SPENCER: Carmen, welcome to the Clearer Thinking Podcast.

CARMEN: Hello, Spencer.

SPENCER: So when COVID struck, after a little while, we began to hear about the scary idea of long COVID, that some people, after getting COVID, would have these symptoms that would last and sometimes be debilitating. It was really quite scary for many people, but not very much was known about it at the time. Everything was being figured out, tons of papers were coming out, but there was a lot of confusion. Today, I know people who are still very concerned about long COVID. They're worried, "Oh, maybe I'm going to get long COVID and be sick for the rest of my life." So today, I want to explore with you, what do we now know about long COVID? How serious is it? Is it treatable? And so on. Thanks so much for joining us.

CARMEN: Yeah, it's a pleasure.

SPENCER: My first question is about the definition. The early papers suggested that any symptom that people experienced right after getting COVID that didn't go away would be considered long COVID. Do we have a clearer definition now of what long COVID is?

CARMEN: Well, actually, long COVID is not a medical diagnosis. It was defined by patients quite early, around late spring in 2020. The first patients reported that they had ongoing, lasting symptoms. So long COVID is broadly defined as persistent symptoms following COVID, and these may be various symptoms and may also be specific diseases in a few patients. Later on, the WHO, I think they were among the first to better define this, and they defined it as post-COVID condition and made a clearer definition based on the duration of symptoms and the severity of symptoms.

SPENCER: So post-COVID condition, which I guess is the formal diagnosis. What does it include? What do you have to have to meet the conditions of it?

CARMEN: So it is a condition that needs to last for at least two months, and it should start within three months after having acute COVID. It needs to impair you in daily activities, and it should not be explained by an alternate diagnosis. This is a formal definition. This is still quite broad, but that is a good working definition.

SPENCER: Are there any particular symptoms it has to involve, or could they be any type of symptom? It seems so broad if we include every symptom.

CARMEN: Well, the WHO listed several symptoms that are very common, such as fatigue or pain, but the condition is not defined by specific symptoms.

SPENCER: Is that unusual? Are there other disorders that we have that are like that, where there are no particular symptoms that define it?

CARMEN: Well, we have post-infectious syndromes other than long COVID, and that's actually a group of conditions with a lot of overlaps, but also with some differences. In many of these conditions, we do not have clear diagnostic criteria, but it's more the coming together of several symptoms, and when there are specific constellations, it's called a syndrome. Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a variant of this. This has been known for decades, and actually, it's triggered by various infections, but also by SARS-CoV-2. That's what we learned, and that is a good example of such a constellation of symptoms.

SPENCER: So did we learn that nearly every virus can give you a kind of post-viral syndrome, or is it sort of unique to certain viruses like COVID?

CARMEN: Well, actually, we don't really know, and what we know for sure are the viruses that can trigger such post-viral syndromes. The best known are Epstein-Barr virus, influenza, dengue virus, and Lyme disease. So there are actually several, but we also have many patients who have a respiratory tract infection and then develop, for example, ME/CFS. In adults, we often do no testing when they are acutely sick, so we do not know the whole spectrum of infections that may trigger such syndromes. But actually, we think it's probably not the virus itself that determines the disease, but more the severity of the infection. By having just a mild flu, you usually do not get such a disease. So it's usually a more severe infection that is required to trigger a post-infectious disease.

SPENCER: Is that true of long COVID? Because this might not be accurate, but I'd heard that actually there's not much correlation between the severity of the initial infection and whether someone gets long COVID or not.

CARMEN: Well, I think one needs to see what is mild COVID by definition, and that was originally defined as not developing lung disease or pneumonia. So mild COVID, at least during the first two years, often made people quite sick too. It often lasted for more than a week, and there was still a virus present in the second week, and that's already a pretty long and severe infection for the immune system. What is special about SARS-CoV-2 is that it was a novel virus, so we had never had contact with this virus during our childhood days. Therefore, the immune system had to struggle more to get control of this virus.

SPENCER: There's different versions of severe, but the original definition...

CARMEN: That's probably the reason why we have quite frequent long COVID, these post-infectious symptoms because of this new virus our immune system had to face.

SPENCER: I see. Now with a virus like varicella-zoster, for chicken pox, it can kind of be maintained. It can stay in your body. It's typical that it sort of never leaves your body. It becomes inactive, but then it can come out later again, maybe much later in your life, as shingles, if you have a weakened immune system. With viruses like COVID, do they work that way, where they can stay in your body, or does your body actually eliminate them? And any kind of post-viral syndrome is not about the virus still being in your body.

CARMEN: Actually, there's no definite answer to this question. In the beginning, we didn't think that SARS-CoV-2 could persist at all. It was considered an acute viral infection, a virus that we could clear quite fast, as with many other viruses.

