Long COVID: What we now know

Unpicking the latest on who's at risk, what might be causing it, and how we might diagnose it in the future...
17 August 2021
Presented by Chris Smith, Eva Higginbotham
Production by Eva Higginbotham.

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This week, long COVID: we’re 18 months into the pandemic and there are thousands of people with long-term health consequences of having caught the infection. We're asking the experts to find out who is most at risk, what could be causing this to happen, and what research needs to be done in trying to treat it. Plus, in the news, an even gloomier outlook on climate change as the latest IPCC report confirms we need to drastically reduce emissions; also a new carnivorous plant discovery - the first for 20 years - and we're asking why COVID vaccine uptake is lagging among the under 30s in the UK... 

In this episode

There is no planet B - climate change march slogan

01:11 - IPCC report gloomier outlook on climate

Newspapers have described the IPCC report as a wake up call; but perhaps we already knew the facts...

IPCC report gloomier outlook on climate
Joeri Rogelj, Imperial College London

As wildfires wreak havoc across Greece and California, off the back of shock floods in parts of Europe and a heatwave across the western half of North America that saw temperatures touch 50 degrees Celsius in Canada, the message this week from the IPCC - the intergovernmental panel on climate change - was chilling. Imperial College’s Joeri Rogelj is one of the authors of the new report that spawned those headlines. Chris Smith wanted to know what’s changed since the last such update was published, in 2015, and how reports like this might or might not be able to help stimulate action to combat what many regard now as a full blown climate crisis…

Joeri - For the first time, the intergovernmental panel on climate change now states unequivocally that our human actions are responsible for the change that we are seeing around us. The report also states that to stop global warming, we have to bring down our global emissions to zero. These two pieces of information really tell us where we are today, but also what we should be doing.

Chris - It comes across as quite a sort of slap on the wrist slash finger waggling, 'we told you so' and now we're even more sure this outing of the report, the message hasn't greatly changed, but the tone of the language and the certainty certainly has.

Joeri - Well, these reports from the IPCC, we publish them every five to seven years. So, as climate change has been progressing, the report can say things with greater urgency, can show greater impact. and so on. At the same time, the report also has made great improvements in what we scientifically understand and attributing what we see to human activity. It's one of those great advances of this report.

Chris - Words like unequivocal are really very powerful. So, what has changed in the last five years that means that you can now say pretty much unequivocally, this is because of what we're doing. Whereas five years ago, there was a lot more uncertainty around the word.

Joeri - The reason for this is really twofold. First of all, we have seen more climate change, more warming. And so the signal of what we're seeing is coming out of the noise, unprecedented extreme events that could not have happened if not for climate change. The second reason is that methods and computer power have increased a lot, and these are necessary for the calculations to be able to make these statements.

Chris - And when we say IPC, it's often not reported as to exactly what the intergovernmental panel on climate change is. Who's on that panel and how these reports get put together. So, can you explain it for me?

Joeri - I'm an author for the IPCC, but the IFCC are 195 countries, all the countries, pretty much of the United nations and this one at 95 countries, they come together, they commission reports and then the scientific community, we are producing those reports, following a very rigorous, transparent and open process that runs over many years. For example, in this report, we prepared roughly three years for it. We answered more than 70,000 review comments. The report then gets signed off sentence by sentence by those 195 countries, which makes these reports very powerful in the political arena.

Chris - Yes indeed, because obviously having buy-in from all those different member countries means that it's relevant to a global community, but is not part of the problem, there are some countries that are accounting for a disproportionate amount of emission and the report doesn't point fingers. It's very smooth in its language around human activity.

Joeri - Yeah, that is one aspect of IPCC reports. IPCC reports have to be policy relevant, but can't be policy prescriptive. That means that there is very little finger pointing going on. For reports that are more pointing fingers there are other organisations, including NGOs that do a much better job at this.

Chris - But there is some sort of facility being made for legal action now isn't there around this so that countries can be brought to the table and their behaviour, in terms of emissions and so on, can actually attract some legislative manipulation?

Joeri - Absolutely. There are a few avenues where this can happen. First and foremost actually, the report will be feeding into political discussions. For example, in the context of the climate summit at the end of this year in Glasgow, it's not legal action, but it's definitely diplomatic action of countries putting pressure on each other. But then indeed, as you say, this report really provides a very good basis for legal action. First, we can now attribute changes that we see around us to human activity. So, we can really say also in a court human activities are responsible for much of the damage that we are seeing. On the other hand, as the report also shows what needs to be done to limit warming to safe levels, this also provides a really interesting puzzle piece for legal action.

