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Where are we with long COVID? Researchers at the Allen Institute and Fred Hutchinson Cancer Center are working to understand the science behind this new chronic disease.
By Rachel Tompa, Ph.D., and Rob Piercy / Allen Institute
17 min read
People in our study would get their blood drawn and we’d do the nose swabs, and then they would come back for another blood draw in about a month or so. And the people with COVID, when they came back, I remember texting Julie McElrath and saying something strange is happening, people aren’t necessarily getting better. And there’s this thing that happens if you have a virus, or can happen, where you can have some of these negative effects, post-viral syndrome. But it seemed to be more than that. And about the I think it was the third, maybe fourth, totally healthy first responder who had recovered from COVID and was reporting to me that their heart was acting funny, or they had been diagnosed with AFIB. I was like, you know, it’s normal to have that in some, you know, level in the population. But not, I’d never seen it like that. And so it’s like, okay, there’s something strange happening.
That’s Julie’s Czartoski, a nurse practitioner at Fred Hutchinson Cancer Center who specializes in infectious disease. She’s describing the very early days of the COVID-19 pandemic, when she and infectious disease scientist Julie McElrath were just beginning to explore this emerging virus and getting the first hints of what would later be known as long COVID. They launched a study in April of 2020 to look at COVID and first responders, people like EMTs and firefighters, as well as other people in the Seattle area who had just been diagnosed with COVID.
And, you know, when we started this study, we had collected, you know, we collect symptoms from people. And we had all the symptoms that we knew about with COVID. And so those would be boxes, you could check, you know, do you have this? Do you have a headache? You know, do you have chills, fever, all of that. But we didn’t have any of these boxes for brain fog, and the tingling in the hands and feet, and some facial numbness and lots of symptoms that, you know, we didn’t have these boxes for. And so we would just write them in, you know, all these different symptoms. And that turned out to be really helpful, because then we could go back now people that we know have long COVID, and we can go back and say, okay, these were all the symptoms that they had.
What was it like when you’re kind of writing in all these extra symptoms that you didn’t know about? I mean, it’s like, you’re kind of discovering this thing as it’s happening.
Right. It was really strange. And I thought at the time, I have to write all of this down, because, you know, we’re missing something.
I’m Rachel Tompa.
I’m Rob Piercy.
And this is lab notes, a podcast from the Allen Institute.
Today, we’re talking with Julie about her experiences studying some of the first people in Seattle who came down with long COVID, more than three years ago. And we’re also talking with an immunologist at the Allen Institute, Troy Torgerson, who’s part of a team working to understand the science behind this chronic disease. They’ve recently made some interesting discoveries about the potential role of ongoing inflammation in long COVID.
Troy and his collaborators at the Allen Institute and at Fred Hutch wanted to study what happens in the immune system as people recover from mild or moderate COVID. What does a quote unquote good immune response to COVID look like? But the scientists soon realized that some people in the Fred Hutch study just weren’t recovering.
Tell us about when you first started hearing about this thing called long COVID.
Fairly soon after the pandemic started, we began this collaboration with the Fred Hutch and Julie McElrath’s lab. And the initial idea was that we were going to use the tools that we’ve developed here to try and study in depth how the immune system responded to the virus. And so we were doing that and we, the initial set of patients that we enrolled, there was a subset of them that just did not resolve and get better after they had been exposed to the virus. And all of the patients that we were studying initially had mild COVID symptoms, none of them were hospitalized, none of them were on ventilators, you know, it was just it was more of the routine of what most people experienced with COVID. And so, we were surprised by the fact that about in this case, almost a third, a fourth to a third of the patients, went on to just have persistent symptoms, one of them was really quite severe with, experienced symptoms that lasted for months after the initial infection that was quite mild. So that was when we began to realize it. And then we started to hear about, you know, more broadly, people are describing the same thing.
So what is long COVID.
So it’s been kind of poorly described and specified, there’s no really great criteria diagnostic criteria for it, because the symptoms that people experience are really broad. It includes everything from brain fog, to fatigue to severe joint symptoms, autoimmunity, it’s any persistent symptoms that last after the acute infection. They need to last at least now 90 days beyond the initial infection before you call it that.
Julie Czartoski and Julie McElrath had both been studying HIV for many years when the pandemic began. So they were already experts in how viruses in humans interact. They needed to make a quick pivot to launch the new COVID study. At a time when nearly everyone had left their offices and labs to work remotely.
