The Latest on Long Covid
This week, the latest research findings on Long Covid. What did a study on over a million people reveal about who's at risk of the condition and for how long? What studies are now being done to discover the cause, and what role do reactivating dormant viruses like EBV, more normally the cause of glandular fever, play in the disease? Plus, the doctor disabled by two doses of Covid explains how her life has changed...
In this episode
00:39 - Life with long COVID
Life with long COVID
Nathalie MacDermott, King's College London
Long Covid is essentially what it says on the tin: symptoms which persist long after a person is diagnosed with Covid-19. This can mean different things for different people, however. James Tytko spoke with clinical academic at King’s College London, Nathalie MacDermott, about her personal experience with the condition…
Natalie - Before I got Covid and before the pandemic, I was a very active person. I had relatively recently returned from living in Sierra Leone for a prolonged period of time where I'd been doing research into Ebola. And I guess in terms of my passions at that point, certainly career wise, I'm very passionate about doing disaster emergency response and medical response.
James - And Natalie when you first got Covid, what was that like? Was it a similar experience to maybe how many others describe it?
Natalie - So I first had Covid in about March of 2020, the end of March. And I guess, yes, it was very similar to a lot of people. It floored me for about a week. I had a fever for about five days and, and pretty much slept for most of that time. Lost my sense of taste and smell and then also became a little bit breathless in that second week. But I felt well enough to return to work after a couple of weeks. About a couple of months after my first infection with Covid, I believe I was infected again. I had a very similar illness to the first time, maybe slightly milder. My fever didn't go quite as high. But then I developed nerve pain in my feet during the first two weeks. And that then kind of progressed to having other neurological issues even once all of the sort of acute symptoms of COVID had settled down.
James - And what sort of impact does that neurological condition have on, on your active lifestyle, maybe on your career aspirations? Has it, has it been quite detrimental in that respect?
Natalie - Yes, it's certainly been quite difficult. I can't walk very far without crutches. With crutches, I can walk a little bit further, but my mobility is significantly limited. So it does make everyday life and any kind of travel just that bit more challenging. I'm someone who thinks that nothing should be impossible, irrelevant of the limitations we have. So I go to great lengths to overcome those barriers. I have yet to respond to a disaster overseas, but I reckon that if they just provide me with a quad bike, everything would be fine. That's kind of my plan for the future. But yes, it certainly made work very difficult. For quite a while, I didn't return to face to face clinical work just because I needed a lot of adaptations to be in place to be able to do that. And they weren't in place at that point, particularly because combined with the commute that I have to do, I'm just completely exhausted at the end of the day, which is kind of what happened this morning where I get home late and I just completely kind of pass out on the sofa and then wake up in the middle of the night and kind of then wake up the following morning with a migraine. It certainly has an impact on my life outside of work because I don't really do much outside of work. I'm part of a lively church and I go to church on Sundays and I try to get to groups in the middle of the week, maybe once. But other than that, it's very difficult for me to do much outside of work.
04:02 - How many people still have long COVID?
How many people still have long COVID?
Theo Vos, University of Washington
The number of people affected by Long Covid has been hard to put a finger on. Some studies suggest that it might be as high as one person in five, others suggest lower. This week, the Journal of the American Medical Association - JAMA - has published a massive study considering data from more than a million people worldwide to try to get at the answer to this question. Chris Smith spoke to the lead author of that study, the University of Washington’s Theo Vos…
Theo - At the start of the pandemic, early reports came out of people who had become infected and did not recover within weeks as we would expect, but kept having problems going on for months after their illness. First thing we did was look at published studies, but we struggled to make sense out of all these different reports because they largely concentrated on counts of symptoms rather than really saying, you know, how severe is this and how does this affect people's health overall? So we turned to people who had registered to study long COVID and asked if they wanted to collaborate with us so that we could in much greater detail with information on each individual that they followed up, determine what the true extent is of long COVID.
Chris - Do we have an actual definition of what constitutes long COVID?
Theo - No, that is one of the problems. And so what we decided was, uh, rather than doing this sort of, you know, just reporting counts of symptoms, we said, Okay, well what are the big ones? And we concentrated on three large clusters of symptoms. One is people who have ongoing fatigue, often with bodily pains, you know, all over the body and mood swings. The second were people with ongoing breathing problems and then a third cluster of people with cognitive problems, you know, memory loss, lack of concentration, what, you know, popularly has been labeled brain fog.
