The Latest on Long Covid

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.

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.