Cytokine storms explained

What are cytokine storms, and how do they affect patients? Our editors speak with immunologist Scott Canna and rheumatologist Rachel Tattersall to help understand this condition.

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Transcript

This transcript was automatically generated using speech recognition technology and may differ from the original audio. In citing or otherwise referring to the contents of this podcast, please ensure that you are quoting the recorded audio rather than this transcript.

Gavin: Hello, welcome to another special COVID 19 episode of The Lancet Voice. I'm Gavin Cleaver. Today, we have a couple of interviews about a very interesting aspect of COVID 19, cytokine storms. Usually, inflammation helps the body clear infection and heal wounds, but as we've seen with some COVID 19 patients, inflammation can sometimes spiral out of control.

Causing a so called cytokine storm. Later on, you'll hear editor of the Lancet Rheumatology, Heather Van Epps, talk with NHS consultant Rachel Tattersall about dealing with cytokine storms. First, here's editor of the journal eBiomedicine, Julie Stacey, speaking with Scott Canner, Assistant Professor of Immunology at the University of Pittsburgh.

Julie: Hi, Scott. Thanks for joining us. 

Scott: Hey, thanks for having me. 

Julie: So we're hoping you can tell us a little bit about the biology of cytokine storm and how this is affecting COVID 19 patients clinically. 

Scott: I'd be happy to try. I think it's a moving target as it has been for, I don't know, in cytokine storm goes back, 5, 000 years maybe, or whenever the Greeks coined the term sepsis.

Because people have been dealing with the bad effects of inflammation for a very long time. I don't know that there is an agreed upon definition of cytokine storm, even though I was part of a textbook that we wrote about it last year. But I think to start with, you have to understand what the word cytokine means.

And the name cytokine is not super digestible, but largely cytokines are usually proteins that the immune system uses to talk to itself. Our immune system is largely made up of cells and the products that those cells make and it exists in every part of your body and so the immune system needs to decide what to mount a response to.

and what to ignore in terms of, the bacteria that live in our gut and on our skin versus the viruses and bacteria and things that try to infect us and cause damage. And cytokines are among the ways that our immune system talks to each other, either two cells right next to each other or cells that are, all the way across the body.

The cytokines that we think about the most tend to be the ones that are most associated with inflammation. And I don't know that we need to get into the specifics of which ones but some of them we, we talk about with some frequency. A lot of people out there have heard of on the radio or on TV commercials for TNF inhibitors.

And there's been quite a number of those around for a long time. So TNF stands for tumor necrosis factor, and it is one of these inflammatory cytokines, but there are literally dozens of them. And when they seem to be, not to get too metaphorical when they seem to be swirling around the body.

and causing damage haphazardly we call that cytokine storm. And that can happen in a variety of contexts. How that might be affecting COVID, I think, is another really important interesting question. To me, I think COVID is really interesting in the really wide breadth of clinical manifestations because clearly there are people who are asymptomatically infected.

They encounter the virus they develop an immune response to it, and they clear that virus, and they never know about it, or if they do notice anything, maybe a mild cold symptoms. And then there's clearly other people who are ending up in the intensive care unit with a real life threatening response to the virus infection.

And so that diversity. Tells us that there's a lot of factors to enter into the equation in terms of who is going to have a really severe response to COVID. So 

Julie: is there thought to be a tipping point then that triggers the storm? 

Scott: A lot of us speak about a threshold effect where, you know, a variety of factors both related to the virus and related to the host response to that virus.

When it hits a certain threshold you tip into the cytokine storm. And I think one of the concepts that, at least for me, has been very helpful in understanding what I'll call immunopathology which is damage or problems that the immune system itself is causing, as opposed to the virus or the pathogen.

And that's the idea of amplification loops. And this is an idea that I largely learned from a former mentor of mine, Rafael Goldbeck Mansky, who's still a very active researcher at the NIH. And the idea for amplification loops came largely from patients that I've been studying for a very long time who have mutations that cause their innate immune system to cycle out of control.

And in these patients, we seem to see especially certain cytokines or certain pathways that when they get revving high enough, self reinforce and in some ways self perpetuate. And while it might take some sort of trigger, be it a virus, to kick things off, if you get into an amplification loop or a nasty cycle, it can continue to rev out of control.

without even needing that initial trigger. And that's when you get into this immunopathology. And if that's happening in the whole body, then that's consistent with cytokine storm. 

Julie: That's a good segue into my next question. Then are some people more susceptible? Is age also a susceptibility factor?