Chris - And does a person have to have all of those things? Some of those things. One of those things. What do they need to have to fit the definition for what you are calling long COVID?
Theo - A person qualifying for one of the three clusters would be labeled as having a long COVID. But what we found was that of all the people who had at least one of these symptom clusters, about a third had more than one cluster and, you know, some unfortunate people had all three of the clusters.
Chris - And how long did they have to have had those symptoms for, for them to fit your definition?
Theo - We used the WHO definition, which says that you start counting someone as having long COVID at three months after the start of infection.
Chris - And how many independent studies did you end up collaborating with and what number of patients did that sum to? So what's your sample size here?
Theo - Yeah, so we had 10 collaborating studies, one in Russia and one in Iran. We complimented that with 44 published studies and two large medical record databases in the US. The strength of that is that you have large numbers and you can compare with controls. Because what's important with long COVID is that all those symptoms are pretty common generally. So to truly define what the occurrence is of long COVID, you have to have some comparison with people who have not been infected, where people reported how different they were with all their symptoms compared to the situation before they became infected.
Chris - So you have tried to capture and get at that problem, which is many people have said, 'well, are we comparing genuinely apples with apples the before and after COVID you'? When you do that, what trends emerge then? What fraction of people and who gets it and who doesn't? And what general predictors are there in terms of who's at risk?
Theo - Women are much more likely to be affected at twice the rate. Children are affected at half the rate of adult men. Overall our estimate is that just over 6% develops these three major long COVID clusters, but at a higher rate in women than in men and lower again in children.
Chris - And did you manage to find anything that would be some cloud with silver lining? Good news for people who have this were people by and large getting better.
Theo - Our best estimate is that 15% still have ongoing symptoms at one year. So the good news there is that the vast majority of people recover. Now what happens with that tail end? And that's still many millions of people and we only have information out going out one year past infection, We don't know how many of them will have a very chronic course of the illness. Time will need to tell. But at least for many people who become a case of long COVID, there's a reasonable chance that people will recover. The severity though of these symptoms is pretty high. You know, in our burden of disease work, we have the so-called 'disability weight' where we give a value to the severity of all the different, uh, diseases and, and their consequences. And if we take the average severity of people with these three long COVID clusters, it is equivalent to the amount of health loss that we estimate for things like deafness and the long term consequences following moderate to severe traumatic brain injury. So not trivial amounts of disability. And this is still the average. There's a spectrum of people who are way worse off and are extremely disabled and people who are less disabled that make up that average.
11:06 - Taking the lead on long COVID studies
Taking the lead on long COVID studies
Leora Horwitz
At the moment, it looks like about 1 person in 20 will get some kind of longer term syndrome in the aftermath of a dose of Covid-19, and 15% of the time, that might persist indefinitely. Women look like they’re more susceptible than men. So how are researchers trying to pursue this? Speaking with Chris Smith, Leora Horwitz is the person helping to lead the charge in the US…
Leora - My name's Leora Horwitz. I'm a general internist. I'm a professor of population health and medicine at NYU Langone Health in New York City. And, I am helping to lead the clinical science core for the NIHS Recover program, which is a program seeking to understand long COVID.
Chris - And have I read this right, that you've scored hundreds of millions in funding to look at this? Everyone wants to be your friend now!
Leora - Yes, but we do pass it all on to others! Congress has appropriated, a billion or so dollars to study long COVID and that includes doing observational studies, electronic health record studies and clinical trials. A portion of that has come to us here at NYU to distribute to hundreds of sites around the country that are doing observational studies of long COVID.
Chris - Do we agree yet, Leora, what long COVID actually is?
Leora - No, it's actually our first goal for the observational work and our foundational work. If we can't define long COVID, we can't do trials to see if we can make long COVID better.
Chris - So how are we defining it at the moment when we're trying to explore this entity? What are we actually thinking or saying we're studying?
