Dr Charles Shepherd,
Trustee and Hon. Medical Adviser to the ME Association.
Member of the 2018-2021 NICE Guideline Committee.
Member of the 2002 Independent Working Group on ME/CFS.
Thank you very much for asking me to talk about ME CFS, myalgic encephalomyelitis, chronic fatigue syndrome, and the overlaps with Long Covid. Just a quick bit of background information, I'm Dr Charles Shepherd, I'm a UK physician. I've had 40 years clinical and research experience of dealing with ME/CFS.
It stems from actually developing this wretched illness myself, following a dose of chickenpox. And I think it's important to stress at this point, that MECFS is one of a group of post viral diseases, post viral syndromes and post infectious syndromes which are much neglected in medicine, both clinically and research purposes.
And I think with the renewed interest in ME/CFS now, and what we're learning about Long Covid, I think there's going to be a renewed interest in looking and bringing together a whole range of post infectious conditions. There's things like Q fever, post polio syndrome, tropical infections like Ebola virus, Zika virus, chikungunya infection and dengue fever, they all produce these fatigue syndromes and they have many features in common, but they also have some differences. So, my main interest in this is obviously with ME/CFS and the overlap with long COVID. And this interest started, um, to emerge round about, it's probably about May 2020.
In other words, a few months into the onset of the pandemic. And we were starting to hear from, here in the UK, people who almost all of these people were previously fit young adults and they'd gone down with COVID. They haven't been in hospital. They haven't been seriously ill with COVID and they'd been managed at home.
They may not have even seen a doctor at the time, but they weren't getting over it. And they were coming to us because they had symptoms which are really very similar or they thought were very similar to ME/CFS. So, they were complaining of this very debilitating activity induced fatigue. If they did too much on one day, when they're feeling a bit better, then they feel really lousy the next day and that's what we call post exertional malaise.
They had cognitive dysfunction, this brain fog. While they're having problems with memory, concentration, attention span, they had problems with sleep, particularly what we call unrefreshing sleep. So even if they've got a decent night's sleep, but still wake up feeling, feeling dreadful.
And they had various symptoms relating to autonomic nervous system dysfunction, dysautonomia. So, they had orthostatic intolerance, they'd have difficulty standing up, maintaining a standing up position. And some of them, particularly the younger ones, um, have postural orthostatic tachycardia syndrome, POTS, whereby the pulse rate would rise significantly on standing and they'd feel faint, nauseous and sweating.
So, that combination of symptoms led us to think, well, you know, a lot of these people with, um, post COVID that haven't been in hospital weren't seriously ill, um, were developing an ME/CFS like illness or actually probably a post COVID ME/CFS. I think it's important to just sort of put that in the context of what is long covid.
There's lots and lots of definitions now of what Long Covid is and some of my sort of highly esteemed medical colleagues have come up with long, complicated definitions of what long covid is, but I think it needs simplifying into really an umbrella term for a wide variety of clinical presentations.
So I like to describe it as people who still have a symptom, or symptoms that date back to the onset of COVID 19, which was either proven with a laboratory test or was highly, um, likely to be COVID and that these symptoms or symptom of lasted for three months or more, and that they cannot be explained by some other condition, which has developed in that time, like diabetes.
So, we end up with long COVID, I think, being an umbrella term for, I would like to try and simplify it again, three different groups of people. So, on the one hand, we've got the people often who've been in hospital. They've been, they've been quite seriously ill in hospital with lung, cardiac, liver, renal, thrombotic complications.
And that this organ damage from the COVID at the time has remained. So, they have problems with respiratory function, cardiac function, et cetera, et cetera. And then there's this other group, which I've been describing which we've been seeing who are very much fitting that the ME/CFS type picture, and there have been several research studies now looking at people, large groups or reasonably large groups of people with long COVID and finding actually reporting that roundabout half people with long COVID would meet a clinical definition of having ME CFS.
And what we've also got besides this is those two separate groups, we've got an awful lot of people who in the middle who've got post COVID symptoms, so they've got their respiratory breathlessness, their loss of taste or smell, cardiac problems, but they've also got ME CFS symptoms on top of it. And I think just to complicate things a little bit further, there's another group of really quite diverse clinical presentations under this post COVID long COVID umbrella. There are people with, uh, who have sometimes developed quite severe, um, mental health problems, depression, post traumatic stress disorders. There are people, and I think this is important and often gets missed, unless you know what you're doing with clinically assessing these people.
Um, there are people where COVID seems to have precipitated the onset of some other illness or autoimmune disorder and the autoimmune component may be relevant. It seems to be an autoimmune component to Long Covid and these people have gone on to develop a diabetes or an arthritis. And I think in that case, it's probably inappropriate to describe them as Long Covid.