SPENCER: Like a cold, right?

CARMEN: Yeah, like a common cold. But then it became clear that at least in a subset of patients, we can detect the virus for quite a while. There were several studies showing viral persistence, for example, in the gut, in the bone marrow, or in the brain. I think in around 2022, there was actually a large part of the scientific community thinking that long COVID is most likely viral persistence. This view has changed, so now we still think that it may play a role, at least in a subset, but we know for sure that it's more than just a chronic viral infection.

SPENCER: When they find it in the body, what do they actually find? Because there's confusion around your body having immunity. If you check immune cells, they could show that you have immune cells for the virus for potentially a year or two years. But that doesn't mean you have the virus, right?

CARMEN: Yeah, but there were also studies showing viral RNA. At least they showed RNA, which does not necessarily mean that the virus is replicating. It may also be that it's silenced, but still there, or there were other studies showing that there was spike protein detectable in a subset of patients. Actually, we did a study, and there's a sensitive assay with which you can detect spike protein in the serum, and we found it indeed in about 10% of people, but that was independent of long COVID or not. We also found it in recovered patients and in those who had long COVID. We also found no correlation with severity of the disease or with any specific symptoms, so we do not really know what this means.

SPENCER: So it could be that some people still have it in their body, but it doesn't affect them in any negative way, and it's still unclear whether it's actually contributing to long COVID or not. Is that right?

CARMEN: Yeah, that's a good summary.

SPENCER: It's kind of incredible that this feels like such a basic scientific question. It's kind of incredible how hard it is to answer definitively. Why is that? Why is it so difficult to get to the bottom of that?

CARMEN: Well, it's probably because it's so complex, not only the clinical presentation, but also what we found biomarker-wise. We found many alterations in the immune system, but also in the nervous system, and we found inflammation in several tissues, impaired mitochondrial function, and alterations in the microbiome. We have many pieces of a puzzle, but we still have no answer to how this all belongs together, and if certain mechanisms play a dominant role in some people and other mechanisms in others. The current concept is that we face subgroups of different pathomechanisms, with the immune system most likely playing a major role. As is always the case in medicine, the genetic background also plays a role, and therefore this influences the variations we see in the different mechanistic alterations we find in patients.

SPENCER: So would a typical study that's trying to understand long COVID say, "Okay, take some people who were diagnosed with COVID, they clearly had COVID, then they developed long COVID. Take another set of controls that had COVID, but then they didn't develop long COVID. Then we're going to measure a bunch of biomarkers between the two groups, and we're going to look for statistically significant differences." Is that sort of how it's generally approached?

CARMEN: Yeah, that is the first approach, how you would do it, or how you are doing it. A major question is whether the findings you have correlate with the symptoms the patients have or the disease severity. If you find such associations, that gives you a good clue that this may be disease relevant.

SPENCER: Right, because if the long COVID group had some trait that the control group didn't have, but it wasn't associated with worse symptomology, it might not be very meaningful. Is that right?

CARMEN: Yeah, it may be just an epiphenomenon. But for example, if I measure an elevated cytokine, and the higher it is, the more severe fatigue is present. That is already a quite good indicator that this also plays a role for the disease.

SPENCER: How much should we worry about possible confounders? Obviously, you're going to try to match your control group to the long COVID group. Maybe you match by age, maybe you match by some kind of health status, or whatever it is. But of course, it's hard to do all those matches perfectly, and you don't know all the hidden confounds. For example, let's say that there were certain lifestyle or behavioral differences, or psychological differences, or anything like that. It seems like it could lead to false positives where you attribute it to long COVID, but it's really just about the groups being different. Is that a challenge for this kind of research or not so much?

CARMEN: Well, that is not so much here, because we have so many controls. Almost everybody had COVID. And of course, what is most important is that you can replicate such findings. So if one study finds this, and the other study can confirm this, then you have much more confidence that this is a relevant finding. And we have several findings now where we have numerous studies confirming this.

SPENCER: Right, because it's such an evolving area. There are new studies all the time, but what are the ones that have really been replicated where we're now really confident that there's a link between certain biomarkers or certain genetic tests and long COVID?

CARMEN: So I think the best evidence we have for immune dysregulation is that there is clear evidence of ongoing low-level inflammation. We find elevated markers of inflammation. Interleukin-6 has been found, I think, in more than a dozen studies. We find alterations in the immune cells. We frequently see a pattern that looks like chronically activated immune cells with activated T cells. We find alterations also in B cells, which produce the antibodies. We have several studies showing autoantibodies, and there is some evidence now that this is probably triggered by SARS-CoV-2 or by EBV proteins, and then can cross-react with our own body structures. EBV is one of the hottest candidates for triggering such autoimmunity. It is a virus that has long been known to trigger autoreactivity. It's also a herpes virus, which persists after infection and has been living with us for millions of years. What we've learned is that in COVID, EBV frequently reactivates, and that the risk of developing long COVID is strongly associated with EBV reactivation during acute COVID.