Leora - Well, it's actually extremely difficult. So the WHO have made some stabs at definitions like having new symptoms or problems that started after COVID and that last a few months. And then others have taken much narrower definitions with specific symptoms. We are doing something in between, which is we are asking people about over 50 symptoms and whether they are new or different since COVID and using those, we will be able to come up with probably not one definition, but multiple definitions of long COVID.
Chris - So is it likely then that what we're dealing with is an entity that is an umbrella term, but it's united by the fact that everyone who's got these complex symptoms has been infected with COVID at some point. But what they've probably got is a range of different syndromes that they arrive at through different roots and possibly with totally different mechanisms and pathologies going on.
Leora - That's exactly what we think. Yes.
Chris - So how on earth are you gonna get a handle on this?
Leora - Well the Recovery study is studying adults, children and also people who have died to come up with some answers to the exactly those questions. What we do is we prospectively enroll people some at the time that they have their first infection and some after they've had an infection in the past. Every three months we ask them about these 50 plus symptoms so we can understand how those evolve over time. We ask them if they've had them before their infection and we also enroll people who've never had infection at all and ask them about the same symptoms because these are symptoms that ordinary people have in the course of their lives, even if they haven't had COVID.
Chris - Because Terence Stephenson, who did a similar sort of thing a bit on a much smaller scale and looking at younger people in the UK, found that while there was evidence that young people who had had coronavirus infection did have a certain complex of symptoms, more often he got a very similar number when he asked people who hadn't had coronavirus infections. So there must be a lot of noise in this system. It's quite hard to disentangle what's really COVID and what's background just because of what we've all been through in the last two years.
Leora - Yeah, there's actually many reasons. This is extremely hard and one of them is precisely that. One is that symptoms like fatigue, exhaustion, brain fog and joint pain and so on and so forth, any particular symptom you could come up with does exist in the general population. That's one problem. But there's other problems too. So one is that the virus itself has changed over time and it could well be that the kinds of symptoms people have long term from the omicron variant are different from the kind that people would've gotten from the original variant or delta or something other. Another challenge is that the treatments for COVID infection have changed dramatically over time as well. They may be better or worse able to prevent long-term symptoms. Another issue is that people are now vaccinated. So it could be that people have a different frequency or type or severity of long COVID because of that. And then finally the world around us has changed too. And living now is different from living in March of 2020, when the world was sort of falling apart and in 2021 and so on. So the other influences on people's symptoms and experiences have also changed over time.
Chris - How do you also get around the question of what epidemiologists and health statisticians call recall bias? If you go up to somebody who's got a problem, they're more likely to be an accurate historian or to remember things relevant to that than someone who never thought about it before.
Leora - Yeah, it's a real problem. We try to get around this in two ways. One is we enroll people who have not had COVID and we ask them about the same things in the same time periods. So hoping that, we're specifically asking them about things and it will jog their memory. The second way we do this is that we've reserved half of the slots in our study for people enrolled at the time of an acute infection, meaning they don't know yet if they have long-term consequences or not. And so we can then prospectively ask them, that means going forward in time every three months, ask them about their symptoms so that there's not bias there. And then I will finally say that we don't just ask questions. We collect large amounts of blood and other specimens.
Leora - We do a huge number of blood tests and other sorts of tests on people. We do x-rays, we do MRIs, we do at physical examinations, we do cognitive evaluations and so on. So we have as well objective data, which is a little bit less subject to bias. We also are doing tests to try to understand causes of long COVID. Here, we look at a variety of hypotheses. We are looking right now for evidence that there's still virus present in the body. We look for evidence of immune dysregulation. We look for evidence of other viruses being reactivated like EBV (Epstein-Barr virus). So we are looking for all of those different types of potential causes. And it's quite likely that some people will have some and others will have others.
18:33 - Do Dormant Viruses Cause Long Covid?
Do Dormant Viruses Cause Long Covid?
Lawrence Young, University of Warwick
One idea to account for some cases of Long Covid is that there may be dormant viruses of different types lingering in the body and which are reawakened by coronavirus infection, and it’s the effect of these agents that accounts for the symptoms. Possible culprits include viruses like EBV - the Epstein Barr Virus - which also causes glandular fever. As he explains to Chris Smith, Warwick University virologist Lawrence Young has been looking at this question...
