Should we stop calling it Long COVID?

While many people with Long COVID have reported neurological symptoms like brain fog, there has, until recently, been no objective measurement of how severely people really are affected. That was until a new study from Imperial College London, recently published in the New England Journal of Medicine, found that people experiencing Long COVID saw cognitive deficits equivalent to a 6 point loss in IQ. The lead author of the study is Adam Hampshire…

Adam - We built on the back of one of the largest epidemiological studies that was run in the UK during the pandemic. It was called React, which is the real time assessment of community transmission. And that was a project where they sampled somewhere in the order of about three and a half million people randomly within the general population to see at different points in the pandemic whether they had been infected with the virus and whether they had covid or not. So we kind of got this background on people's history of covid if you like. And what we did is we recontacted 800,000 of them and asked them to take part in an online cognitive assessment on a platform that's called cognitron that can measure different aspects of cognitive and memory ability through people's laptops, their smartphones. And out of those people we contacted, there's about 140,000, did at least one of our tests and about 112,000 completed the entire assessment.

Chris - How big are the differences that you are detecting? So if I took an IQ test for example, and I was affected in the way that some of the people you registered in the study were affected, how many IQ points down would I effectively be if I were affected in that way?

Adam - If we treat the global score from this assessment like an IQ test, then the group with the largest cognitive deficit is on average people who were in intensive care. And so they showed a difference of around about minus nine IQ points. People who have ongoing persistent symptoms, that is the ones who may have long covid, they perform at about minus six IQ points and that's enough that it could have affected your daily function. You are very likely to be aware and notice that change. The larger number of people of course sit in the short term symptom group and they show a difference on average of about minus three IQ points and that's very small. But we are powered, we are able to detect that because we measured so many people.

Chris - Were there any things that leapt out in people who got SARS CoV 2 infection where certain elements of cognition were consistently impacted or is it just an across the board reduction for at least a period of time in everybody?

Adam - In terms of aspects of cognitive ability, we saw the strongest relationships with having had Covid 19 in memory function reasoning and what we call executive function things like planning. That's the case. If we were looking at, for example, people who had longer term sort of ongoing persistent symptoms. So what some people would refer to as long covid

Chris - And critically, when a person says they get better, because we know that a proportion of people have symptoms for a certain period of time and then they get better. When they get better, does their cognition go back to normal? Do you think?

Adam - We have to be very careful here in terms of the inferences that we draw. What we're looking at are essentially associations. We are not looking at change because we have only measured one time point. Nonetheless, the pattern of results that we see shows that people who have ongoing persistent symptoms perform worse than people who have shorter duration symptoms. Whilst that's the case, even people who had short duration symptoms on average showed slightly worse cognitive performance compared to people who had not had covid at all. The really interesting group of people who had ongoing persistent symptoms. But by the time we cognitively tested them, those had resolved. That set of participants performed at the same level as people who had only short-term persistent symptoms. That is only a small cognitive deficit was still evident.

Chris - Well that's slightly encouraging, isn't it, because it notwithstanding the fact that this is an association would argue that there should be an improvement in someone when their symptoms overall subside.

Adam - Exactly. I think on the face of it, our study has some results that were quite negative and not really what we hoped to see. For example, we don’t see any association between shorter duration covid and cognition. And that's somewhat worrisome. It's not what we were looking for or we didn't predict that. On the other hand, it does appear to be the case that people who have long-term persistent symptoms, when those symptoms eventually subside, they may well have some degree of recovery in their cognitive and memory abilities. Another really quite promising result that we had was that actually several of the results in the study converged towards indicating that this association between covid and cognition has reduced throughout the pandemic. So the association was larger for the original virus and for the alpha variant, but by the time we get to Omicron it seems to have been diminished.

Chris - To what do you attribute that? Do you think that's because by that time it's hitting people who've been either infected before and recovered or vaccinated before and are therefore subject to a less severe infection?

Adam - Well, our model takes all of these things into account, but they're quite hard to disentangle because they correlate across time. So of course if you think through the course of the pandemic, different virus variants were dominant. Right? And then in addition to that, partway through they started to roll out vaccinations and approaches to treatments probably improve somewhat as well. Within the model, it would appear to be the case that if a person was vaccinated at least twice prior to their infection, they have a small cognitive advantage relative to people who had not yet been vaccinated. So I think that's one aspect that's probably coming into play and it's very likely that later variants had a lesser impact on cognition as well. So these things aren't mutually exclusive.

