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Jessamy: Hello and welcome to The Lancet Voice. I'm Jessamy Bagunel. It's the middle of February 2022 and I'm here with my co host Gavin Kleber. Long Covid is a disabling condition for millions of patients with a wide range of symptoms and an unclear prognosis. Six months ago, we at The Lancet wrote an editorial calling it a modern medical challenge.
At that point, we had no agreed definition, no clear diagnostic pathway, many different types of syndromes, and no treatments. There's still much work to do. But since then, we've had two definitions. One from WHO for adults, and in the last few days, a research definition for children. This is crucially important because it guides who is included in studies and really lays the foundation for how we think about the disease.
We wanted to catch up on progress with Claire Steeves, who's a clinical senior lecturer at King's College London. She's also a consultant geriatrician at Guy's and St Thomas NHS Foundation Trust. If you would like to carry on the conversation or get in touch with us, please find us on our Twitter handles.
at jessamy bergenahl and at gavin cleaver.
Gavin: Thanks jessamy and yes now you're going to hear us talking with dr claire steves about long covid.
Jessamy: So claire we've now got a clear definition of long covid what is it and why is it important?
Claire: Yes we do have a definition we've got two definitions i guess which are quite similar. The first one bearing in mind real world is the who definition and so that is defined as a person who has a history of probable or confirmed SARS CoV 2 infection, who then goes on to have symptoms for longer than two months that usually occur about three months from onset of illness.
So I guess we're talking about that 12 week mark and we're talking about previous probable or confirmed infection and also that it's not explained by an alternative diagnosis. And I think that's really important because many have now pointed out that Actually, if you've had COVID 19, you might be more at risk of alternative diagnosis as well, but that's not in the definition of long COVID.
Now, the NICE, the National Institute of Clinical Excellence, also put out a definition before WHO, which is quite similar, but it's different in just one respect. Their definition was signs and symptoms that develop following an infection that's consistent with COVID 19, so both definitions don't require an absolute test positive to start with which continues for more than 12 weeks, but may fluctuate in severity.
And again, not explained by an alternative diagnosis. So they're very similar definitions. I think broadly we can say. that they're the same, then we've got some consensus. That's right. And do you think they're going to change? So I think what's interesting is this whole idea of not explained by an alternative diagnosis.
And I think that we might be able to hone that down a little bit more because some things that currently appear to be long COVID might, as we get more tests and more understanding of, what might be. This syndrome, it might break up into several different bits and we've already got some pointers in research that's already been published that, how that might work.
Jessamy: And I guess, what's the, what are the implications, why is this important for research? What does it mean for studies that are starting up now and moving
Claire: on? So getting a definition is absolutely essential. Because in order to study biomarkers or treatments or preventative strategies, you have to be able to define when you think something is what you're trying to treat or prevent.
And When there's difficulty in defining that, that makes it very difficult to really identify scientific projects even recruit patients, etc. So you do need to have a consensus definition, and it needs to be something that researchers can work with, and people who are recruiting to trials can work with and understand.
Jessamy: Exactly, and that's not to disregard all the research that's happened up to now, it's just that now that we have some kind of consensus over what we think this syndrome or constellation of symptoms and signs is, that we can have a better and greater understanding.
Gavin: Claire, given all that we now know about long Covid, how serious do you think the burden is in countries that have had such huge Covid infection waves?
Claire: I think undoubtedly it is. a significant burden. And I think what's going to be particularly illuminating really about that burden is going to be what happens post Omicron because that's affected substantially greater numbers of people in most countries than previous waves because of the transmissibility.
Already we know from estimates from the office of national statistics, for example, within the UK, that very substantial numbers. Even if you're talking about the 12 week mark over 500, 000 people in December, for example, having a significant impact, life impacting long COVID at that time.
So that's a huge, impact upon the workforce, it's an impact upon healthcare services, it's an impact upon those people's lives, and maybe on their development in their future, especially if we think again about children or about young people, that may have a very lasting impact upon their life, even if they get better from it.
So yes, I think it is, a substantial issue and we've yet to see how substantial it's going to remain to be after we've assessed the effect of Omicron on Long Covid. I've
Jessamy: got a couple of follow up questions on that because it's such a sort of interesting point. One is, do you think that this concept of the definition that we have for Long Covid, and you might be more familiar with the literature, but I'm not very familiar of any cohorts that are based in low and middle income countries.
It does very much seem to be a sort of high income thing at the moment. That can't be true because it must be equally impacting other areas. Do you think we're going to see some of that burden or do you think that it's just a priorities case and actually we're going to be focused on it in high income countries and less focused on it in low and middle income countries?
