In this episode we speak with Dr David Strain, Lead on Long-COVID for the British Medical Association and a key member of the Long-COVID Taskforce for the NHS.
Dr Strain covers the origins of Long-COVID and curious observations that point to possible causes and importantly, evidence based treatment options.
Dr Strain covers what has helped people gain symptom relief based on patient surveys. The research on immune-modulating drug treatments- their cost, scale and accessibility challenges. Concluding with commentary on Neuromodulation and how research has shown significant improvement in symptoms of brain fog, post exertional malaise and myalgia, highlighting it's potential as a very attractive treatment for Long-COVID.
Dr David Strain
Senior Clinical Lecturer at the University of Exeter Medical School
Lead on Long-Covid, British Medical Association
Member of the NHS Long-COVID Taskforce
Dr Elisabetta Burchi
Dr Elisabetta Burchi 0:00
So welcome Dr Strain. Thank you very much for being with us.
And today we are going to talk about long COVID, Dr Strain has been involved since the very beginning of the pandemic into COVID-19 response collaborating with the NHS in the COVID-19 Task Force, so is the perfect person to talk to in this moment.
So Dr. Strain, can you tell us something about long COVID? Everybody knows about COVID-19, of course. But what about long COVID?
Dr David Strain 1:00
So it's a very interesting condition at first, really, we started to see it sometime around June, July, after the first wave of COVID hit us in the UK.
Actually, the term long COVID was coined by an archaeology fellow from UCL who's originally from Lombardi and she caught COVID during the first wave, and in May that year, she started tweeting about these long symptoms.
And it runs very similar to chronic fatigue syndrome, or myalgic encephalomyelitis. It doesn't appear to be related to severity of the original COVID, it could be people who've got a very mild original infection.
But then over the coming weeks and months, they start noticing this post exertional malaise. So they'll do any sort of activity, but they just feel disproportionately tired afterwards.
And people are describing chest pains or palpitations or ongoing cough and shortness of breath. There are people who've been in ICU with a really severe case of COVID.
That was almost expected you know, if you've been a couple of weeks on ICU, it is expected that you're going to take weeks or months to get better. But the real surprise here were people who only got very mild infections in the outset.
And then I started seeing them around June, July, that they were presenting to our chronic fatigue syndrome clinic or their myalgic encephalomyelitis service, because they were just mirroring those patients- generalised aches and pains, palpitations, tiredness, that was an accounting for, unrestful sleep.
And then the key symptom that seemed to come through in long COVID, that's not such a big part of CFS was the brain fog. There's a difficulty focusing, difficulty concentrating, such that people's attention span wasn't getting more than 20 minutes or so.
So they weren't able to get through a conversation, let alone for a full working day. And this was really the position that took us from June right through to October, November, when we started having recognition within the NHS, that this is going to be a major problem that needs to be addressed.
Dr Elisabetta Burchi 3:21
An emergency basically.
Now, so it's very interesting that this syndrome is not related to the severity of the initial acute illness.
So, and I actually read that, while [severity of] COVID-19 is more often found in males over 65. For long COVID is true that young and females subjects are more prone to develop it, maybe because the immune system is involved.
Dr David Strain 4:06
We did start to see that quite early on there.
Whereas the acute COVID as you say it was older, it was men more than women, people with complex co-morbidities, lots of diabetes, lots of heart disease, but you're at high risk of COVID.
When it came to long COVID in the first tranche of people that were identified, this was predominantly young fit females it was females in the 20s or 30s.
There had been no other morbidity comorbidities they were otherwise completely well and that were really hit hard with this.
Now, as we follow this up, we've realised that it's not as clear cut as it was before. So originally it was 80% women and 20% men, it's now about 60/40.
So it still is predominance of women. And the percentage seems to be about 10% to 15%. Pretty much irrespective of the age, the only real fall off is when we get into the younger patients, people under the age of 15, where the frequency does seem to drop off, but actually is this 10 to 15%.
Across the board, women more than men that don't appear to be any comorbidities that predispose you, the one exception appears to be hay fever or asthma, that does put you at a slightly higher risk.
But again, we're not 100% sure whether that's a true account, or whether that's just they are people that are noticing it first. So we do think this fits very much with an underlying autoimmune process.
