Do Dormant Viruses Cause Long Covid?

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.