Scott: This is certainly not my research, but what I and others have tried to glean from the many studies that have come out and are coming out are, what makes people that get severe COVID different from the people who either have a mild disease or an asymptomatic disease. And age seems to be one of the big characteristics here.

And it's not just the extremes of age. It's not simply that, this is only a problem for people in their 80s or older. But it seems that, almost with every passing decade we see an increase in susceptibility to severe COVID, meaning that, there's more problems in 50 year olds than 40 year olds, even though physiologically we don't think the two are so different.

Even without the things that come along with age, like comorbidities, age alone seems to be a big predictor and that invokes a whole line of research into what aging itself does to the immune response, which is a whole other story. In addition to age, there, there's certain to be some risk factors like diabetes, obesity, high blood pressure.

Some very common things that seem to be risk factors for severe COVID. It's not clear to me at least whether, these things are special in their effect in COVID or just that they're common enough that we're able to detect them statistically as being risk factors for COVID and that there may be other more potent risk factors out there that we don't really know about because they're too rare.

to say anything intelligent about them. 

Julie: And we aren't yet able to tie this back to whether they're more susceptible to. Uncontrolled inflammation, then 

Scott: that's correct. I think that to put things in broad categories, it's hard to disentangle whether someone with really severe covid is sick because of immunodeficiency, meaning they didn't handle the virus very well, either to begin with, or in an ongoing basis.

Or because of immunopathology, whether they handle the virus as well as anybody else does, but they have a much bigger inflammatory response to it. Those two things, I think, are often really difficult to tease apart, especially in a sort of complex disease like, like this, that's a moving target. But I think that there's an increasing appreciation that many, if not most of the people who are very sick with this.

Have that sickness, not necessarily because they weren't so good at handling the virus, less immunodeficiency, but maybe more because their inflammatory response to that virus was out of control. 

Julie: How are Cytokine Storm therapeutics thought to work? 

Scott: I think broadly speaking the goal is to clamp down, tamp down on the inflammation.

The way that people have been. Calming inflammation for the last hundred years or so has been with corticosteroids. And I think corticosteroids are probably an important part of the treatment, both for severe COVID, although we have to be a bit careful, and for this PIMS reaction. Now, corticosteroids are a very blunt instrument.

They affect practically all parts of the immune response. And they are immunosuppressive. And so you have to be careful if someone's actively fighting an infection, you don't tamp down their immune system so much that they can't fight the infection. So over the last several decades, there have been a number of drugs that very specifically block just Certain parts of the immune response and this is where this construct of these amplification loops I think is helpful because if you pick the right cytokine in the right disease and you target it Specifically you can often turn off that amplification loop without doing very much To hamstring the immune response and, my experience has most specifically been with the cytokine IL 1 IL 1 standing for interleukin 1.

I think interleukin is actually a good name. It's from the Greek inter between leukin white blood cells. So it's interleukins are proteins that go between white blood cells. And we have, we've had drugs for a while that block IL 1, and we have an increasing appreciation for their ability to be really good in some patients, not necessarily with COVID, but in patients with genetic issues.

Inflammatory diseases, IL 1 blocking drugs have been life changing and very minimally immunosuppressive. If we can be smart about how we understand the biology and how we might understand which of these cytokines are self perpetuating we might be able to just pick the right one and make a big impact without a lot of immunosuppression.

Heather: Having heard about the biology of cytokine storms and how these storms develop, we now turn to discussing what these patients experience clinically and what approaches doctors are using to treat them. Joining me to discuss her experience in treating patients is Rachel Tattersall, consultant rheumatologist at Sheffield Children's Hospital and Sheffield Teaching Hospitals in the UK.

Rachel is also chair of the Hemophagocytosis Across Specialty Collaboration, and her research activities focus on auto inflammatory diseases and a rather difficult to pronounce cytokine storm syndrome called hemophagocytic lymphohistiocytosis, or HLH, and importantly, how doctors decide what drugs and approaches are best to treat patients with these diseases.

Welcome, Rachel, and thanks for joining me. Thank you for having me. Maybe you can start by painting a picture for us. So you're on duty in a COVID 19 ward and a patient with severe disease is admitted to the ward. How do you know whether that person is experiencing a cytokine storm? What are the clinical signs and symptoms?