And we are always seeing that people who are prone to these autoimmune conditions like asthma and psoriasis, do appear to be worse affected in the longer term- three months a very little difference.
But when you're looking at eight to 12 months, it is a very similar picture that we see in other autoimmune conditions.
So if you say for example, crohn's, or rheumatoid arthritis or celiac disease, there is a predominance of women, there is a predominance of a certain otherwise healthy group that get it.
Also, interestingly, that does appear to a genetic be a genetic component. I've had families have been referred, that the mother and the daughter have both been referred to clinic, or mother and son in some cases.
Often 20-30 years apart, very often not even sharing the same household. So it's could be that this is one time. But actually, the fact that we've had people who will not share in the same household have been affected, suggests more of a genetic component.
And we've been doing some work looking at the genetics of long COVID. And trying to match that up with other genetic conditions. So there's a cellular way at the moment called decode and II, that's looking for the genetics of myalgic encephalomyelitis.
We're running a study called Sano Gold, which is with Sano genetic study, looking at the genetics of long COVID. And the idea that we're going to be sat down in a few months time to start matching up the data we're getting from the data that they're getting to see is this a predisposition?
There have been one or two cases that have surprised us where we've got family members who've got this, that are not blood relatives. So we've had a few cases of husband and wife partnerships, catching it.
And actually one of the Olympic teams, where the entire Olympic team caught COVID. And that team, then we all went on to get long COVID. Now there was no blood relative whatsoever, but they were athletes, and they were training really hard. And then they all got it.
So that's left us in a position where we're not certain, could this be an a particular environment element?
Could it be the fact that these are people who trained through this rather than taking time to relax, and therefore that in some way trigger this immune response, or could even be microbiome, that bugs are living in our gut, and we know the virus is infecting us, it's theoretically possible that the virus could be infecting some of the bugs that live in your gut.
And if you've got a specific type of bacteria in there, and that's obviously more likely to be shared in the same household foods, then there could be a nutritional element to it. And these are all things that we're considering going forward.
Dr Elisabetta Burchi 8:39
So there are many different hypotheses that you're thinking about and pursuing.
Behind the pathophysiology of long COVID. Probably the most backed up for the moment is this involvement of the immune system clearly, because of greater reactivity, as females have, as you pointed out, or maybe there is a reactivation of the virus, because of its presence in reservoir.
So probably, so you're pursuing different paths, or maybe the involvement of the microbiome and the gut in so there is there are other factors, environmental factors that, as in every disease.
But so Dr Strain, while we are still exploring different hypotheses, what's the current status for the treatment options?
Dr David Strain 9:50
Treatment options are incredibly difficult, because the first thing to say is we still don't really know the Natural History of the disease.
As we don't know, is this a relapsing remitting condition? Is this a condition that will continue for a long period? Or is this a condition that for no apparent reason gets better?
And so we've been looking at lots of different options as they are available and trying to draw parallels from other diseases.
And so for example, when it came to when we rolled out the vaccination, we got lots of anecdotal reports that some people said the vaccination made them worse. Other people said it made them better.
So we ran a survey of just over 1000 people to find out what impact vaccination had on individuals.
Now I stress that this is a survey. So it's not in any way randomised, then everybody was getting a vaccine. But what we identified was about 57 to 64%, depending on which vaccine you got, of participants actually said all of their symptoms got better.
Only a very small proportion said that their symptoms got worse over a long term. So that suggested to us again that this might have some immune modulation.
But the question then is how do we do a study in that because it would be completely unethical not to give a vaccine, is the single best route out of the pandemics to be vaccinating as with the other measures in place.
So there is a possibility going forward that we might look at recurrent vaccination. But then we've got other things in that survey, we just ask people what's working for you.
A large number of people said, I'm sorry, nothing's working for me. I've tried this. I've tried this. Nothing's helping.
And lots of people reported anti histamines or simple Loratadine or Famotidine, anti histamines that people use in ME or chronic fatigue syndrome, and they tried it and it worked.
We had other people have trialling all sorts of things multivitamins, N-acetyl cysteine (NAC), Colchicine has been trial by some or at least they've reported that they tried it for the gout and it got better, it took away the palpitations and the chest pain.
So I believe the difficulty we have is that we don't know what the Natural History of the disease is.