Lawrence - Early evidence, Chris, that if you look at this infection, which is the most common infection in humans, so most of us - that's 96% of the world's population - sustain a lifelong, largely harmless infection with Epstein Barr virus. But what was seen early on in the pandemic is that people who had very severe Covid actually reactivating the virus. The virus was becoming more active and replicating at a higher level. And when people have followed those individuals who had more reactivated EBV during the acute phase, it looks like that translates into an increased risk of developing Long Covid.
Chris - But, as some people have pointed out, like Natalie McDermott, who we heard from earlier with a very tragic history, she said she had a pretty trivial run-in with Covid both times she thinks she had it, and it was only subsequently that she got very bad manifestations. So is that probably a distinct entity from the cases that you are considering?
Lawrence - No, because we've also seen in studies, and some of the studies we've started to do ourselves, but looking at other, other, other studies around the world that, that actually some folks with mild acute Covid are developing more long-term reactivation of EBV as measured by antibodies in the blood, elevated antibodies, to this virus. So it looks like this could be this could be an explanation for why there is a subgroup of individuals, irrespective of whether they had severe infection to start with in terms of Covid or mild infection, but a subgroup who for some reason that we just don't understand are more prone to reactivated EBV and that's contributing to some of the symptoms of Long Covid.
Chris - Do you have a feel for what might be the mechanism that underpins why a prior coronavirus infection should recruit and reactivate this underlying Epstein Barr virus - EBV - infection that almost all the population has got in some people?
Lawrence - Yeah. There's a very fine balance in the immune system with this virus. We've all got it and it lives - persists - long term in our lymphocytes - in our B cells - in our body, which is a very unusual and dangerous place to live for a virus because if it becomes reactivated in those lymphocytes, it can cause those lymphocytes to become or to misbehave and to produce autoantibodies, for instance. It's something we're seeing in relation to the role of Epstein Barr virus in multiple sclerosis, where you also see autoimmunity and you also see, incidentally, increased risk in, in women. So we're wondering whether what's going on here is it's something specific to do with the way that this persistent EBV lives in the body's immune system and this very fine balance between the immune control of this virus and what can go wrong if for any reason there's immune dysfunction.
Chris - Do we know why Covid causes that immune dysfunction? And indeed, is that exclusive to SARS-CoV-2, the coronavirus that causes Covid-19? Or would other viruses, if you looked hard enough, do this too?
Lawrence - Yeah, I think this is what we've got to try and tease apart. It's a cause and effect issue really. Is it that this reactivation is more likely in certain people? Are certain people more predisposed to this or are you just exacerbating in some way underlying autoimmune risks and pathologies? And I think it's teasing that apart and it's why we need to integrate all the sort of immunological work that's going on in terms of long covid with understanding how E B V and indeed other viruses might be reactivated as a consequence of SARS-CoV-2 infection.
Chris - There are other members of the herpes virus family, which are close relatives of EBV, which also are very, very common. There's one called CMV, which isn't quite as common as EBV but about half of of adults have had and are carrying that. There's also the classic ones we've all heard of, like chickenpox and the simplex virus that causes cold sores. Do they also manifest unusually in the wake of Covid, like EBV might be doing?
Lawrence - Where people have looked, there is some indication that in a few individuals that you're getting reactivation of varicella zoster - that's the chickenpox virus - and indeed, looking back in the literature, some early manifestations of acute Covid were people presenting with shingles; but it doesn't seem to be a very common effect. So I think there's something a bit peculiar about EBV, and I suspect again, it's something to do with the way the virus is living in B cells. Incidentally, there's a preprint from a group in the States who have looked at this in detail, confirmed an association between EBV reactivation and Long Covid, but they also found a rather bizarre thing, which was those individuals who had evidence of CMV infection were relatively protected from Long Covid. So this is all rather mysterious and it's gonna take a lot more work with a large well-defined population to really understand what's going on.
Chris - And the other thing that was alluded to by Theo Voss at the beginning was that the really strong signal corresponding to women getting Long Covid. How does that square with what you are finding with EBV? Because that's equivalent in both boys and girls, men and women, isn't it, in terms of who carries it? So why would there be that sex difference?