Chris - When you say how much carbon dioxide we can still emit, that answer isn't very much though is it? We don't have very long before we really have run out of runway.

Joeri - Yes indeed. If we want to limit our warming to levels that are considered safe. That is kind of the iconic 1.5 degrees of global warming, the carbon budget, that we can still admit is very small. I'm now going to throw around a few numbers, 500 billion tons of CO2, and putting that in context on an annual basis, we admit around 40 billion tons. So, that means in slightly more than 10 years, this budget would be used up if we don't decrease our emissions from today.

Chris - So, are you optimistic or pessimistic?

Joeri - I'm a typical optimist. At the same time I'm a realist. While I know that it is necessary, while I know that we can do it, and for example, the great efforts that have been done during the COVID pandemic show that if the need is there and if the will is there, change can be implemented very rapidly. But I'm also a realist in my own research, I research where emissions are heading based on the promises that governments have made today. And that really shows that we are not on track to limit global warming to safe levels at all. By mid century we would be well beyond all the global goals that we have set ourselves. So, I also see that side of the coin.

A fly

09:04 - New carnivorous plant discovered

A well-known flower is actually a carnivorous plant, hidden in plain sight...

New carnivorous plant discovered
Thomas Givnish, University of Wisconsin-Madison

Thomas Givnish from the University of Wisconsin-Madison recalls playing in the Pine Barrens of New Jersey as a child amidst an off white, yellow flower perched atop a long green, hairy, sticky-looking stem. Decades later, the previously documented, Triantha occidentalis has been re-designated as a carnivorous plant. As Harry Lewis reports, this particular species has stood innocuously next to roadsides and gone unnoticed, until now…

Tom - It has a very unusual kind of trap mechanism. Its flower stalks are sticky and this runs counter to a theory, actually to a theory I devised a number of years ago, that carnivorous plants should not place their traps next to their flowers less they eat their pollinators. But it turns out that this plant Triantha, found in Western north America, is able to do this because it's tentacles, its glandular hairs, have a relatively weak glue to them so they can catch nats and midges. But they're too weak to immobilise the larger much stronger bees and butterflies that act as pollinators.

Harry - How unique is it to find a carnivorous plant in this day and age?

Tom - It's quite unusual, but not unheard of. It's only the 12th lineage in which carnivory has been discovered in plants. By lineage I mean all the plants descended from some common ancestor.

Harry - Carnivorous plants, they're quite specific to where they grow in terms of location. So, what is the advantage of being carnivorous?

Tom - That's an excellent question. All carnivorous plants have costs, right? They have to construct digestive enzymes or lures like odours or showy leaves to trap prey. So, there has to be some countervailing advantage to those energetic costs. And I argue that the most likely advantage would be an increment to photosynthesis. Photosynthesis is sunlight; it's limited by nitrogen and sometimes phosphorus. And so carnivory should evolve when the energetic benefits through enhanced photosynthesis exceed the costs of carnivory. And the conclusion is simply put that carnivory should evolve when nutrients and nutrients alone are limiting.

Harry - And when discovering this new lineage, I'm sort of imagining you wading through bogs and rainforests in order to find it. Was that the case?

Tom - Not at all. This story began with Sean Graham who had been studying the relationships among plants related to the Philodendron family, the aroids. And he found that a particular gene ndhF had been lost. Sean recognised that a number of carnivorous plants have lost that gene, for reasons we don't understand even to this day. So he said, "Oh that's interesting." And he also recognised that has these sticky inflorescence stems and thought, "Hey, maybe this is a new carnivorous plant." So, he interested one of his star graduate students. Qianshi Lin in the project? Qianshi designed an elegant set of experiments in order to test whether the plant was indeed carnivorous. He first of all grew up fruit flies on a medium that included a lot of heavy nitrogen. So, it comes in two stable isotopes, the common one being N14 and a somewhat heavier one being N15. And he applied them to the leaves of the plant and to the tentacles. And he was able to show 64% of the nitrogen in the plant was coming from prey.

Harry - Which is really high isn't it, Tom?

Tom - Yes, for a plant to be recognised as being carnivorous you have to demonstrate two things first that the plant is able to take up mineral nutrients from dead animal bodies, and secondly, that it has some unequivocal adaptation for prey attraction or pre capture or prey digestion. And in the case of the bog asphodel the ability to take up nutrients from the prey, finally, he was able to show that it had specialised adaptations for prey digestion. So, it turns out that the leaf hairs secrete phosphatase, which is a digestive enzyme that is found in many, but not all carnivorous plants.