Claire: That's a really good point, actually some of the first studies, one of the first population based studies of of long COVID was from the Faroe Islands. There were other studies, there've been other studies from Nigeria, other studies from India that have, again shown the same sort of figures around long COVID.
So this is not something that only affects high income countries. It might be something which is more talked about and more researched in high income countries, but we do have quite a number of longitudinal population studies across the globe, and one thing that I've been involved in is in developing, for example, questionnaires that can be used in any longitudinal study.
study and as part of the Welcome Trust sort of body of longitudinal population studies, we're sharing that with researchers worldwide. So these are tools that can be used in any setting to identify long COVID and investigate it in different settings.
Jessamy: Fantastic, that's very good to set me straight on that and also great that you're going to have some kind of calibration tool which can go across different spaces.
But about this sort of Omicron variant, the potential impact of differences in short term symptoms to long term symptoms, do you have a sense of some of the biological hypotheses or sort of foundations of why things might be different? Or do you think we're not really there yet in our understanding of what's causing long COVID?
Claire: So I think there are two questions there, aren't there? There's like understanding of what's causing long COVID and then understanding of symptom differences between different variants. I think that they're potentially quite separate but Possibly related issues. Let's maybe break them down and take it.
Shall we take the first one first, which is the mechanisms that underpin long COVID?
Jessamy: Exactly. Do we have a good enough understanding of the mechanisms that are causing long COVID to be able to not necessarily predict, but to feel that there could very well be a difference? in different types of variants?
Claire: And I don't think we're there yet, actually. I don't think we can say we can predict, for example, how Omicron is going to fare in terms of long COVID. What we, so what we can say is that Omicron appears to affect the lower respiratory tract differently to Delta. And to other wild types and so on and so forth.
And so that might definitely have a significant effect on who goes, for example, to intensive care. And the ventilatory burden and the respiratory disease appears to be different in Omicron. But it appears that breathlessness ongoing sort of respiratory lung involvement is only one part, one subset in a way, one potentially sub cluster of this syndrome of long COVID.
And so I can't, put my hand on heart and say actually because it doesn't affect the lungs, Omicron is not going to lead to long COVID because it might not lead to that particular characteristic of one group of long COVID, and it might not lead to such respiratory damage or post ITU sequelae, which are definitely.
There and certainly were there from the first wave. But what about neurological differences or changes, brain fog? What about the long term fatigue? These things, the mechanisms behind them may not be respiratory so much. as much as immunological or indeed neurological. And I guess we've got less confidence therefore, we would imagine that we might have less confidence that those are going to be not such a big issue with Omicron.
But this is where we need to keep going with this research, keep going with this identification of individuals and test what the effects of new variants as they come across us. Oh,
Jessamy: thanks Claire. I think that's a pretty comprehensive answer. So much more work to do on that essentially. And what are we starting to understand about the role of vaccines and how they might interact
Claire: with long COVID?
We published with the Lancet infectious diseases back last year a paper, which we were looking at two things. We were looking at what's the characteristics of individuals that get breakthrough infection. And then secondly, what are the symptoms and manifestations of the disease that they then carry?
And one of the first things we saw was that certain groups were more likely to have breakthrough infection, particularly frailer older adults, frail, frail adults in particular, individuals with certain comorbidities more likely to have breakthrough infection. And we know as well from serological studies that seems to be likely that's because of a difference in response to the vaccine.
The immunological response might be different. They are therefore less protected by a double vaccine. And then so the great sort of question, which is still not fully answered is, does a boost to vaccination help? redress that balance and I think there's definitely research coming out that suggests that is the case and so that the booster is a leveler in terms of that, that difference in post vaccination infection after two vaccinations.
But the second question is around what is the nature of infection post vaccine. We saw very early on after vaccines were brought in that hospitalization and the intensity of the initial illness was lower after vaccination. And we certainly see that there's a much greater proportion of individuals that are asymptomatic at all, don't have any symptoms at all.
Even if you ask them about 30 odd symptoms, they don't have symptoms. And then of people that do have symptoms, there are fewer of them that we found in our study that have more than five symptoms in that first week, which was a severity marker that was associated in the wild type with going on to needing hospital and going on to get long COVID.
And then the final thing we saw was that there was a substantial reduction in the risk of going on to have more than 28 days of symptoms. And so that's what we published in that Lancet Infectious Disease paper. But of course, that's not strictly the definition of long COVID as we've discussed, which is more than 12 weeks.