Given the broad range of symptoms, from brain fog, to fatigue, muscle pains and signs of nerve damage, it’s likely that Long COVID is not one single condition but an umbrella term uniting a host of different syndromes, all with different mechanisms, outcomes and best treatments. I went to see Cambridge University virologist Ben Krishna, who branched out into working on Long COVID during the pandemic. He agrees that “Long COVID” can be an unhelpful term…

Ben - So the problem with the terminology of long covid is just that it's a very broad and umbrella term. You can imagine three different people. You've had one person who was very, very sick with COVID-19 in 2020. They went to the hospital, they were put on oxygen, they were given what we call mechanical ventilations. They essentially had a tube put into their lungs and then their lungs were inflated artificially for a certain amount of time. And then eventually they've recovered and they've been discharged from the hospital. And you're thinking six months later, are they feeling back to where they were before COVID-19? The answer is probably no. But is that really Long COVID or is that really just them slowly recovering from the initial infection? You then have person two, they lost their taste and smell that hasn't come back for whatever reason. I don't think we exactly know what causes that yet, but for whatever reason, they can't go to restaurants.

But at the same time, they can go into work and they can do everything they normally do. It's just a taste and smell that's gone. And the third case, and these are perhaps in my opinion, the strangest cases where somebody got sick with COVID-19, they had the similar symptoms that a lot of people are familiar with. So they were in bed and feeling fatigued and most people got better and they went back to their normal lives. And for these people, they just didn't get better. And in some cases, it's been a year, sometimes two years, and these people still feel like the first early days of a viral infection and they just never recovered.

Chris - What do we think the underlying mechanisms of cases like that latter one might be?

Ben - So it's still quite controversial what might be causing it. There is a growing body of evidence that the immune system switches on and then fails to switch off. What exactly is causing that is not entirely clear. It could be, for example, that people got infected with the virus, the virus has infected some parts of their body and is still there at a very low level and is just continually making small amounts of virus. And as a result of this, their immune system is still on and still fighting the virus. And that's what's making them feel sick. Because we know that a lot of what really makes you feel sick when you've got a virus is actually the immune system's response fighting the virus, not the virus itself. Alternatively, it could be something autoimmune. So it could be that the immune system started off fighting the virus and now it mistakenly started attacking a part of the body that it's not supposed to. And actually a lot of long covid does look a bit like autoimmunity. Particularly many patients say they have cycles of symptoms, so they get better and then they get worse and they get better again. Or finally it could be something that we're just not aware of right now. It could be that the immune system is switched on, it's not switching off and it's for some reason that we just don't know about yet.

Chris - How are you trying to get underneath that and find out which of those, or whether all of them are behind this?

Ben - Our research suggested that the immune system had switched on in people who had COVID-19. And in most people it switched off. But in this small group of patients with long covid, it just was still switched on and it was particularly switched on. It was making one particular protein. This protein is called interferon gamma, and it is known to make you feel quite sick. We tried looking for viruses in these patients. So what we did was we took blood samples on these patients and then we just looked for signs that the virus is still there. We didn't find anything in the patient's blood. We were particularly interested in their intestines. So there's some data out there showing that patients continue harbouring the virus in their intestines and it comes out in their poo. That is actually where we're moving at the moment, is trying to understand that side of things.

Chris - If that is the case that either the virus has tickled the immune system and it's stayed locked on in some way, or the virus is hiding somewhere and tickling the immune system from a covert hiding place, possibly the gut. In either scenario, the immune system's overactive, what can we do to turn it off?

Ben - So this is why the mechanism is so important because you might approach those in completely different ways. If you are harbouring a small amount of virus somewhere in your body, you might actually be able to treat long covid by giving people antivirals. Alternatively, if it's autoimmune, an antiviral is going to do absolutely nothing. And actually what you want to do is to give people some sort of immunosuppressants. I have heard that there are clinical studies looking at both of those, but I haven't seen any convincing results one way or the other yet. But that is obviously something that people are very excited by.

Chris - Do you think this phenomenon is unique to SARS-CoV-2, the coronavirus that causes covid? Would other coronaviruses do this? Or more broadly, might all viruses be capable of doing this? So if we had a bad dose of flu, this could happen. And is it just that we got so many people all at once catching SARS-CoV-2, that it disclosed this phenomenon and it's always been there. We just didn't see it.

Ben - You've put it in better words than I could have right there. So yes, it's probably the case that you had this new virus. It turns up no one has any immunity to it. Everybody gets sick all at once. And so you get this big wave of people with what we call post viral syndromes. They're just sick for long periods of time after the virus. There is evidence from SARS-CoV-1 commonly called SARS. That was an outbreak that happened in East Asia, particularly South Korea and Japan and China back in 2003. There were patients there who got sick at the time and they were reporting years later that they still didn't feel better. I have seen some evidence that flus can do this. They had a patient who got Spanish flu in 1919 and were still sick into the 1920s, and they just didn't know what to do with this person. So yeah, there's this view now that maybe all viruses cause this, and if you have a brand new virus that springs across from animals and then causes the pandemic, you are going to get a big wave of post viral illness. And of course that's very worrying because we expect there will eventually be another pandemic. And so trying to understand long covid now might help prepare us for the next one.