 

Person sticking a pin into a roadmap

15:17 - Black howler monkeys create mental maps

By optimising their route-based mental maps as they go, black howler monkeys navigate just like us

Black howler monkeys create mental maps
Miguel de Guinea, Oxford Brookes University

Although we’re now all used to looking at Google maps to navigate, in the absence of technology and written maps humans use route based navigation - that is, we go the way we know will get us to where we want to be, even if it’s not the shortest way, and will normally optimise over time. Now, researchers at Oxford Brookes and the University of Texas, Austin have shown that black howler monkeys, who previously have been thought of as having low cognitive abilities, actually navigate through vegetation in search of fruits using mental maps just like us, and are capable of refining their mental maps as they go to optimise their journeys. Eva Higginbotham heard from lead author Miguel de Guinea from Oxford Brookes University...

Miguel - Black Howler monkeys use routes to navigate that resemble the navigation system of humans to a level that we have not seen ever before. So, for a year I was waking up almost every day at four in the morning to follow these guys, we were following them 12 hours a day. We would get to the field, find the tree where they were, sometimes they would howl in the morning. So, howler monkeys howl which means that they engage in very loud vocalisations which you can hear one kilometre away.

Eva - Can you do an impression of one, how do they sound?

Miguel - I think I can do something like that after hearing them so often. It's something like [rather impressive howler monkey impersonation].

Eva - Sounds terrifying!

Miguel - It's kind of terrifying. It resembles a lot like Jaguars. It's pretty...it's very intense when you hear it in the jungle the first time! So, then we will find them in this tree and then we would follow them for the rest of the day. They will be foraging, socialising, having encounters with other groups, and then they would go to their sleeping tree and we would go back home to the research house, and go back again for the sunrise the next morning. So, these monkeys wouldn't travel long distances, but maybe between 300 metres and maybe 800 metres. The thing is that this area's very sloping, it used to be a Mayan city. And on top of this ancient Mayan city, there is a forest. So, there are several changes in elevation that we have to deal with when we are following the monkeys. They navigate in the canopy, but we move on the ground. So, we are all the time going up and down cascades and Mayan temples. So, it's sometimes very daunting, very challenging to get there!

Eva - And what did you find?

Miguel - We found that they do rely on routes very often. It was pretty clear since the beginning that they were using the same routes, but the thing is that they do manage to move very efficiently in the forest. So, when I was analysing the data, I was like, this is not just it, it's not that they are using these routes. So, I was like, there is something going on with the structure of these routes because they navigate in a very straight line despite using previously established routes. Then what I decided to do is to say, okay, so how would a monkey move if it had no cognition? And I simulated movements using an algorithm to just compare. And then what we found is that the observed monkeys develop this set of routes that are highly efficient. So, it allows you to navigate in between any location in the area that is highly relevant to any other location using a very short path. So, they do develop this set of routes that are highly efficient and that's why it seems to me as if they were navigating in a metro. So, they just have the Metro network in their minds and they just use it to navigate.


 

A globe lying on a facemask with a syringe stuck into it.

19:03 - Reduced COVID-19 vaccine uptake in under 30s

Unravelling why younger age groups appear to be sluggish when signing up for their vaccine

Reduced COVID-19 vaccine uptake in under 30s
Linda Bauld, University of Edinburgh

The UK’s vaccination programme has been one of the successes of the pandemic, and high vaccination rates are likely what has led to the dramatic drop in Covid fatalities. However, as younger age groups have gradually become eligible to receive their vaccination, we have seen the uptake is much slower. At the moment three in ten people under 30 have still not received their first dose of vaccine. Sally Le Page asked University of Edinburgh public health specialist, Linda Bauld why this might be...

Linda - If you look at the 18- to 29-year-olds in the UK, around 72% of them have had a first dose of the vaccine. And you can see that in people in their thirties it's significantly higher. We're looking at about, I think, 80% at the moment and higher than that in people in their forties. What I would say though, there are some caveats around that. Although there are a number of 18- to 29-year-olds who will have been eligible for quite some time, because they've got an underlying health condition, there are others who only relatively recently have become eligible earlier in the summer, for example. So it's natural that they would have a slower uptake. But what I would say is striking, and I've been looking at the figures very closely over the last, for example, month, is the rate of increase is slower than it has been for older age groups, and that does cause me some concern.

Sally - Why do you think uptake has been so low in younger groups if it's not just a matter of there hasn't been enough time?

Linda - The first point is we could do better, but let's face it over 70% with the first dose is not bad. So credit to the young people who've come forward. That's absolutely brilliant. Main reasons for not taking up the vaccine are; the first one would be convenience, and the fact that they may not be in their locality, know where they can go, or the vaccines may not be as available to them.