SPENCER: Is this similar to what we find for other post-viral syndromes, or is this kind of a unique constellation of findings that makes long COVID distinct?

CARMEN: Well, actually, there's a hypothesis that EBV is probably the cause of many of these post-infectious diseases. First of all, we know that EBV, by itself, can trigger ME/CFS, which is a severe form of post-infectious disease. Then we know that EBV frequently reactivates when you have another infection, and that is because EBV persists in the B cells. The B cells are the cells you always activate when you have an infection because these are the cells making antibodies, and every time B cells are activated and proliferate, EBV can reactivate.

SPENCER: And could you explain what EBV is?

CARMEN: EBV stands for Epstein-Barr virus. That's one of the herpes family viruses, similar to shingles or herpes simplex virus.

SPENCER: I see. So essentially, these people already have Epstein-Barr, which is extremely common. But it's something about it getting re-manifested in the body after COVID or after other viral infections. Is that what's happening?

CARMEN: Right. So, almost every adult has EBV. You usually get it as a baby or early in childhood from your parents. At the latest, you get it in adolescence. It's called the kissing disease too because you frequently get it from your first partner. For many, it's a quite harmless infection that you hardly recognize, but especially when you get it later in life, it may be a quite severe infection called infectious mononucleosis, and there you have a quite high risk of developing post-infectious symptoms, especially the risk of developing ME/CFS. The risk of developing Myalgic encephalomyelitis is quite high. So it might well be that at least a subgroup of long COVID is actually triggered by the EBV reactivation.

SPENCER: Okay, so COVID somehow is reactivating it in your body.

CARMEN: Yeah, COVID reactivates EBV and then EBV induces the post-infectious symptoms. That's one possible concept.

SPENCER: And as I understand it, many people with long COVID report PEM or post-exertional malaise. Is that a common symptom? And tell us what that means.

CARMEN: Yeah, that's quite frequent. Actually, I think it's among the top symptoms. So the most frequent symptom is fatigue. Fatigue means that you feel tired, exhausted all the time, although you have slept enough and haven't overexerted. Exertional intolerance often goes along with fatigue, but it means that you cannot exert yourself as you used to. Even minor daily activities can make you feel pretty much exhausted. You're unable to do this. Post-exertional malaise is a special form of exertional intolerance, meaning that after minor activities, you not only feel exhausted, you feel terribly worse. All your symptoms get worse, and this may last for days, and you may really be severely ill. Post-exertional malaise is actually the key symptom of ME/CFS. So coming back to ME/CFS, I should explain it now.

SPENCER: Yeah, let's talk about what is happening, and then we'll talk about how it connects.

CARMEN: So it's actually a disease we've known about long before long COVID, and it's now, with long COVID, also a part of this long COVID spectrum. But not all patients with long COVID have ME/CFS. ME/CFS has several key symptoms. You always have severe fatigue and post-exertional malaise. Part of ME/CFS is also cognitive impairment, which is called brain fog, and you often have pain in the muscles and joints. You often have orthostatic intolerance when you get up. This is actually a disease that is well defined, so we have diagnostic criteria, and we know now that approximately 20 to 30% of long COVID patients have ME/CFS. However, we have many patients who had it already before the pandemic, often triggered by EBV or influenza, and then it becomes a long-lasting and usually chronic disease. Patients are usually quite sick, and many of these patients are housebound and have been suffering for decades. Until today, we have no real good concept of how to treat it and how to help these patients.

SPENCER: ME/CFS, I think a lot of people would have heard the phrase chronic fatigue syndrome. That was sort of the older name for it, as I understand it. There's been quite an intense history of people debating what it is and its nature. Could you tell us briefly about that history?