Prior to the pandemic for the Hutch, what I did with Julie McElrath, who’s the study leader, is I usually worked with folks who had HIV but naturally controlled the virus. So when the pandemic started, Julie McElrath contacted me and wanted to meet about potentially looking at what was going on with this new virus. And so when everyone else left the Hutch, we were walking around looking to try and find where is the safe place to see people who are sick. And so with the help of the team at the Hutch Engineering, we found a garage, and we set up a tent, and we started bringing people in who were sick with COVID. And we also brought in, ended up seeing about 252 first responders. This study started in mid-April of 2020. And you know, at that time, we were thinking it would be a pretty typical disease progression and what started to really stand out, I think, to everybody seeing people with COVID, how everybody was very different. And, you know, within a household, you could have people who didn’t even know they were sick, people who were super sick, you know, going into the hospital with respiratory problems. And then you’d have people who had weird things happening, you know, brain fog, loss of smell, or change in taste.
So you’re working out of this garage, and the rest of the world I think is still you know, struggling to come to terms with what is actually happening, right. Talk about the very earliest days of getting this going and what did you think going into it you might find? Or did you have any inkling?
I didn’t have an inkling so much, but I thought we would, you know, figure out how transmission worked and how long the incubation period was, and that kind of thing, things that were pretty mediocre looking back, you know, and how it’s interacting with the immune system. So back to my work with HIV, you know, because the people I see with HIV are doing something a little bit different with it. Looking at, you know, what is happening in them in the immune system, you know, as much as we know, our bodies are really like the final frontier. And there’s so much we know, and there’s so much more that we don’t know about how our bodies function, even our immune system, like what exactly is happening when we make antibodies. And everything about our interaction with our world is you know, there’s a lot there that we still don’t know. And so I thought we would learn more about, okay, what’s happening with a novel virus, you know, humans haven’t seen this before. What’s happening? How is our immune system responding? What kind of cells are important, you know, in terms of fighting off the infection? How long is it going to last? That’s what we’re, you know, collecting all these symptoms, what day did your symptoms start? What day did your symptoms end? And then that became difficult because while some people sometimes kept going on and on, so we had to change those definitions. A lot of you know, the term people have used a lot is building the boat while you’re in it, or building the plane while you’re flying it. That’s what it felt like.
It seems like things turned out to be even weirder than you were guessing going in?
Do you remember the first patient that had long COVID symptoms that you saw?
I do, I remember the first day that I realized this was different was I saw two people who had a new onset arrhythmia. And then there was a person that came in that was really struggling, really struggling. And I just thought, you know, what is going on here? And at the time, you know, I was thinking, well, was something else activated? You know, are they just having this big immune response? We weren’t sure exactly what was happening.
As mysterious as long COVID seemed, in those early days of the pandemic, the story just got more complicated the more scientists learned. We still don’t understand many of the important details of long COVID, let alone how to best treat it. But it’s becoming clear that it might have multiple causes that could require multiple different kinds of treatments.
What do we know at this point about what causes it?
So it’s a mixed bag. And you can, you can imagine that there are people who get infected who have a really bad initial course, who might experience organ damage, so say lung damage, there’s scarring that follows that and then they’re left with persistent symptoms, because of the organ damage. And that might be one thing that causes it. There has been a hypothesis that that in some patients it kicks off an autoimmune or auto inflammatory process, that that could be a cause of it. And then there have been, I think, the other prevailing theory has been that there’s persistence of the virus for a long time after you get infected, and there’s now data to show that in some patients, it does, at least, whether the virus is continuing to replicate or just fragments of the virus, hang around in our cells and take a while to get cleared out, it’s not entirely clear yet. But all three of those probably can lead to persistent symptoms.
And as you’ve been looking at these samples for nearly three years now, what have you found.
All of the things we’ve learned with other viruses held true here. There was a big robust immune response initially, but then it would typically in most people would resolve. But like I said earlier, there’s a subset of individuals where it didn’t resolve and it persisted. And we became very interested because as an institute, we’ve been more focused on autoimmune disease and on inflammation. We became very interested in that part of the COVID, the cycle of COVID, infection and resolution, and why didn’t things get better? And that then became known as long COVID. So one of the questions that we wanted to ask was in in these individuals who have persistent symptoms, these long COVID individuals, because of the different types of infections that are sorry, the different causes of long COVID that we mentioned before, we wanted to really look at those and say could we identify those, that group, that group within that broader cluster of individuals with persistent symptoms that had either autoimmunity or persistent inflammation. And we’ve used a variety of approaches, the first one that we used was looking at the proteins in their blood, could we just see inflammatory proteins in their blood, and it turned out to be really informative. And we found that around half of the patients that were followed, longitudinally, had ongoing inflammation, and that they sort of those individuals that had ongoing inflammation sort of fell into two groups. There was one group that had signs of what looked like almost a persistent viral, an immune response to viruses, like a persistent viral infection, and we are still trying to determine whether that’s the case, is that the group that have persistent, you know, viral fragments that they’re shedding? And then there was another group that had another form of an immune response, more just persistent inflammation and so we’re trying to understand those two groups. I think the bottom line is that, you know, if you think about the whole bucket of long COVID, you know, a lot of different treatments have been hypothesized as maybe being you know, could these be effective and, and many of those are anti-inflammatory type drugs. And you really if you’re going to use one of those drugs, they have side effects associated with them. But you would anticipate that you’d want to use an anti-inflammatory in individuals who had persistent inflammation. So this was an effort to try and identify that subset of long COVID that had persistent inflammation, where we could apply drugs that we know about, and, you know, study in the lab to try and control their persistent inflammation. And so that was the initial, the initial focus. And it turned out really interesting. And we’re now following up on those findings.