So if you look at our vaccine survey, the majority of people who responded had had Long COVID, for between six to nine months. So that would make it on first glance unlikely that their symptoms would suddenly get better a week after their vaccination, or by no means impossible.
The other thing, of course, is that vaccination, the whole point of it is to generate an immune response.
If this is an autoimmune condition, could it be making a few people worse, if they've got an autoimmune response, or all the auto antibodies, something that are actually suppressed by producing lots of antibodies to the spike protein, and then you suppress the other spike protein, or nucleocapsid proteins or whatever, that the antibodies were working against.
And there's so many unanswered questions. But actually, this is a disease that we can't wait to have the perfect explanation for what causes it.
As in our practice, I think realistically, we're going to identify three or four different types of long COVID with three or four different causes. And if we wait until we know the cause for certain, we're never going to get around to doing the therapy.
So there's more and more of an emphasis on saying, okay, you do the work, finding out what the underlying causes, we'll do the work to find out what works for different people. And we can carefully get as many details as possible for the things that we're treating.
So if, for example, we do a randomised control trial with loratadine, we're going to get as many details as possible a blood test, MRI scans, their, their genetics. And then if we then find out that half of people get better and half the people don't, then we'll know what to do going forward.
And that's one of the difficulties of running these studies that we have to have an extra level of complexity. To know that it probably, because it's more likely to be two or three different conditions, with similar presentations, we're probably going to end up with a disease that half of our patients do respond and the other half don't.
And we need to try and find out who the responders versus the non responders are.
Dr Elisabetta Burchi 14:25
So basically this long COVID is a heterogeneous syndrome. And we may need get the phenotype, and to, clearly from the natural history and the pathophysiology standpoint, we need to understand the what's behind, the mechanisms behind, and then tailoring the therapy.
But we cannot afford really to waste too much [time]. And so we should maybe use a trial and error approach to see what works and what doesn't work.
So in your experience, and from what you know from the literature, the studies, are there any constant findings in these people, for instance, in the in blood exams.
There may be something of a common denominator that is present in all these patients?
Dr David Strain 15:33
So there's been a few indicators.
We saw, I mean, there was a brilliant case series that came out of Belgium, where they followed 352 people who tested positive for COVID and included everything, including the immunoglobulins that they made at the time of their acute infection, and followed them right through.
And it appears that the one predictor was high levels of IGM and IGG, at the time of the initial infection that fits with it being this autoimmune processes going on.
There's been great work that's come out of Imperial College in London that has demonstrated that there are some auto antibodies that are present in people with long COVID that aren't present in people who tested positive, but don't have long COVID. Or they can't tell us exactly what those auto antibodies are reaction against.
And we're seeing some other anecdotal data. So you may have seen that there was a monoclonal antibody, looking at one of the guanosine receptors that seem to cure long COVID within an hour.
Now that's hugely interesting if that's true. And you know, monoclonal antibodies have this history of being incredibly expensive. But actually, if that ends up being mass produced, for a condition that is affecting millions of people, that will drive the price down.
Also, this is a disease that's keeping people away from work, away from the jobs, of the marketplace, looking after children, the responsibilities, the education, all of those other elements.
And therefore, even if it is expensive to manufacture, it would be hugely cost effective, because it's giving young adults chance to go out and start paying tax again, which actually is the way the government looks at these things.
All of these things are very much in an experimental phase. I mean, in the case of that monoclonal antibody that was used, it had an n=1, and they managed to demonstrate really effectively in that one patient, that it killed long COVID, almost immediately.
Another group in America have the auto monoclonal antibodies in a population of 12. And again, it made 12 people better to varying degrees. They are tremendous when it happens. But we're not about to go into mass production on the basis of 12 people or 10 people.
And that's where there is this need for these studies going forward.
Dr Elisabetta Burchi 18:05
So in the pipeline, we mostly have immunotherapies. And with the caveat that they are very expensive and probably not scalable.
I would like to have your opinion about, seeing that we have talked about inflammatory states and this reactivity of the immune system that is clearly involved in the pathophysiology, even if we do not know exactly how.
So we have clearly immune drugs. But we may also think about Neuromodulation as a putative approach that we may use, i'm thinking about vagus nerve stimulation.