CARMEN: Yeah, well, actually, there are reports from more than a hundred years ago about this disease. It's usually reported in certain epidemic situations. For example, in the US, there was an epidemic, and then many developed ME/CFS. In London in the 50s, there was an epidemic in a hospital, and many nurses developed ME/CFS. For a long time, it wasn't really known what it was. Following the outbreak, concepts were developed that it was a psychiatric disease, a form of hysteria, and one of the reasons was that it mainly affected females. There was a concept that these patients had illness disbelief, that they were just thinking they could not exert themselves. They recommended treatment to convince the patients that they were not that sick and that they should exert themselves. This treatment concept, called cognitive behavioral therapy and graded exercise therapy, was then tested in clinical trials, and these clinical trials came out with results suggesting that this was helpful in improving disease symptoms. That was sort of the start of decades of the concept that ME/CFS is a psychosomatic disease that can be treated with CBT. However, patients said, "This cannot be true. This is not my experience. I feel that I am not mentally ill. I'm mentally completely healthy. I just feel terribly sick." Patients also said that nothing helps them at all; if they overexert, they experience a dramatic crash. What then started was a re-analysis of these studies, and in the end, it was found that the results were inconsistent and that the patients included actually did not suffer from ME/CFS. These concepts remained quite solid within the medical community for decades, and still today, there are physicians who believe that it is a psychosomatic disease. This is probably the main reason why, until today, we haven't adequately researched to understand the disease and why we have never really had the chance to develop effective treatments.

SPENCER: So you think that the psychosomatic view of it kind of held back the research development?

CARMEN: Yeah, of course. Because why should governments give funding to a disease that is psychosomatic, where we already have concepts to handle it?

SPENCER: How similar are the symptoms of long COVID to ME/CFS? I think you said about 20% of people will meet criteria for ME/CFS who have long COVID. But are there other connections, or is it just that a subset of them will have ME/CFS?

CARMEN: Well, many symptoms overlap, so fatigue, brain fog, and autonomic problems are very frequent in long COVID too. I think there are many similarities in a major subgroup of long COVID with ME/CFS. The disease ME/CFS is not so clearly defined until today because there are different diagnostic criteria in Europe. We use different diagnostic criteria than in the US. According to the US criteria, about half of long COVID patients have ME/CFS. If you use the stricter European criteria, which are usually the Canadian consensus criteria, then it's only about one quarter of the patients. In the UK, they have other criteria. Again, they have the NICE criteria, which are closer to the US criteria.

SPENCER: Interesting. So it sounds like it's still evolving. And for studies like that, how do they define who has long COVID? Because that also seems a little bit unclear.

CARMEN: Yeah, that is, again, we have different diagnostic criteria. So we have criteria that include everything that can be triggered by COVID. For example, COVID can also trigger known diseases. We know that almost all autoimmune diseases are more frequent in the year after COVID, but also cardiovascular diseases. Then we have patients who had severe COVID, were in the intensive care unit, and had lung problems afterward. According to broader definitions, this is also termed long COVID. But I think the WHO definition is more helpful because it only includes those patients for whom we cannot explain the symptoms by an alternate diagnosis. I think that is a group of patients that is, first of all, the largest, and secondly, not fully understood now, and in which we really need to find good concepts and develop therapies.

SPENCER: You mentioned subgroups earlier. It sounds like the definition of long COVID is pretty broad because you're essentially getting symptoms after COVID. The symptoms can't be explained in another way. But of course, it could be that some percent have some other disease that's just not being identified, or that there are some other factors. So does it really make sense to think of long COVID as one thing, or do we really need to think of it as there are multiple possible situations going on here?

CARMEN: Well, I think we need to think of different subtypes. That is not only important for diagnosing, but of course, also for treatment. As long as we do clinical trials just including everybody according to the post-COVID definition, I think we are too broad and unspecific, and that's what we learned during the last two years from clinical trials. Several clinical trials turned out to be negative. The drugs that were tested had no effect.

SPENCER: What were those drugs?

CARMEN: Well, there were several drugs tested so far. There were drugs targeting the virus itself. Paxlovid was tested in randomized trials and came out negative. There were also several drugs and supplements given. One trial, for example, tested vitamin B3, and this came out negative. There was also a trial testing an anti-inflammatory drug called colchicine, which was negative. The major problem of these trials is they did not include the patients who really had evidence of viral persistence or evidence of inflammation. As long as we do these broad trials, it's probable that we miss a subgroup of patients who may benefit from this treatment. The next step for therapies, at least in Germany and probably worldwide, is that we now do it in subgroups defined by biomarkers or clinical subgrouping. For example, we are now doing clinical trials just in the subgroup of ME/CFS patients, which can be defined much better and which we think is more homogeneous mechanism-wise.

SPENCER: So if we think about everyone who's diagnosed with long COVID, some percentage of those people will be misdiagnosed. That will happen for any disease, but especially for diseases that have sort of fuzzier boundaries. Some of those patients may have this ME/CFS subtype, and some may have some other version of it. Do we have any sense of the relative proportions of how many people we think might be misdiagnosed versus might have this ME/CFS subtype or versus other subtypes? Or do we really just not know at this point?

CARMEN: Well, if you use this broad definition, there will, of course, be patients who, in the end, have developed a disease that was not triggered by COVID. They had just COVID at that time but developed something else. This is quite likely. On the other hand, many of these patients are quite young, so there are many people who were completely healthy before they developed the disease. I think in general, these cohorts are quite well defined, even if you have probably 10% of patients not being real long COVID cases.