Sally - Especially as I imagine more young people are likely to move house more often. Certainly I was. So having to change GP surgeries all the time is another thing on top of that.

Linda - Well, that's right. And with students with university and college students, that's a big issue, you know, registering with another GP. The other point, which is probably the main one is that young people don't see COVID-19 as a direct threat to their health.

Sally - You're right. I mean, as a 29-year-old, I remember a good period in the spring and early summer where everything was opening up, we were told non-essential retail, that's safe for you. Workplaces, pubs, museums, even small gatherings inside is all safe, even though I hadn't even been offered my first dose of the vaccine because of my age. If it was safe, then why do young people need the vaccine now?

Linda - Well, that's the thing. I think the communication has been mixed. The key thing is that we know that COVID is still in the community and it was there at that time when other things were opening up. But the comms has been complex and to try and communicate relative risks by age is quite a difficult thing to do. And perhaps we forgot that young people needed to be protected as well. The other thing from a scientific point of view is long COVID. The evidence on that is accumulating all the time. And we now know that younger people are also at risk of long COVID, not as much as older groups, but they are. And then the third point is younger people are more common consumers of social media than particularly much older groups. And that's where a lot of misinformation about vaccines exists. And I think young people may be seeing more of that misinformation than older groups.

Sally - Now obviously COVID isn't the only public health issue that has ever existed. Have there been any successful initiatives in changing public behaviour in past public health issues?

Linda - Oh, there's loads and loads. Reducing rates of smoking in young people where people have come forward and recognise that reducing smoking in indoor public places or encouraging people to take up the offer of a quit campaign. Those are things that we can do. So behaviour change, generally, I think has some basic principles. Clear evidence-based communication, accessible affordable interventions, whether that be a vaccine or a treatment or a counseling option, whatever, and also changing social norms. So I think there's things we can learn from other aspects of public health. And then the final one, I would say, which is a bit of an outlier for vaccines is even incentivising people to come forward to take up a public health intervention is something we've done actually tried and tested.

Sally - Yeah. You mentioned these vaccine incentives. We've seen recently things like discounts on takeaways and taxi services, but there are also, I suppose, non-vaccine disincentives. So making it harder for people who aren't vaccinated with things like restriction on travel. Which tends to work better; carrot methods or stick methods when it comes to changing public behaviour?

Linda - Well it's very interesting, because there's at least one study on this for COVID vaccines. And actually interestingly, in that study from Germany, for younger groups, they were more motivated by not being able to do things, not go to a pub, not being able to go on holiday, etc., if they were not vaccinated than by, you know, winning a prize or having the option of an incentive. And internationally, the need for vaccine certification is something we're just going to have to live with for travel. And I think for young people, actually that is a motivating feature, whether we do it much to get into a nightclub or other aspects of social and economic life, I'm not so keen, but I do think it has its place.

Person suffering with long Covid

25:21 - Long COVID: how many are suffering?

Who is most at risk, and what are the most common symptoms?

Long COVID: how many are suffering?
Lawrence Young, University of Warwick

We’re looking at long COVID - long term symptoms that some people describe in the aftermath of an acute covid infection. They include breathlessness and extreme fatigue, heart problems, cognitive issues, diabetes and some people have developed neurological syndromes. What are the latest numbers on who is getting long COVID, and what are the most common symptoms? It turns out that’s a pretty complicated question, with multiple concurrent surveys using different methods leading to different numbers. Lawrence Young from the University of Warwick spoke with Eva Higginbotham...

Lawrence - Well it looks like from different studies now it's around a million people in total, including adults and youngsters. So as you said, this is complicated because the diagnosis is still a little vague in pinning down exactly the different types of long COVID, but it looks like something like 10 to 30% of adults can end up with this disease.

Eva - It's such an incredibly high number. How are those numbers being acquired? How are we measuring how many people?

Lawrence - Well, there are lots of different studies going on. There's a study, the REACT study that we hear about, which has looked at the prevalence of infection and long-term consequences. There are studies using the ZOE app, which is where people are self-reporting, those are often complicated because obviously that could be a bit biased if you're self-reporting. And then we have the Office of National Statistics data. So there's lots of different data coming in. And that's why we have such a broad range of percentages here, because we're still not exactly sure how best to define long COVID and therefore how many people are suffering, but it's clearly a lot of people.

Eva - And what do those data say about who is most likely to suffer from long COVID?

Lawrence - Well, whilst a lot of this suggests that you don't need to be symptomatic, you don't need to be really sick to develop long COVID, it's quite clear that if you experience five symptoms or more during the first week in which you're sick, then you're more likely to get long COVID. It is associated with increasing age, it's associated with obesity, with body mass index, and it's interestingly found more commonly in women than in men.