Rachel: So that's a great question. And I think the first thing to say is that as a hyper inflammation specialist, and hyper inflammation is probably an easier way of describing the complicated side to kind storms, we're often looking for patients with hyper inflammation. And pre COVID we would always recognize a pattern in patients with very frank hyper inflammation.

So they have a persistent fever. They have a particular set of blood tests or patterns of blood tests and some biomarkers that we use very commonly, particularly serum ferritin. So I guess if COVID has precipitated this frank hyper inflammatory storm, then that's. an easier pickup than perhaps what people are more interested in for this podcast, which is the more subtle or localized inflammatory storm, which COVID causes.

And that's probably because instead of having this very widespread system wide inflammation, COVID attacks initially the lungs and causes a much more localized hyper inflammation. So we don't use the same measures clinically that we use in standard hyper inflammation. So the patients are often not.

consistently febrile. They often don't have, frankly, abnormal blood. So you end up looking at patterns of blood and looking at the patient. And I think most clinicians managing COVID will recognize people who seem to have had the illness, have come into hospital and actually often seems to be getting better.

Sometimes you're just thinking, or maybe they can go home tomorrow and suddenly their blood tests, particularly the marker of inflammation, C reactive protein or CRP doubles or triples in a few hours. People often become suddenly much more breathless. They're not always aware that they're breathless, but you can measure the number of breaths they take a minute at the side of the bed.

And I guess once you're sensitive to that, then you start to request blood and then you add in some of the more typical biomarkers of inflammation. We've learned that we see with this more limited COVID hyper inflammation storm things like LDH, D dimers. And these are tests which on their own are a bit non specific, but as part of a pattern in somebody who's deteriorating like that can be hugely useful.

And that's the point at which I then have a discussion with intensive care about these patients and we've got much better over a few weeks in recognizing this sort of sudden stepwise deterioration and escalating care. Quickly at that point. 

Heather: So what is actually done at that point? How are these patients managed?

Rachel: The big problem with COVID as we don't have a treatment for the trigger of COVID. And we, I'm sure we'll come to talking about trials of those treatments, but there's a sort of standard of care, which is to essentially support the patient. So usually that's respiratory support. So you start with oxygen.

Delivered just by standard masks, you might need to use a more fancy higher flow mask. And then you get to the point where people need not just oxygen, but assistance with the mechanical aspects of breathing. And that's usually with this thing, CPAP, continuous positive airway, pressure ventilation, or formal ventilation, where you actually intubate or put a tube into the trachea.

I think we're recognizing that the lung damage, which often becomes this syndrome, acute respiratory distress syndrome, or ARDS, Which goes hand in hand with the covert hyper inflammation usually often requires assisted ventilation, but we recognize that probably should be prone. With people on their front and where possible with CPAP rather than with the more invasive ventilation.

Strictly speaking. the first thing to do is standard of care. And then I think there is a discussion if the patient's got frank hyper inflammation, like we've always managed, like we recognize often there are more disciplinary teams in hospitals specifically to manage these patients, then you think about standard of care for hyper inflammation.

So in infections, other than COVID, that's often steroids, but steroids are a bit tricky in COVID because there is some suggestion, although it's not really proven that steroids can worsen ARDS, and there are some of the cytokine inhibitors, which are standard use in some forms of hyper inflammation and in teams who are experienced in using those, you may have access to those medicines.

So you've got to both support the patient in their COVID state, but also do what you can for hyper inflammation. The other drug we commonly use is intravenous immunoglobulin, although in the COVID pandemic, that's a very scarce resource, and we're trying not to use that unless we really have to. The one indication in COVID hyperinflammation is where the hyperinflammation affects the heart, and we're seeing a number of people who develop this hyperinflammatory syndrome seeming not only to affect the heart, but also the, not only the lungs, but also the heart, and they get intravenous immunoglobulin.

Heather: And what about issues of timing with these patients? It seems like there's probably a very precise window of opportunity to treat them. 

Rachel: That's a sort of an issue that although the hyper inflammatory community are, absolutely committed to enrolling patients into trials. I think it's very much part of the, you need to have the intention to treat right at the beginning.

And what we know from cytokine storms in general, is that the earlier you treat, the easier it is to switch off the storm and the less chance there is that the storm becomes self perpetuating. The reason there's such a high mortality in cytokine storm is that they can become self perpetuating. And even if you have a treatment for the trigger, which we don't in COVID, but we do for many other triggers, you can't actually get on top of the storm because the storm is self perpetuating.