So what is inflammation?
Oh, good question. So, so I think of it in two things really, whenever you have something that enters from the outside, so you could think of your body as really like a homeland. And your immune system is sort of like your defense system that protects your homeland from being invaded by viruses and bacteria. And so whenever somebody breaches a border, so say, you get a sliver in your skin, or your, you know, you get an infection that then invades past the borders of the mucosal borders that line your airways, for instance, then the immune system gets riled up, and it attacks that and that process is called inflammation. And it does that so that the initial response is, is an inflammatory response that causes the fever, the redness, that all of those things that happen when you get, say, an infection. But then the follow on to that is then other parts of your immune system then sort of take those cues, and they then come in and develop memory so that the next time you see that same pathogen, or that same virus or bacteria, you can respond to it better, you can respond to it more quickly, because you’ve been exposed to it before and you develop memory. So inflammation is that initial response of everything getting riled up and angry. But then it’s supposed to settle back down, and there’s a whole mechanism of revving up and a whole mechanism to wind it back down. And if it persists, then we don’t know, does it persist because it doesn’t wind down appropriately? Or does it persist because whatever the inciting agent was, is not gone? It’s still they’re sort of poking you and keep going. It keeps revving things up,
Is having these chronic effects, is that more common with COVID than with other viruses? Or is it just that so many people got COVID at the same time?
initially, we thought that it was more common. There’s recent data that suggests that maybe now after we’ve had you know, after people have had a chance to get vaccinated after they, you know, they’ve had some time to potentially resolve that if you look further out that maybe it’s in the same neighborhood as with other viruses. I think that certainly the point you bring up of so many people getting infected at around the same time, it really was a huge wave that happened. And so it’s probably more of that, I would say, then, specifically COVID driving a higher percentage of these, maybe initially, after the infection, if it persists, there’s more people who have persistent symptoms. But over time, as that sort of settles down, and you’re left with sort of the ones who have really long term, persistent symptoms, more in the range of what has been seen with other viral infections.
Do you feel like there’s hope for these patients?
Oh, yeah, definitely. I think there’s hope and, you know, one of the cool things about COVID in the scientific community, I think, which, you know, with everyone in the community working on different things, you sort of forget about just how big the community is. I think one of the remarkable things about the pandemic is that almost everybody who was doing research got involved in COVID in some way. There’s, there’s this pathogen, this virus has been studied more deeply. And we know more about this pathogen than like, probably any other pathogen ever, I would guess. I don’t know, maybe that’s not true. But we know a lot now, due to all of the research that everyone really in the community, it was a community effort. People dove in, studied it. And you know, we’ve learned a lot. We’ve validated a lot of what we thought we knew before. We said, oh, yeah, that’s really true. But there’s still a lot we don’t know. And so I think there’s still discoveries to be made, that can make a big impact for people. So yeah, I’m very hopeful. Yeah, I think we’ve got tools available now that we just didn’t have even five years, 10 years ago, we didn’t have the sorts of biological scientific tools that we have now to try and untangle this. And so that’s exciting.
Oh, for sure. There’s hope. I’m always hopeful, the good things that have come out of COVID. I mean, I know there was a lot of political turmoil around the vaccine. But it wasn’t an accident that those things happen so quickly. Everybody who knew about that type of science stopped what they were doing and worked on COVID. Everybody, and that’s pretty incredible, and just shows how mighty we can be. And there are still a lot of scientists and a lot of effort put at what is happening with long COVID. And you know, it’s a mystery. And people like to solve a mystery. You know, I don’t know that tomorrow or any day, it’ll be like, oh, here’s the cure. I think it’s going to be an unfolding process of learning and figuring out and kind of making steps forward. So for sure, there’s hope.
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Thanks for listening.
The 21st century is the century of biology. Discoveries made in the lab today will shape the cures of tomorrow. Hosted by award-winning science writer Rachel Tompa and creator Rob Piercy, Lab Notes pulls back the curtain to reveal the human stories behind headline-grabbing scientific studies and breakthroughs. Lab Notes is a production of the Allen Institute.