Eva - And what are the most common symptoms of long COVID? Is it often sort of a continuation of what you had in the acute phase or are people developing symptoms that they never had before?

Lawrence - Yeah, I think some of it is a continuation and there is a category of long COVID, which clearly is defined by continuing symptoms from the symptoms that you develop during the acute phase. But most of this is stuff that just lingers and it actually fluctuates a lot too. So it's defined by extreme tiredness and fatigue, shortness of breath, chest pain, joint pain, this thing called brain fog, which seems to be a very common feature of long COVID where you have problems with memory and concentration, insomnia, heart palpitations. So I think this is a range of symptoms, which makes defining long COVID quite challenging.

Eva - And of course we're still going through it. People like Freya are still sick 16 months later, but do we have any idea of how long most people might experience long COVID for? How long does it last?

Lawrence - Well, that's something where, again, the data is looking quite interesting. The data from the Office of National Statistics, which estimated about a million people were reporting COVID symptoms for more than four weeks also found that something like 385,000 folk had COVID19 for at least a year. And that's the data that came through in June of this year. So it's likely that quite a significant number of people will be having one or more of these symptoms for a long time.

Eva - And what about other viral infections? Cause we hear things like chronic fatigue syndrome; that can be set off by things like glandular fever as far as I'm aware. Is this really special to COVID or is there something more general to other viral infections too?

Lawrence - I think there is an element of something that is common in sort of post viral syndromes. And this is where I think it gets very complicated in terms of diagnosis, because - I think - it's quite clear that we're not looking at a single disease. We're probably looking at multiple diseases. Some of them associated with the severe infection and lung problems that people have if they've sadly had to go into intensive care, but a lot of the fatigue related illness, it's very reminiscent of chronic fatigue syndrome. And so I think we and others are looking at that in detail to see whether or not there is something very specific about SARS-CoV-2, or whether this is a general feature that we see with chronic fatigue.

Coronavirus particles.

31:40 - What's causing long COVID?

Scientists are looking for the mechanism behind the condition...

What's causing long COVID?
Akiko Iwasaki, Yale University

What’s the mechanism behind why some people are developing these syndromes? Chris Smith spoke to Yale Immunologist Akiko Iwasaki...

Akiko - So there are a couple of theories that are now posed to explain long COVID. One is a lingering virus or a viral reservoir that persists in a person that can stimulate chronic inflammation. The other possibility is autoimmunity; that even a mild viral infection can trigger autoimmunity, which has long-term consequences.

Chris - So when you say long-term infection, this would be that although the virus has, say, disappeared from the lungs, it could be loitering somewhere else in the body, and it's the physical presence of it turning over gently and indolently somewhere that's continuing to drive the immune system and cause some of the symptoms that people describe?

Akiko - Right. So that's one of the theories of lingering virus or viral reservoir. And data from studies have already shown that the gastrointestinal tract of people who recovered or who had COVID months ago still contained viral antigens and RNA. And so it's possible that a reservoir like that, where we cannot capture the virus from the nasal pharyngeal swabs or saliva may still exist somewhere.

Chris - The surprising thing though, is that it's not everybody. Why would that happen to just a magic 10 to 20% of people who catch the infection and the rest would get rid of it?

Akiko - That's a critical question that many of us are trying to answer. Some of it has to do with the demographics that Lawrence just discussed, which has to do with, you know, women of middle age or ages between thirties, forties, fifties. These are also the age group that is at high risk for developing autoimmune diseases. And so if COVID is triggering autoimmune diseases, it might explain why that's predominant in these, this age group of women.

Chris - And when you say auto-immune disease, this is the immune system being persuaded to turn on itself. Instead of defending us, it starts attacking us. Why would coronavirus infection do that though?

Akiko - Well, we don't really know why it would do that. We've certainly seen evidence of auto-antibodies that develop in COVID patients. And there are many theories out there as to why a viral infection can trigger autoimmunity, but there's a lot of autoimmune diseases that have known links to a viral infection. How exactly a viral infection induces autoimmunity still unclear.

Chris - You therefore have two theories. One is that the virus loiters for longer than you'd like in some people, the other is that it does nasty things to the immune system. Or it could be both, I suppose, couldn't it going on at the same time. How are you trying to find out which it is?

Akiko - Right, so long COVID is likely a collection of distinct diseases. And we're trying to understand the underlying cause by casting a wide net, looking at immune phenotype and metabolic phenotype in people with long COVID. And so we are trying to understand how the immune response differs between long COVID patients versus those who had acute COVID, but recovered completely.