But now, in the last week or so, we've had a couple of papers. One from the ONS and one from an Israeli team showing the same finding that in the case of the ONS, at least, that long COVID defined by more than 12 weeks was substantially reduced by vaccination, about the same as what we found in our paper.
So about, I think it's 41%.
Gavin: Can I ask a potentially stupid question, which is generally my role on this podcast anyway. I was wondering about, when we talk about the definition of long COVID, obviously people who have had mild to severe and hospitalized infections, then developing these symptoms for 12 weeks, that seems a fairly.
clear case of long COVID. What about people who have really severe infections and end up in hospital, maybe spend days, weeks, perhaps even months in ICU? How do you separate out the after effects of the long battle they've had with COVID from what might then be long COVID?
Claire: On an individual level, that's really difficult to do, isn't it?
And I think it's a question of those individuals who've been in ITU and had a long Time that we'll be seeing a sort of post ITU recovery clinic and set up and the clinicians multidisciplinary team that will be involved there will be really looking for all of the things that we know are associated with ITU admission in whatever.
the illness that you have. So I guess on an individual level they'll be looking for key differences. From a research point of view, I guess the way that we often separate that is by making sure that analysis is holding true in individuals that are not admitted to hospital. And that we investigate people in the less the less severe spectrum.
And we see findings which are corroborated. And I would say that people who were admitted to hospital there's a much greater proportion of those that go on to be classifiable as long COVID people living with long COVID than people who are living in the community. That is found across the board in all countries of the world.
that there's an increased risk for more severe disease early on.
Gavin: Yeah, that was going to be my follow up question. So is it relatively rare for someone who has quite a mild case of COVID to go on to develop long COVID symptoms?
Claire: Yeah, so we saw and we looked at 10 longitudinal studies within the UK and we found that your risk of going on to get to live with long COVID was substantially different depending on which age group you were at.
And it was about one to 2 percent of individuals that got COVID that went on to get more than 12 weeks of symptoms that affected their ability to carry out their activities. usual activities that they would want to carry out. But in the older age group, sort of 50 60 age group, it was about 5%, so 1 in 20 people had long COVID, which was significantly affecting their life.
And that's substantially lower than studies like FOSP, which have looked in hospitalized populations.
Gavin: Yeah. Was there any difference in in gender groups as well?
Claire: That's right. There is. And almost all studies actually have found that that the risk of going on to get longer term symptoms is higher in women than it is in men.
Gavin: That's very interesting, isn't it? Because COVID early on we found had worse effect, as far as fatality went, on men rather than women, but so I guess there's probably no point speculating as to what the mechanisms there might be, but it is a very interesting finding, isn't it?
Claire: I think what's interesting is in the last sort of a couple of months, really, we've had a number of research outputs on long COVID, which have hinted at what might be the source of this.
And there are at least two papers that I've seen that have shown differences in auto antibodies. Associated with long COVID. And of course that's something auto immunity is something which has a clear gender bias that women are more likely to suffer for most autoimmune conditions than men. And there, there may be a sort of certainly a pointer towards autoimmunity or auto reactive antibodies being relevant in the development of long COVID.
Jessamy: Just moving on Claire, to the next six months and a sort of semi research agenda that you see is important that we might be able to get some answers to over the next six to twelve months. What do you think are the key questions and do we have a good chance of answering them?
Claire: Yes, I'd say that one of the first questions is what actually is the burden now going through from now because what we need to make sure is that we scale our resources. to what is required. So we do need ongoing epidemiology of how long COVID is panning out as the pandemic progresses in terms of recovery of individuals that have already been affected and in terms of new individuals that are suffering from this condition.
So that's number one. Number two, which actually is probably really number one, is we really need to scrutinize interventions, interventional strategies. Whilst there are trials going on in long COVID, there are bigger trials and potentially more relevant trials for prevention going on with antiviral.
treatments. And I'd be really keen to see those trials report on the risk of subsequent long COVID. Because ultimately the thing that everybody wants here is to prevent future long COVID to cut the stem, the tide of it. And the earlier that's done the better. So that's why we were so interested in.
how vaccines work because that's the first preventative step that we have in our armory. And the second one is early treatment strategies for people who, you know who have COVID. And on that note, that's where to be able to really scale that up. We need to have good biomarkers really early in disease, potentially before disease.
Of people who are more at risk. And if we have them, then that means that we can target our interventions, which could be quite expensive interventions to people who are most at risk.