So the common sense position would be The sooner you can identify that pattern that suggests hyper inflammation, that would be the point of intervention. Again, I can't say that as an evidence based statement in the context of COVID, because we're accumulating the evidence, but as an experienced hyper inflammatory physician, it's absolutely clear that whatever flavor of cytokine storm you're treating, The quicker it's identified and the quicker it's treated, the better the outcome for people who experience it.

Heather: So that brings me to the last topic that I wanted to touch on which is exactly what you mentioned, the clinical indicators that tell you that a person who's not yet experiencing cytokine storm is likely to develop that, giving you that window of opportunity. So do we have those clinical?

Indicators or biomarkers yet and are we close to having them if not? 

Rachel: No, so one of the issues with hyperinflammatory medicine is it's very rarely one test that gives you the answer The exception to that is probably the serum ferritin in classical hyperinflammation or hlh where Really, a ferritin, serum ferritin are highly elevated of over 10, 000 is an indicator.

Certainly, we would say you should actively exclude hyper inflammation and treat if you can't find another cause. And a number of patients with COVID are undoubtedly tipping into a classical hyper inflammatory storm with a very high ferritin. And the other absolute indicator, which is true cytopenia, so very low platelets and often another line like the haemoglobin or the white count.

So that group of patients whose coronavirus has precipitated a standard cytokine storm, you can use the standard biomarkers, the highly elevated ferritin and the cytopenia. However, in the COVID hyper inflammation group, this more perhaps localized hyper inflammatory storm, predominantly affecting the lungs and perhaps the heart, it's much more difficult.

And you're reliant on patterns of blood tests rather than absolute indicators. The one exception to that perhaps is the CRP. The C reactive protein is probably a proxy for interleukin 6, that's the cytokine blocked by tocilizumab. And I think the really suspicious and perhaps the one take home message for clinicians is watching that CRP, and if it does suddenly double or a patient comes into hospital with a CRP of three or four hundred, that's absolutely the group I would watch really carefully.

And then there's additive information. Ferritin is not as high in covid, hyper inflammation as in other cytokine storm syndromes. But the Chinese data clearly showed that high ferritin. So one to 2000, not 10 or 20,000, but one to 2000 definitely correlate both with severity of illness and chances of dying and other indicators, D dimers, LDH.

So I think the message for Covid hyper inflammation is. Look at the patterns of blood tests. CRP is probably the best absolute biomarker, but it's in the clinical context of how well or poorly the patient is doing and I guess disappointingly for easy bedside markers, I think fever is less indicative in these patients than it is perhaps in other groups like the cytokine release syndrome in CAR T cell therapy or macrophage activation syndrome in Stills disease.

Heather: So it's clear that there are many flavors of this type of disease, if you will. 

Rachel: Yes. And I think there's a very healthy debate in the literature about a couple of things and as a result of that, one is that there's the lumping and splitting approach. I'm a lumper. I think it's very helpful to have an umbrella of cytokine storm under which many Flavors of cytokine storm reside, and I do firmly believe that COVID is a cause of hyperinflammation.

I think the other thing is that one of the bedside scores, which we have previously used, is a good marker of hyperinflammation, the H score. At the beginning of the pandemic, our group proposed that this might be a useful bedside test for identifying this group with hyperinflammation. But I think as the pandemic's gone on, it's clear that the markers in that either can't be accessed because they're so high risk in COVID.

So the bone marrow aspirate, which is key to that and CT scanning of the abdomen to look for organomegaly, but also the absolute levels of ferritin as we've discussed and the cytopenia are not as marked. So I don't think the H score, which we propose people use in general medicine to identify hyper inflammation is so useful in COVID.

And I guess that's when a new disease comes along, something that you think six weeks ago becomes outdated, but I think we're becoming clearer about what COVID hyper inflammation is and what we now need is data, firstly, to confirm that this clinical phenotype exists and be able to answer much more succinctly than I have been able to here and give you absolute indicators, but also to be able to help patients understand what's happened to them.

It's very frightening when they have this sudden deterioration, go off to ICU. And we know that people need ventilating often for a long time. So I think we have to put the patients and their families right in the middle of this and have a way to describe what's happened to them in all this as well.

Gavin: I'd like to thank Heather, Rachel, Julie and Scott for their insightful and informative chats. And I'd like to thank you for listening to the Lancet voice. You can subscribe to the Lancet Voice across lots of different platforms. And if you have any feedback, you can reach me right away on podcasts at lancet.

com. Thanks so much for joining us, and we look forward to having you again next time.