Chris - And does it?

Akiko - Well so far, the evidence is still very premature, but we are seeing some distinct differences in people who have long COVID versus acute COVID and studies have already come out showing presence of auto-antibodies, different cytokines that are elevated, activation of different cell types. So we are getting a early glimpse into how the long COVID is being driven.

Chris - And do those changes that you're detecting, these antibodies that recognise us rather than foreign invaders, inflammatory signals and so on. do they actually marry up with the sorts of symptoms that people are describing? Do you see more of those sorts of things in people with worse symptoms? Do you see those things disappear as people's symptoms improve and how do you disect away what's cause and what's effect because could it not be that if someone's got problems in a certain part of their body that's making the symptoms, they get the antibodies because of that, not causing that?

Akiko - Right. So the cause and effect issue is a little bit more difficult to untangle. Currently a lot of the evidence is correlative. But we are seeing symptoms that may be consistent with the type of autoreactive reactions that people are making. For instance, if a person is making antibodies against, you know, cells of the brain that could result in inflammation within the brain that can trigger fatigue or brain fog or memory loss.

Chris - A question which is surfacing a lot, and I think with very good reason, and it's even as an argument being used to justify why we should target vaccination at certain groups is vaccination could reduce your risk of long COVID. Would you agree?

Akiko - Vaccination in general will reduce the risk for getting infection as well as subsequent diseases. So definitely, you know, it's very important that we all get vaccinated. However, vaccination may not guarantee a person from not getting long COVID. In fact, there is some evidence that's arising that shows that people who are fully vaccinated can get long COVID from breakthrough infections.

Chris - The other thing just since we're talking about vaccines, there have been a number of people saying I've had the vaccine, my long COVID got better. What do you think?

Akiko - So there are a couple of groups, mostly patient led groups that are reporting about 40% of long haulers who get the vaccine feel better, whereas about 15% feel worse after the vaccine. And so we think this is a very interesting phenomenon and that the immune response to the vaccine may be causing this difference in the symptoms. We're actually starting a study where we are collecting blood and saliva from long haulers before and after the vaccine to try to understand how immune changes that result from vaccination might contribute to symptom improvement or worsening.

Chris - Do you think it's just the coronavirus vaccine or is it the immune modulation that's conferred by having a vaccine? And so it could be a flu jab that would achieve much the same outcome.

Akiko - So that all depends on which of the two hypotheses are true. So if the viral reservoir is what's causing long COVID, then it has to be a specific coronavirus vaccine in order to eliminate that reservoir. Whereas if it's auto-immune disease, any vaccine that could trigger the right kinds of cytokines may be helpful. And in fact, I have heard from people who've gotten other types of vaccines and also feeling better. So we have yet to discover which of these hypotheses are true, but there are some early signs of indicating that it could be the autoimmune disease.

Chris - So it'll be interesting to see what happens with the forthcoming flu season.

Akiko - Yes, it's a great opportunity, actually, to monitor how long haulers might respond to flu jabs and whether that could be helpful, and if so, why.

a blood sample on a slide in a lab

39:20 - Long COVID: Developing a diagnostic test

Why is it so difficult to definitively diagnose long COVID?

Long COVID: Developing a diagnostic test
Danny Altmann, Imperial College London

One of the difficulties in studying and treating long COVID is that we don’t currently have a definitive way to diagnose it. And without a diagnostic test, the condition becomes much harder to manage or study. Eva Higginbotham spoke to Danny Altmann, an immunologist from Imperial College London where he’s been looking to see if there are any similarities in the blood of people suffering from long COVID...

Danny - Well, this follows on from the kind of ideas that the Akiko was talking about just now, that if you start from the assumption that long COVID means that something has gone awry in the long term in the immune system as a consequence of having been infected with SARS-CoV-2, there are many things one could look for, many signatures one could look for in blood. One of them is this thing of autoimmunity, the idea that the body has started attacking itself. So if you can work out a signature of antibodies against self, autoantibodies, that long COVID people tend to have in their blood that others don't you're on the way to having a test.

Eva - And so does that mean you're taking blood samples and then looking in those for specific signs of these antibodies?

Danny - That's exactly what we're doing. We're working with cohorts as widely as we possibly can. People who were hospitalised, people who were not hospitalised, people who didn't even manage to access a PCR test but who now have that clear set of persistent long COVID symptoms. And we're looking at the array of antibodies in their blood and working out which parts of the human proteome, the human protein antigens, they respond to so that we can work out what that test could look like and make something that could be accessible that could get them that diagnosis that they need.