SPENCER: I see. And then what about the other subtypes? Do we have any sense of how common they are? Or really, it's too early to say?

CARMEN: Well, for ME/CFS, I think it's roughly 1/3. Then we have another diagnosis we know already, and that is called postural orthostatic tachycardia syndrome. This is a disease where your cardiovascular regulation is disturbed. It's often a more general disturbance of the autonomic nervous system. That is the part of your nervous system that works in a remote fashion, controlling things like your breathing, your heart rate, and how you distribute your blood. This is severely altered in a subgroup of patients. Postural tachycardia syndrome is a clinical definition for patients who have symptoms of orthostatic intolerance, who get dizzy when they stand up and when their heart rate rises above a certain level. This is called postural orthostatic tachycardia syndrome. We have another well-defined subgroup, which is probably, again, 20% of long COVID patients. There is some overlap with ME/CFS too. Then I think there are about 50% of patients where we have no clear diagnostic criteria yet. But again, we already have distinct subgroups we can define, for example, those with severe neurocognitive impairment that can be measured by certain tests. This is definitely a group that also needs better development of drugs because this can be defined, and we already have a good concept that there is probably ongoing neuroinflammation or impaired perfusion of the brain, which may then be targeted by respective drugs.

SPENCER: You mentioned Tachycardia Syndrome. Is that what people call POTS?

CARMEN: Yeah, POTS, postural orthostatic tachycardia syndrome, or POTS.

SPENCER: And a typical symptom of that would be, after standing up, you might get lightheaded or have a funny heartbeat, things like that. Is that correct?

CARMEN: That's what I call dizzy. Isn't dizzy the right term?

SPENCER: Oh yeah. It's the right word, absolutely. Something that I find a little baffling, and you're an expert on this. I'm not an expert, but it really confuses me is that some people have gone and done interviews with people who've recovered from long COVID, and I don't know. Also, ME/CFS, they've done interviews with people recovered. I don't know how strict their definitions are that they're using. They're probably not very strict, but you could find there are literally hundreds of these people who say, "Okay, I had this, and I recovered." If you look at those case reports, many of them report that psychological methods essentially helped them or even cured them, which I find very strange. I don't know whether that's because there are psychological methods that could help people with these medical disorders, or if there's some subgroup where it is more psychological and not more medical. I'm curious what you think of that, what you make of that.

CARMEN: First of all, of course, long COVID can heal. We know for sure that within the first month a lot of people get better and become healthy again after having long COVID.

SPENCER: Well, would that even be long COVID at that point?

CARMEN: Well, in definition, long COVID persists for months, then you can get much better and become healthy again. But that was long COVID, and it has been shown in several studies. On the other hand, if you have been ill for more than six months, then the risk is quite high that you remain ill for longer, although we also know from clinical trials that you can also recover after one or two years. It's not automatically a chronic disease. With ME/CFS, unfortunately, it comes along with a very high risk of a chronic disease. What we've seen in our studies, and several other people have seen, is that the risk that you remain ill is quite high, so 90% or higher. I know these reports; some patients, first of all, do recover. That's what we see in our studies. What is the role of psychology in these diseases? It's, of course, not the cause of ME/CFS, but it's definitely a consequence. If you are so severely ill, and if the situation is so frustrating with so little perspective, you are, of course, distressed, and some patients need psychological support. That is evident, and in some patients, this psychological support also helps them manage their disease better. That is common sense too, but that you can cure ME/CFS just by psychotherapy, I still have no evidence that this is the case. Of course, then we have a situation where you really don't know if the diagnosis was right in these patients, because here we have a problem. ME/CFS is still not that well known among physicians. Before the pandemic, I think many physicians worldwide had never heard of ME/CFS. Now, after five years of facing long COVID, there's still a lot of uncertainty in several medical communities to diagnose long COVID properly, to diagnose ME/CFS properly. What is terribly confusing is the name chronic fatigue syndrome, because fatigue is a very common symptom of many diseases, or you can have fatigue without any obvious cause. You just feel more fatigued, more stressed, more exhausted. That is quite common nowadays. If you do not know the disease well, some physicians and also some patients tend to call their disease chronic fatigue syndrome. That is probably a major problem of these confusions.

SPENCER: Because they might just have a lot of fatigue, and then it sort of fits, but it's not.

CARMEN: Yes because they might not have chronic fatigue syndrome. That is a different condition and that is a very severe complex disease and has nothing to do with just being fatigued.