Lawrence - Yeah, I think when you are looking at something that's so multifactorial, we know for instance that there's a similar association of autoimmunity in women with other types of syndromes and diseases. And indeed, even if you look at cancer, women mount much better anti-tumour immune responses. They seem to have a heightened immunity. And that's something to do with the sex hormones. It's something to do apparently with work that's shown increased autoimmunity shaped by the degree to which sex hormones influence the microbiome in the gut. So there's lots of, lots of handwaving here, but there, there is something peculiar about the immune response in women, and that doesn't manifest itself in terms of other EBV-associated diseases. But it is worth mentioning however, that there are these similarities between Long Covid and chronic fatigue syndrome. And many of us have been grappling with chronic fatigue syndrome for years and the role of EBV and again the fact that women are more commonly affected by chronic fatigue syndrome than men.
Chris - And in terms of what the future holds, what can we therefore say about the lightly outcome; if EBV is doing this and is driving at least a proportion of the cases, what's going to happen to these people? We, we heard earlier that about 15% of people get really persistent symptoms that don't seem to go away after years. Do you think there's something special about them and EBV's doing that, or do we just not know? Have we got any insights yet?
Lawrence - Not really. And I think, you know, sometimes the only way to deal with this is to think about are there possible ways of performing some interventional trials? Is there some way of looking at moderating the disease? So for instance, there's interesting work in multiple sclerosis using vaccination and EBV-specific adoptive T-cell therapy to control that particular disease. You wonder then whether or not if there is a subgroup of patients who have Long Covid as a consequence of EBV reactivation, is there some way of dealing with that? The problem I have with that is that it looks, it's a bit of a hit and run scenario because what we're not seeing in these patients with Long Covid is high levels of EBV reactivation ongoing. What we're seeing is like the history really; we're seeing in their blood historical reactivation of EBV. So in a way, if you're gonna control this particular virus, EBV, you'd have to do it in the acute context of Covid. But I think what we need to do is think about clever designs for looking at interventions and certainly what we need to do is study large numbers. A lot of the studies I've mentioning are somewhere involved in, are sadly just looking at a few hundred patients. We need to look at a few thousand.
27:30 - Causes of long COVID
Causes of long COVID
Nathalie MacDermott, Imperial College London
Apart from being down to reactivating dormant viruses, long COVID in some people might be an inflammatory condition whereby the immune system remains activated long after the infection has passed and targets the wrong tissues. Nathalie MacDermott is in the fairly rare position of experiencing what it’s like to have long COVID as well as being an infectious diseases doctor. She thinks an inflammatory reaction against the wrong tissues might be part of the story for her…
Natalie - Nothing is definite, but I certainly have some kind of spinal cord damage or dysfunction related to COVID. I think some of it could have been the direct effect of the virus at the time when I was unwell and maybe some lingering events thereafter. But my illness certainly in the first year to 18 months was somewhat progressive, and that wouldn't really be explained necessarily by the direct effects of the virus. You know, during the very acute illness that I had with COVID, I think some people think there's virus lingering in the body. I'm not sure that that would be the case for, for me. I think maybe the virus has triggered my immune system to mis-recognize some of my own cells in my body. And so my body's created antibodies to those cells and is then attacking elements of my host cells. And particularly in my case, nerve cells and causing some kind of ongoing damage or dysfunction of those cells.
I suppose the other possibility, and there's some data to support what I just said, there's some early data to support the possibility that, so when you're first infected and your immune system is interacting with the virus, it produces these pro-inflammatory chemicals that we call cytokines, and these can trigger inflammation within the body. So I think the other possibility is that one of those chemicals were triggered at the time that I had acute COVID and they caused some damage, but for some reason they may also be lingering in my body. Whether that's because I've got these antibodies that are mis-recognizing my own cells and that are triggering them, or whether that's just because there's some kind of persistent inflammatory trigger in my body that's, that's constantly resulting in some of these chemicals being secreted and those chemicals themselves can cause damage to cells and inflammation. I guess those are the three things that I'm kind of considering when it comes to myself. As you said, I think there is a huge variety in the symptoms and presentations of post-COVID problems that we sort of term long covid, but that's very much a big umbrella term for what's probably several different pathologies going on in different people's bodies.
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