Eva - And what have you managed to find so far?

Danny - Well, so it's fairly early days, we're trying to expand our early data out further as we go, as are many other labs around the world, including Akiko's at Yale. And so far we've been working especially with people where we've got quite a good handle on their long COVID from things like MRI analysis. And we have been finding some signatures that are reproducibly found in people with persistent symptoms that aren't found in those rapid recovery people. So we feel we're well on the way to having the kind of test that we want.

Eva - Do you think this kind of test, if you are looking for autoantibodies and those are causing the disease, could account for all the different kinds of long COVID that we see? Because there's such an array of symptoms.

Danny - Yeah, well, you know, long COVID is a very diverse and sort of scary business, isn't it, with so many different possibilities. And in medicine, yes, sometimes we like to stratify things as much as we can and show all the differences. For the purposes of this initial analysis, we've kind of gone to the other extreme and said, let's be completely agnostic about all the different things that long COVID could be and say, if we simply put together our long COVID groups and our rapid recovery groups and our healthy control groups, are there any blood markers we can find that are useful? And so far we feel like we're winning, but you know, I accept that down the line, you may want to say, well, could this be useful for telling the difference between a skin rash long COVID person and a brain fog long COVID person? And I'm sure it could be

Eva - And you mentioned all these different groups, is one of the groups you're looking at the people who are actually asymptomatic for COVID, but now seem to have developed long COVID afterwards?

Danny - Very much so. So to me, they're one of the most interesting groups, but they're also one of the most... everybody's desperate, but they're particularly desperate, aren't they? Because if you have long COVID - bear in mind this isn't obviously just a UK problem, it's a world problem - so we're talking about something like 20 to 40 million people on the planet with long COVID, all trying to access care, all kinds of convince their doctors they have a problem, and all trying to get into that care pathway. Imagine how much harder that is if not only do you not have a diagnostic test for your long COVID, you can't even prove to them you had COVID in the first place because you were asymptomatic, and perhaps people in your household had it or whatever. So, you know, I'm especially interested in those people.

Eva - And finally, if you did manage to make this kind of test, how do you think it could be used? Do you think it could be used to help predict who's most at risk of having long COVID for a really long time?

Danny - I think there are many nuances to be brought out of it, but in the first instance, I'd like it to be within that battery of tests that your doctor can order as for other autoimmune diseases like diabetes or arthritis, where your local hospital can just do the test and say, yes, tick the box, this is long COVID, of they go to the long COVID clinic, you know, let's try and help this person and do something for them.

A line of differently-shaped pills.

44:04 - Trying to treat long COVID

Why is it hard to develop treatments, and what clinical trials need to be performed?

Trying to treat long COVID
Mark Toshner, Royal Papworth Hospital

While research into mechanisms and causes of long COVID continue, how can we help the thousands of people already affected? Mark Toshner is a respiratory doctor at the Royal Papworth Hospital in Cambridge who spoke with Chris Smith...

Mark - Yeah. So it's a really difficult area right now, and I have a long COVID, or a post COVID clinic, in Papworth. And if I'm very honest, I don't have an awful lot to offer patients right now. And it's partly related to some of the things Akiko and Danny have spoken about. There's a lot of very exciting science going on, but it's going on, it's active right now, and it hasn't drawn its conclusions. So that's really hard to then feed into clinical trials to kind of figure out which therapies might work

Chris - Well, you mentioned clinical trials - surely that is the linchpin, isn't it? It's trying to dissect away who's got what, when, why, and which of their syndromes is caused by what mechanism. Because we seem to have so many different balls in the air. Part of the problem is that we're being completely overwhelmed with information, and dissecting out what is going on for each person seems to be difficult.

Mark - It's really challenging, and it's an evolving space, and some of this can actually be dealt with by the type of trials you set up. So for example, it's not very dissimilar to the situation when we first encountered COVID and the best response to that was a trial called the Recovery trial, where they were completely - and I thinkDanny used the word agnostic and I'm going to follow that theme - agnostic to what's causing it, what the major players might be, and just have very big trials that are able to put lots of different therapies in depending on how the evidence changes. So I think there are some things we can do about that, but it requires a lot of funding and it requires most patients, or a lot of patients to be enrolled in clinical trials to clarify what therapies work.

Chris - Are you tending to approach this then as a doctor who's saying, what symptoms have you got, and what can I detect that I might be able to fix? So rather than saying, you're labeled as long COVID and I'm going to treat you as long COVID, I'm going to treat you symptomatically and try and improve your function?