SPENCER: On the psychological front, obviously this is a difficult topic to talk about, but one possibility is that there are patients who could benefit a lot from therapy or from psychological techniques, even if it's not the cause of the problem, and even if it doesn't cure them. It could just be helpful. Cognitive behavioral therapy has been used for many different disorders of all different sorts, and many people have found it helpful as a way to live with difficult challenges. I know that some early trials were done on cognitive behavioral therapy for these conditions, and what do you think about the current state of evidence? Is cognitive behavioral therapy helpful or not so much, even if it doesn't cure anything, or even just as a way of helping you do better with your symptoms?

CARMEN: The question is, what is cognitive behavioral therapy? That is just a term for many different approaches. The strategy may be that you have chronic pain and that I try to help you cope with it and learn certain strategies. But in ME/CFS, for example, cognitive behavioral therapy was to tell the patients that they can do these things as they did before, so that they just have to believe that they can do it again.

SPENCER: To push them to do all the normal behaviors.

CARMEN: And that is very dangerous. The right term is actually not cognitive behavioral therapy, but supportive psychotherapy, so that you really support the patients in their daily needs and problems. For example, help them find strategies for how to live with the disease, how to manage the emotional problems that come along with the situation, or how to learn pacing. Pacing is actually a major challenge. Pacing means that to avoid overexertion, you have only a very limited amount of activities possible during the day, so you have to make decisions about how to use this time. You probably have just an hour per day in which you are active, and then you have to decide how to use this hour. That often means saying no, and telling your children, "No, I can't play with you," and so on. This is also a major challenge, and for this, such an approach of supportive psychotherapy may be helpful.

SPENCER: I see. Right, right. Because, as you point out, cognitive behavioral therapy could mean many things. A lot of cognitive behavioral therapy is about getting people to think about the way they interpret events and asking, "Is there a more helpful way to think about this?" For example, I imagine people who are suffering from these disorders often lose all hope. They think, "My life is over. I can never enjoy anything anymore." You can imagine the therapy being helpful to say, "Okay, you can still have some meaning in life, some value in life. You don't have to feel that way." And help them be less depressed or less anxious with the exact same symptoms. Versus telling them that, "No, actually you just need to push through. If you just push through, you'll be fine."

CARMEN: Yeah, yeah. This is a concept.

SPENCER: I've looked at a lot of interviews and case reports of people who say that they had either ME/CFS or long COVID and then say they got better using psychological methods. I've looked at many of them, and one thing that I notice is the pattern is not so much that CBT-like exercises help them; largely what they say helps them is learning to interpret their symptoms differently. They noticed that they were having a kind of fear reaction to their symptoms or viewing their symptoms as really bad, and that it was more through learning to view their symptoms with equanimity, where they're sort of learning to not react to their symptoms, that they found that was life-changing. I wonder, has a study ever been done looking at this kind of question of how people view their own symptoms?

CARMEN: I think what you are referring to are techniques which are called the Lightning Process or Gupta Program.

SPENCER: Yeah, there are tons of names for these.

CARMEN: You just say to yourself several times a day that, "I feel okay and the situation is not so devastating, and I have to be positive," and so on. This is actually dangerous because this is also emotional stress, and it doesn't work. At least in the large majority, it doesn't work at all. I don't think that there are any high-quality studies really confirming that this works in a subgroup, or the other interpretation we had is that it's probably patients not having the diagnosis or having a very specific form of ME/CFS, but probably another pathway mechanism.

SPENCER: Okay, so maybe there's some subgroup that has similar symptoms that has benefited from these techniques, but this is not the patients that you're treating in your trials. This is a different group, but they have similar enough symptoms that they get bucketed the same. Is that kind of the idea?

CARMEN: Yeah, that is right. And what is really the dangerous thing about this concept is that it's also a matter of being responsible about your disease, and that it's your fault that you do not get healthy because you're not trying hard enough.

SPENCER: Well, I'm not an advocate for any particular viewpoint, but I think the people that do advocate for this way would say, "It's not that it's your fault. It's that you've learned a kind of fear response to your own symptoms, and that by learning to have a more equanimous reaction to your own symptoms, that actually will cause the symptoms to go down." The most scientific viewpoint I've seen put on this, and I'm not saying that this is a scientific viewpoint, but in the pain reprocessing therapies for chronic pain conditions, there is some evidence, and there is at least one randomized controlled trial looking at getting patients to view their pain symptoms differently. And there's some evidence that if you have a chronic pain condition, but there's no organic disease, like, let's say you have low back pain, but on MRIs and stuff, there's no sign of disease, that patients can learn to view the pain symptoms differently, and over time, the pain might fade. So I guess that's maybe the most scientific way of looking at it that I'm aware of. What do you think about that?

CARMEN: Yeah, I agree. Although I'm not a specialist for CFS, I know that this is working, and that makes sense. And this is very different from a disease like ME/CFS.

