prevent the progression of patients who come in with mild symptoms to go through the second and third phase of the disease where they accrue more and more inflammatory damage, which includes the development of ARDS, severe lung injury, and potentially other organ systems that fail afterwards.

So those are two critical questions. That's all embedded with many other strategies that are currently pursued. You mentioned a couple of them that might be focusing on targeting the virus itself, and other strategies that might be important to prevent the risk of infection with the virus by blocking receptors.

And ultimately, I think there is, uh, the greatest interest of finding a vaccine that could potentially prevent us from getting the virus and the infection in the first place. But it seems like that is nothing that we will have answered in the next six months.

JOHN WHYTE: Do you get any weird responses from people when you're a rheumatologist studying an infectious disease?

MAXIMILLIAN KONIG: Well, I think it is fascinating to observe what a diverse group of people is currently coming together, tackling and trying to tackle this epidemic. And pandemic.

It is fascinating, for example, that I get emails from patients-- from other physicians who might be plastic surgeons at a different part of the United States who have ideas and contributions to actually contribute to this.

Um, so I think there is strength in an approach where very different specialties are coming together to tackle a-- a similar and-- and shared goal.

In our group, for example, we have oncologists, neurologists, neurosurgeons, rheumatologists, and a bunch of other incredibly talented research statisticians and even economists working together to try to find answers. I think it's an incredibly inspiring time, and to be part of it is fantastic.

JOHN WHYTE: Well Dr. Konig, I want to thank you for sharing your insights today.

MAXIMILLIAN KONIG: It's my pleasure. Thank you so much for having me.

JOHN WHYTE: And I want to thank you for watching Coronavirus in Context. I'm Dr. John Whyte.

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