Mark - At the moment, that's very much the case. So largely we are restricted to looking for the things we know about and excluding coexisting or complicating diseases that have established therapies. But for most of the patients who have residual symptoms in my clinics, I don't have anything evidence-based to offer them at the moment. What we really need now is a really huge effort in the clinical trial space to try to feed in some of the mechanistic work, some of the work being done on what might be causing the different parts of post COVID or long COVID syndromes into clinical trials, to get some actual answers and to make meaningful differences to patients.

Chris - But what we heard from our previous three contributors was very much that this is not just one syndrome. It appears to be lots of things going on and different people are affected differently. So does that mean then that just going to see one doctor who's very good at doing one type of medicine might not necessarily be the answer, do we need broader clinics with a wider range of expertise in them to try to fix people up?

Mark - Yes, we almost certainly do. So this is not going to be solved by one doctor, it's going to be teams of both clinicians and healthcare workers, and that's what the very best services that are in evolution right now are looking to do, they're looking to draw on expertise from a wide variety of different areas. But again, we may find in another six months that we need to change the composition of those teams, because at the moment we still don't have absolute clarity over the proportions of patients we're going to see with different problems. So it very much is a space that needs to be dynamic.

Chris - Well, one factor that seems important for many people is time, time to get better. We heard at the beginning of the program from Freya Jephcott, who told us about her run in with COVID earlier on.

Freya - I used to have big problems with brain fog and this insane fatigue that would just make it hard to lift my limbs. And I was getting ridiculously high fevers up until a few months ago, and quite bad rib and joint pain, and deafened by tinnitus and smelling garbage everywhere. It was really horrible. But actually at this point, everything's bearable, and I think if it stays at this level, then I'll be able to sort of, to some degree, get on with my life, be able to do my desk job and hang out with my partners and see friends. But I think it's going to be a while before I could, say, go to the shops and carry bags, and I'm not sure if I'll be able to drive again.

Chris - So presumably you're just being confronted by people with that sort of story in these clinics, Mark.

Mark - Yes, but I think there's also a positive part to that story which is, she is getting better. It's slow and it's painful, it's frustrating, and often it comes and goes, and that is very much what we're hearing. But as a respiratory doctor, this isn't new for us. So when I see patients after pneumonias who've been admitted to hospital, quite often at three to six months, they are not back to normal. They're nowhere near back to normal. So the underlying idea of convalescent trajectories varying is well established. It's just that in COVID we seem to have a really big burden and a huge amount of patients who've suffered from it, as well as a kind of very dizzying variety of potential new complications that we're having to unpick. So I think there is a positive message here which a lot of the patients I see are getting better, and some of them are back to normal, but there's a big rump, there's a big proportion of patients out there who still have a lot of symptoms and we're really going to need to put a big effort into the research space to try to clarify why, and then to figure out if there's anything we can do to improve things for them.

Chris - Do you have optimism, really? Are you feeling that, in fact, we are funding this properly, we're addressing this properly and it's actually going to be alright, or are you nervous that in fact we're storing up trouble for tomorrow?

Mark - So I'm nervous because there are so many patients out there, and I think funding structures are slow. There definitely needs to be more money pumped into this. I'm optimistic because everything in the pandemic has been turbocharged and research has really proven it's worth time and time again. And this is another scenario or another situation where research can give us the answers. It's going to be slightly more challenging because it is a complex set of different diseases and it's chronic, so it's going to take us a while to get answers because by definition, we're going to have to prove that treatments stick months down the line, not days or weeks.

Chris - I think probably one question going through people's minds who are listening to what you're saying is going to be well, I've got long COVID. What advice can you offer me for both the short term and the longer term?

Mark - So my biased take on this is that you need to be pushing your centres to be enrolling in and taking part in clinical trials, because without clinical trials, we won't get answers to this. There are going to be a lot of snake oil salesmen, and already there are, colonising the space. So just be really wary of anybody who tells you they know the answer. If they are pretty convinced and pretty convincing, they are probably not right, because there are no really good, well-evidenced treatments yet. And there are things that might work, but this space is going to be, you know, just watch as people left, right, and centre tell you that therapies X, Y, and Z are absolutely going to cure your symptoms. I think time is going to be an important thing here, and if I was a patient, the major thing I would be doing is I'd be banging the door donors to see that clinical trials are actually set up and that you get a chance to contribute to them.

Cartoon of the brain.

52:01 - QotW: How much of the brain is memory?

Is there a specific region dedicated to memory? You won't forget this week's question in a hurry

QotW: How much of the brain is memory?

Amy Milton from the University of Cambridge helps Naked Scientist Harrison Lewis wrap his head around this week's question.

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