And we, actually at Parasym, we invested in this path. We ran a pilot study that demonstrated the use of [Nurosym], [targeted] vagus nerve stimulation worked in improving objective or subjective symptoms present in long COVID. And we are planning to run a randomised clinical trial at Imperial [London]. And what do you think about neuromodulation after everything you have well displayed about long COVID.
Dr David Strain 19:35
So as you say that immune modulation seems to be a gold standard to fix the underlying cause.
But as you highlight, it's not going to be scalable, it's not going to be affordable.
And actually, for a disease that appears to be getting better over time. What we really want to be doing is controlling the symptoms as soon as possible.
And actually the only randomised control trial I've seen to date was all about singing was a really interesting one. It was singing lessons, it was deep breathing. And that demonstrated benefit very rapidly.
There's been a similar study that was performed looking at yoga, and their meditation and the exercises appeared to improve symptoms really rapidly. Yeah, people hypothesise. Okay, breathing around there, they're singing, that's going to help the breathing.
And yeah, if that was the main symptoms got better and agree with it. But actually, the main symptoms got better with a brain fog. They're the post exertional malaise and the myalgia.
Now, that's not from that breathing exercise alone. But we do know that controlled breathing and a singing process in the same way as a control breathing in the yoga classes are both very potent vagal nerve stimulators.
And what you're suggesting is, let's cut out the middleman let's take people who are not able to, or not well enough to go for this, these singing classes, who actually don't have the energy to go through a yoga class, and actually try the direct vagal nerve stimulation to see if that can give them the same effect.
And actually, biologically, that makes a lot of sense, it seems plausible. And it's something that would fit with the observations coming from elsewhere, we've seen in ME that there is actually seem to be a hyper adrenergic status for the people who are having their crashes.
And therefore a vagal simulator would seem to be a sensible choice in those patients.
And this long COVID, would then in the same group, [VNS] will actually make very attractive treatment option [for] patients who were most severely affected.
Dr Elisabetta Burchi 21:48
Exactly, especially if this simulation can be external and not invasive.
For instance, at Parasym, we have this device that is not [invasive], it's external, so we can put this device at the level of the ear.
So it may be an option for that subset of patients that have this autonomy, and in which the hyper inflammatory state is connected to a dysfunction of the parasympathetic system.
So to sum up, what would you say? Where are we? Where do we stand right now.
Dr David Strain 22:32
At the moment, we have a disease that we don't really know what the natural history of it is, we don't know the underlying cause, we don't really know what the best treatments for it are.
When we have very little conclusive data about what is the best way to treat it, it's affecting hundreds of 1000s of people [in the uk]. And many of these are desperate for any sorts of solution.
Actually, the the idea that you sort of suggests that the vagal nerve stimulation, particularly a non invasive approach, is going to be very attractive, it's something that would be relatively easy to try.
Because we're not putting drugs into people, it requires a lot less about the regulation to make sure it's not going to interact with things.
If it's half as effective as some of the singing lessons or the yoga, that could effectively give an immediate response to 1000s of people who don't have the access to those sorts of treatments and it becomes a very attractive treatment option to control the symptoms.
It may well be that it's more than symptom control, and may well be that actually the vagal nerve stimulation down regulates the immune modulation and actually treats the underlying cause.
But actually, for the 1000s of people with the disease, they don't care how they get better, as long as they get better.
Dr Elisabetta Burchi 23:52
That's totally right, because the simulation may affect the the pathophysiology underpinning, because of yes, direct stimulation of the system, but also for the action on the on the hypothesis [of] the other axis [HPA] and the TNF alpha and multiple paths.
But you are right as long as patients get better, they don't really care how it happened by must happen.
So let's go on with the, with the research. And let's hope that we can, we can manage this new emergency, after all the success we have had with the vaccine.
Dr David Strain 24:43
And I think one of the advantages that we've got with long COVID is that there are as I say, 1000s of patients that are desperately keen to join the studies, are desperately keen to report it.
And if we can show benefit for them, if we can make them feel better using any of the pathways that we've got. They will very happily donate some of their blood, they'll donate their inflammatory markers, we can almost say, okay, we're going to see if you get better first.
And if we do, we're then going to try and figure out how you got better or why you got better.
But actually the fact that they're getting better is all that they'll care about.
Dr Elisabetta Burchi 25:17
Absolutely. Thank you very much.