SPENCER: I see. So just a different kind of category. That makes sense. You mentioned physicians, and I imagine a lot of people who have ME/CFS or long COVID that go to a regular general practitioner, I imagine the GP doesn't necessarily know what to do with them. What kind of experiences are people typically having when they go to their GP?

CARMEN: Well, there was a recent study in Germany asking long COVID patients about their experience, and many report that they feel not taken seriously, and they experience a lot of psychologization, as we call it in German, so that their disease is interpreted as being psychological. Many also say they feel stigmatized due to this, and this is, of course, getting better. I know this because I have been taking care of ME/CFS patients for almost two decades, and I know the situation before the pandemic was much more difficult. Many physicians didn't know about the disease. Nowadays, I think almost all physicians, and now I'm talking about Germany, where I know the situation best, know the disease, but still there is great uncertainty about how to help these patients, how to diagnose, how to treat it. Therefore, we think it's still important to have ongoing public awareness about the disease and also offer education so that the physicians learn how to handle these diseases. We also need guidelines, which is the way medicine works nowadays, that you have guidelines for all diseases, which tell you how to diagnose, how to treat it, and that has been largely missing before the pandemic for ME/CFS. Now we do have guidelines for long COVID and ME/CFS, and that at least helps patients get their basic treatments. Many patients suffer from symptoms that are not so difficult to handle, such as sleep disturbances, pain, or orthostatic intolerance. These symptoms can all be treated by drugs that are available, licensed, and can be prescribed. That is the current situation; we really try to bring this to the physicians and to the patients so that at least the care for the patients in general gets better. That's the situation at the moment, and the situation for the future is that we really develop drugs that target the disease mechanisms and bring us a promise that we can effectively treat and cure these diseases.

SPENCER: Right now, as I understand it, all the treatments are essentially treating symptoms. Is that accurate?

CARMEN: Yeah, more or less. Many of these drugs we have just treated symptoms. For example, fast heart rate or sleep pills are frequently used now to treat these symptoms, but we do already have some drugs that can also treat these mechanisms. These are usually off-label therapies, so they are not licensed for ME/CFS or long COVID, but they are used and prescribed by some physicians. The most frequently used drugs, like low-dose naltrexone or methylene blue, are all currently tested in large randomized trials. I think that within one to two years, we will have definitive results on whether they are active and in which subgroup they are active. Then we have a good chance of having the possibility to prescribe these drugs, although these drugs, in general, are not curing the disease. We know that a subgroup of patients can get much better with these drugs, but what we really need is a drug that can cure the disease. I'm convinced that we actually do have these drugs already in use for many other diseases. What we need now is to really understand which are the right drugs we need to develop, and then we need to do the clinical trials to get clear evidence that they are effective and in which subgroup. In the end, we need to have these drugs licensed and prescribed.

SPENCER: That's fantastic. So it sounds like you're optimistic that some of these new trials that are going to come out in a year or two, on naltrexone, will actually find positive effects.

CARMEN: I'm pretty sure about naltrexone. We have been using it for years, and we know it's quite effective in a subgroup. Our main interest is autoimmunity and autoantibodies. We know that in a subgroup of patients, we most likely have an autoimmune mechanism. It's an autoimmune disease, like many other diseases that are autoantibody mediated. We have many diseases nowadays, rheumatoid arthritis, multiple sclerosis, and so on, which are autoimmune. For these diseases, we do have several very good drugs, and we got funding. In Germany, since 2023, we are doing clinical trials here, and we already have good evidence that in a subgroup of patients, the removal of autoantibodies is effective. The first trials we did were with immunoabsorption, a technique with which you can wash out all antibodies. When patients get better, you know that this must be the antibody you removed. This is not a curative therapy because the cells producing these antibodies still remain in the body. The next step is that we are doing clinical trials with the drugs we already have from other diseases, which delete these antibody-producing B cells or plasma cells, and that is what we are currently preparing. We are ready to start with two clinical trials at the end of spring.

SPENCER: Oh, that's fantastic. The hope is that this could lead to a true cure for the disorders.

CARMEN: Yeah. We are pretty sure that this is an effective treatment for a subgroup.

SPENCER: And is that the subgroup that also has ME/CFS?

CARMEN: As we have been doing research on ME/CFS already, before the pandemic, this is still our main focus. We are currently doing these trials in ME/CFS patients who developed ME/CFS following COVID or other infections. This is probably not only restricted to ME/CFS, because we have evidence that in post-COVID, in a subgroup, it's autoantibody mediated. There are two very important animal models performed, one performed in Yale by Akiko Iwasaki, and one in the Netherlands by Jeroen den Dunnen. They both isolated the antibodies from patients and transferred these antibodies to the mice, and then the mice developed very similar symptoms. They also showed that these antibodies from the patients are bound to, for example, neuronal structures, and this was associated with the symptoms in the patients and in the mice. So this is pretty convincing data that this is also a relevant mechanism for a subgroup of long COVID patients not having ME/CFS.