I think they are post COVID diabetes or post COVID arthropathy or whatever. And then there's one other important group, I'm not certain how prevalent this is in the United States, but certainly in the UK, there are people, sadly, we know this from our experience with dealing with people with ME CFS is that they have been misdiagnosed.
They've been given a label of Long Covid, because they're breathless, they're tired and whatever, and they haven't been properly clinically assessed. And very sadly, they've turned out to in actual fact have a malignancy. So, I think it is very, very important in making a diagnosis of long COVID that we as doctors do what we should be doing with all patients who've come along with unexplained fatigue and other symptoms.
We should be taking a very detailed clinical history. We should be examining these patients to see if there are any abnormal physical signs, which are going to take us in another direction entirely and we should be properly investigating them. So, the overlaps between ME/CFS and Long Covid, I think are two way.
First of all, there's the clinical overlaps, which I've already described. And then there's the pathology, the causation overlaps. And here again, I think there's an awful lot of overlap between the two conditions and the four or five main pathological tracks, which people are obviously investigating Long Covid
And it's interesting that they all overlap with ME/CFS and what those of us who are involved from the ME CFS side have been very disappointed by, is the amount of time and effort that's been put into research, um, looking at these tracks in Long Covid. When we've already looked at most of these in ME, and I think there were important lessons which could have been learnt.
And it would have been nice to have had some more cooperation much earlier on. It is now happening in looking at these causal mechanisms that overlap between the two. I think the four main ones are obviously the role of infection. Both conditions start with an infection. Um, I think there's a slight difference here with COVID in that there's certainly some evidence, whereas there's very little evidence in ME/CFS, but certainly in the COVID people, there's some evidence that there may be persisting viral infection, um, going on With possibly pockets of persisting COVID infection in areas such as the gut or even the brain with evidence of spike proteins as well being present. So, I think that has a question mark over it.
And it's obviously an interesting observation from the possible treatment point of view, um, where we've got common ground, um, is the role of reactivated viral infection in both conditions. And then, we start off with the infection and then we move on to the immune system response.
And again, there's a lot of overlap here because we, we've been spending a lot of time looking at the immune system response in MECFS over the years and come to the conclusion that there seems to be a low level immune system activation persisting. In other words, the virus has switched on the immune system, but then it hasn't settled down again, which is why these people with both conditions continue to feel on top of their main symptoms, they continue to feel just unwell and flu like all the time.
And so it may well be that there's an ongoing production, an overproduction of particularly cytokines, things like interleukin 6, which can obviously have an effect on muscle performance. And there's a certain amount of evidence now coming through, which is mirroring what we know, um, in ME CFS about Long Covid and immune system activation.
The other component in the immune system, which I think is interesting, is the finding of some degree of autoimmunity in Long Covid. And that's the same applies in ME/CFS and it may, um, help to explain why there's this big female predominance both in Long Covid, and in ME/CFS. So, the third pathological mechanism is then what may be going on within the central nervous system.
And again, there's this overlap of both conditions having autonomic nervous system dysfunction, um, and dysautonomia and the symptoms that follow from that. But another interesting observation which has come through from the work that's being done at, I think it's Yale, was looking at hypothalamic pituitary adrenal axis function and the role of cortisol.
And we know that in ME/CFS, there's a degree of hypocortisolemia going on low, lowered levels of cortisol. And it seems to be in Long Covid that this is a finding that's there as well. The final, I think very important potential finding that overlaps is what we call mitochondrial dysfunction and for people who are not familiar with the mitochondria, they're the sort of batteries within cells where energy is produced.
And we know that in both conditions now, there's been some research, good research from, uh, particularly for Wüst in Germany, looking at muscle energy production in Long covid. And there does seem to be an overlap with the sort of mitochondrial dysfunction that we know exists, um, in ME/CFS.
There’s one final one after that, which is a bit of a plus or minus at the moment, something which goes in a lot of disease conditions at the moment. And that's obviously the brain gut connection, the mind brain body connection and whether there is disturbances in the body's microbiome.
We certainly know that there's some evidence of that in ME/CFS, and there does seem to be some evidence in Long Covid. The one outlier where I think things are different in Long Covid, and this is an area of, I think, uncertainty at the moment, certainly controversy, is that we know that people with COVID have quite often have problems with um, blood clotting thrombosis.
And there is this hypothesis that there may be microclots involved in Long Covid. This is small clots involving amyloid and fibrinogen within the capillaries. Um, it's an interesting theory at time, at the moment, but it's not something that has been proven. But certainly, if that does turn out to be the case, it could have important implications for treatment.