Jessamy: So what we're saying is earlier the better. We need to understand who's at risk better. We need to understand the burden, and we need to have an interest in what's going on with antivirals, paxlovid and things like that.
And how that's gonna play out in terms of long covid. .
Claire: And the other thing, the other things that I think is really key is that, we need to in a sense, scale up and integrate the research into management of long COVID. And what that means is that these long COVID clinics that have set up, I think it's really important for patients, for people who are living with this condition, and for the research community, as it were, to really escalate and develop its strategies, to really work together in a strategic way so that people can get early access to, Trials and interventions, and also that we accelerate the delivery of this because, we can't be waiting around.
And I think that we did that very well in the beginning of COVID, that we did the regulations, the ethics, the whole process worked very quickly to get studies up and running for acute COVID. What we need to be doing is bringing that in for long COVID as well now.
Jessamy: And I guess taking a real health systems approach to that management structure and architecture that we've already got in there in terms of making sure that we've got the right governance, making sure that we've got the right finance, making sure that we've got all of these other, building blocks to, to really be dealing with this in a holistic and strategic way, as you say.
And I guess outside of the kind of clinical questions that we have, there's also a sort of. Historical element to it almost in the sense we've got this new disease. And how do you see our understanding of this and our relationship with long COVID playing out over the next couple of years from a sort of, almost as a sort of societal point of view and a, and a meaning point of view?
Claire: Yeah. So I think, and that's very interesting. In a way, because so many people have been affected by this condition at one time, this is an opportunity to really study and understand the impact, the longer term impact of some of these infectious diseases of which COVID, might be unique or it might be similar to many others actually and this is an opportunity to understand that better.
But then of course that the other thing is that COVID, it's not just the disease of COVID that's had a massive effect on us, it's actually All of the lockdown, all of the social distancing measures the stressor for us all, the impact upon family relationships and dynamics bereavement, et cetera, big.
big difference in schooling we can go on. So there's been huge impact of this pandemic upon the way we've lived, which is going to have long term implications beyond long COVID, but in terms of the impact of the pandemic as a whole. And I think that that's going to be something that's going to have a very long legacy in terms of research and in terms of learning about how we should be dealing with.
pandemics in the future.
Gavin: So just me, I was reading up on the definition of long COVID after you and Claire were talking about it. And it really strikes me how important it is to have this definition, not only for the reasons that Claire was saying, but there is such kind of wildly differing statistics out there. There was this amazing estimate that between 1 percent and 51 percent of children who had COVID ended up with long COVID.
And those kind of stats are just unworkable, aren't they? So it's like this, to have this definition is really important, actually.
Jessamy: Yeah, it's extremely important. And I think obviously we had the adult definition. earlier on in the year not in this year, sorry, last year. And then just recently in the last couple of days, we've had the research definition for long COVID in children, which is pretty large.
The way they've gone about this is through a Delphi process. So they've essentially got a whole group of experts together and gone through several rounds and with involvement of patients as well, several rounds whittling down what the symptomology and definition should be to gain some kind of consensus.
So what they've come up with is that long COVID in children and young people is a condition in which a child or young person has symptoms, at least one of which is a physical symptom, that have continued or developed after a diagnosis of COVID 19 confirmed with one or more positive COVID 19 tests.
So it's pretty broad reaching, you can imagine that there are lots of people that are going to maybe fill that category. But why it's so crucial is because the way that research programs and agendas are developed is this is going to guide who's included in those studies. So it really sets the foundation for understanding of this condition.
Gavin: But it just shows how early we are in the process, doesn't it? Two years into COVID we, we feel like we know a lot about it by this point, but we're really only now getting around to defining long COVID and then research into What causes long COVID, what effects it will have, how we cope with the burden of disease has to follow on from that and that'll be even, that'll be another few years.
Jessamy: Yeah, and it could be a very long time because it's a very difficult disease to really pin down. We know that there are lots of different symptoms. People probably have, very different broad groups of being severe to less severe. We don't really have any clear diagnostic pathways. We don't really have any clear treatments.
And, you heard when we were speaking with Claire, that there are some key things there that we really need to understand, particularly around the impact of, say, antivirals or vaccines. on what happens to long COVID. Two studies recently they're both observational with an element of matching.
I think probably the major problem with it is there's going to be an element of recall bias, which is because we're asking the adolescents involved who ranged from an age of about 11 to 18 about symptoms that have happened in the past. They might recall things differently. And the message that those two studies bring are really quite nuanced.
And what it almost seems is that all of these symptoms, including mental health, headaches, many of the common things that we associate with long COVID have probably increased both in patients who were positive for COVID, but also in patients that were negative, that just in, in the general population.