Finally what we do about managing Long Covid from what we know about managing ME/CFS. And I think there's a great deal of help and I think it's very sad that people with Long Covid didn't have the opportunity to have this help very early on in the condition, because there's a lot that we know about managing the symptoms.
There's no treatment for ME/CFS. There's no treatment for Long Covid, at the moment, but certainly, that there are things that we can do to help people with Long Covid learning, from ME/CFS. So certainly, from the point of fatigue management it's terribly important that these people pace their physical and mental activities, so they don't do too much, they don't bring on post exertional fatigue.
So, they do little chunks of activity, physical, mental activity, have a rest and then do a little bit more and accept that this is a condition which is going to fluctuate from day to day, but don't push yourself beyond your limitations. There are various self help strategies, which can help with brain fog.
There are again, important self health strategies, which can help with dysautonomia and for people who are more severely affected with dysautonomia, particularly POTS, then there's drug interventions such as beta blockers, Midodrine, Ivabradine, various different types of drug, Fludrocortisone to increase blood volume as well.
But that requires, you know a skilled physician who's used to dealing with these things to give help. So,there's a lot of help we can give in in managing Long Covid and as I say, uh, that is in the absence of being able to treat long COVID until we know much more about the pathological mechanisms that are involved.
We’re not going to treat it. But, finally, on this sort of management treatment side, there are a number of drugs under consideration in clinical trials, some of which have certainly been tried in ME CFS, unfortunately, without any great success so far. But some of these are drugs which are being assessed in both ME/CFS and Long Covid from the point of view of possible persisting infection, then there's, you know, there's the trials looking at whether there's a role for antiviral drugs, such as Paxlovid. There are several immune system trial drug trials going on at the moment I think there's 3 different trials looking at a drug called Low Dose Naltrexone, there's a trial looking at immunoglobulin G. And then I think what's probably more interesting and may produce some interesting results. And again, it's something we have looked at in ME CFS is whether if there is this low level immune system activation continuing, whether some of the drugs which are used in conditions like rheumatoid arthritis for dampening down this type of immune system activation and inflammation could be a benefit.
There's certainly a trial at the University of Leicester here in the UK with a drug called Tocilizumab, which I'm not familiar prescribing, so I hope I'm pronouncing it correctly. But there are these as I say, powerful anti inflammatory drugs, which may be of help. And then with the mitochondrial dysfunction, um, we've got a trial going on here, been going on here in Oxford with Dr Betty Raman, um, looking at, uh, uh, an American, um, product called AXA 1125, which has gone through, I think, up to a phase two clinical trial, um, looking at whether you can, in some way, boost muscle energy production, um, in the mitochondria.
So, there's a lot going on. I don't think we're going to have any simple, easy answers for quite some time as far as treating or curing Long Covid. And because it's an umbrella term for so many different conditions, including an ME/CFS type illness. I think it's highly unlikely, we're going to get a drug, which is going to treat both or all conditions. I suppose my final note is just to say a note on prognosis.
I think the prognosis in long COVID seems to be rather better than that in ME/CFS and I think the overall figure that we use at the moment for people fully recovering and having a sustained recovery from ME/CFS is around about 5%, and certainly no more than 10%, which is really a very, a very low figure.
But certainly, there are people who are getting better improving with Long Covid, but at the same time, and we're now getting follow ups, obviously, from people with Long Covid who've been ill for three or four years almost now. And some of these have not made any progress. They're following very much a familiar MECFS pattern of relapsing, remitting, illness, and in some cases deteriorating and becoming really quite severe or even very severe. So, I think it's a very mixed prognosis at the moment, and until we are a bit further into this condition, we're not going to have any truly definite figures on prognosis.
Final point, I suppose, is whether we can prevent Long Covid and I think there are certainly two things which, which have been shown to be of help here and there's certainly some good evidence that people who are vaccinated against COVID have a reduced chance of picking up Long Covid.
And from the point of view of prevention, if we could just get buildings with COVID is not going away and there's still crowded, buildings, transport and whatever, where people are mixing. And if we could just get buildings better ventilated, I think that might help to reduce the amount of COVID that is going around.
And then thirdly, that there are these drug interventions, again, looking at things like, um, Paxlovid, whether there's some indication that this may be the case that if you pick out the people who are more vulnerable to developing long COVID, whether you give them something like Paxlovid during the acute phase of the infection that may well be a benefit and help to reduce the incidence of long COVID, but COVID is not going away.
It's not going to go away. And with that, I'm afraid long COVID is not going to go away because so many of these people with long COVID have not been in hospital. They've just had a very minor infection with COVID.
So, I think this is a very serious health problem. It's going to be with us for many, many years to come.