And that might be because of the pandemic, but it's also hard to know because there weren't any really comprehensive studies. that was done before COVID 19 about what the burden of these symptoms were. So there's a nice comment that kind of tries to bring out some lessons from it. And I guess one of the key things that brought out for me was contrary to the sort of research definition that we've got, that actually it might not be from a kind of useful empirical point of view.
It might not be that useful to have a single definition because of the breadth of what this condition looks like. So it's extremely complicated.
Gavin: Yeah, and like you said, we still have a kind of top line understanding of what this burden might be following COVID, even compared to pre COVID times. There was a stat that really stuck out for me that was in the Financial Times a couple of days ago that said that the number of people not looking for work due to long term ill health has increased by 230, 000 from pre pandemic levels just in the UK.
And when you start to generalize that out to other countries, I'm sure part of that is attributable to other things, but it also feels like quite a lot of that will be attributable to the after effects of COVID infection. When you start to generalize that out to other countries, it really feels like a significant burden for workforces.
Jessamy: Yeah, exactly. I think it's a significant burden for society and the economy potentially, and one that we're not really going to have a proper grasp on. For a little while, yeah, because we've only really just got these agreed definitions and what we are going to include in what we consider long COVID and there might even be some uncertainty or invalidity almost about those definitions.
Gavin: I think phrasing it as a burden serves probably to obscure a lot of the suffering as well of people with long COVID because when you think that, there are countries like Australia and New Zealand that operated a zero COVID policy that have had a few thousand infections and a few hundred deaths overall since the start of the pandemic.
People who have long COVID in a lot of these countries are going to be suffering because of policy choices. The burden of their ill health can be directly traced to decisions made at the top level. And I think that's it's a shocking, it's a shocking line to draw between those two things. And I think, yeah, maybe the word burden doesn't really come close to doing it justice.
Jessamy: Yeah, I think you're absolutely right. Obviously there's a sort of burden at the macro level, but there's very much the burden at the individual level. And that's huge for patients. And also. extremely challenging because there's a lot of uncertainty around the prognosis and there's also very poor access to proper, care and therapy.
I think it's quite an isolating thing and I think Claire mentions in her interview that, it's often something that gets left behind or forgotten because you don't necessarily see it, and people aren't necessarily demanding care about it.
Gavin: Yeah, it doesn't feel very visible, does it, a lot of the time.
The media often runs stories that are from a particular individual point of view, of someone who's been hugely impacted who maybe can't get out of bed several days a week. But then from a very individual point of view, it doesn't feel like we have many stories so far of this kind of broader impact of COVID beyond Just repeating things like numbers of people in a Facebook group, all of whom are talking about symptoms and the impact on their lives.
Jessamy: Yeah, it's interesting, isn't it? Because I'm not sure when that will become clear. And also we've got so many competing interests at the moment from a health point of view. It will be difficult, but also interesting to see how we level that up on the sort of prioritisation agenda and how we make sure that is an absolute priority because it is obviously as we've said, individually, very difficult, but also on a larger scale, we're starting to see some of that impact, for work and life.
Gavin: Yeah, and you could argue, of course, couldn't you, that so many disabilities are invisible on a societal level just because the people involved don't have the, don't have the voice, don't have the power to make themselves heard.
Jessamy: Yeah, and we tend to take them out of society. We tend to leave them behind and to, look away from that because It's often too complicated or too complex to try and solve that problem.
And I think, there's amazing people in the NHS and, all around the world doing excellent work on long COVID at the moment, but I'm sure we'll not allow that to happen and we'll push it through the agenda, as well as the patient voices as well. But In terms of kind of evidence based, therapies and treatment management pathways, all of these things will take some time to come up with because it's not so straightforward as an acute disease where you can have a clear end point or outcome where, this is what you should be doing.
And I suppose also that the comment in the Lancet Child and Adolescent Health You know, also said that we should be aiming towards an outcome of overall wellness. But all of these things are broad and therefore difficult to measure and difficult to set an agenda towards almost.
Gavin: Yeah, that's quite quite amorphous, isn't it?
And I think Claire mentioned in her interview as well, they were talking about up to 30 different symptoms that could have been part of long COVID, which just goes to show we've got a definition, but we still don't have much of a handle.
We hope you enjoyed this episode of The Lancet Voice. Please do find Jessamy and I online to continue the conversation. Do subscribe on the platform of your choice if you'd like to hear more, and we'll see you again in two weeks time. Thanks so much for listening.