SPENCER: Now why would a drug like naltrexone help? I think people have heard of that, maybe as a drug for alcoholism or opioid use disorder.

CARMEN: Naltrexone has several interesting mechanistic effects. It can also ameliorate inflammation, so it inhibits an important Toll-like receptor 4 (TLR4), which is a trigger situation. It also influences an ion channel which we know is impaired in function in ME/CFS and long COVID. It was shown, at least in vitro, that naltrexone can restore the function of this ion channel, and therefore restore the immune function and probably the function of neurons.

SPENCER: So it basically has nothing to do with the mechanisms for alcohol.

CARMEN: Also, it's a concept that it may upregulate the receptors for opioids, and it's known that we produce opioid-like molecules in the body, and they may therefore be more effective, and we may have less pain. That is also a concept of the treatment for low-dose naltrexone.

SPENCER: And what about post-exertional malaise? Is there any known treatment for that?

CARMEN: Well, if we can treat post-exertional malaise, we probably have a drug that can treat all patients suffering from post-exertional malaise. It may be triggered by different mechanisms. Therefore, there are also scientists trying to develop drugs that can directly inhibit the development of post-exertional malaise, because post-exertional malaise is not present all the time; it comes and goes. Therefore, it could be a sort of preventive treatment. What we know in the end is that post-exertional malaise most likely occurs because, upon exertion, you do not adequately perfuse your muscles, which is disturbed in many patients, in all patients with ME/CFS and long COVID. Your autonomic nervous system is not working properly. If you exert yourself, if you start to run, you need much more blood in your muscles, and if you cannot open your vessels adequately because your autonomic nervous system is not working properly, or because your vessels are inflamed, which is quite frequent in long COVID, then your muscles do not get enough energy and oxygen, because that is what you need to make energy. You have mitochondria in the muscles, and these mitochondria produce energy from oxygen, from the blood, and from sugar or proteins. Without enough oxygen, you cannot make enough energy, and then you rapidly develop muscle aches. You use up your sugar in a form that is inefficient, called lactate, which produces a lot of protons and makes the muscles acidic. After exertion, you need to get rid of these protons, and you need your ion pumps, which is a complex and energy-demanding process. In the end, this is probably what causes post-exertional malaise, because your muscles get severely damaged. You cannot recover your muscles to a normal state. It's probably like if a healthy person runs 20 miles; that is what happens in the muscles of someone with post-exertional malaise after walking 400 meters. If we have a drug that can improve perfusion or avoid these alterations in the muscles, that would be a drug that can prevent pain. That's quite complex. I know it's even a bit complicated in simple words. But there have been several reviews already written about this topic. For those who are interested in more details, I can provide the literature.

SPENCER: Yeah, that'd be great. We could put in the notes. Is it understood why the post-exertional malaise can be so inconsistent, where maybe the patient will walk for 20 minutes and then three hours later they might have a crash or five hours, or maybe even the next day?

CARMEN: That's probably due to what I just tried to explain, because it's what we know too. When we run too fast, the muscle pain will be worse the next day.

SPENCER: I see. So it's a similar mechanism to why it's delayed. Interesting. Now, when long COVID was beginning to be understood, people started getting really concerned that this might become a major percentage of society that eventually gets it. If every time you get COVID, there's some chance you're rolling the dice that you might get long COVID, then you might think that just over time, with COVID still running rampant in society, you might just get a higher and higher percentage of people that end up with long COVID. What's our current understanding of that? Do we expect that we're kind of at peak long COVID, or do we expect it to continue going up in society?

CARMEN: Well, the bad news is that you can still get long COVID, even if you had no problem after your first or second infection. That's what the studies tell us now.

SPENCER: Do we expect it's less likely if you've gotten COVID once and didn't get long COVID. Then you get COVID again. Do we think you're less likely to get it the second time?

CARMEN: You're less likely, but you still can get it. There was a recent study in children which showed that the risk is similarly high from infection to infection.

SPENCER: So if it was truly similarly high, though, wouldn't everyone eventually get it? I assume I probably get COVID once a year, right?

CARMEN: Well, at the moment, I think we have numbers that are no longer increasing, but they are also not decreasing, because many patients stay ill for a long time, and then there are new cases coming. The risk of developing long COVID in general is much slower nowadays than it was in the early days.

SPENCER: And that is because of the severity of the virus...

CARMEN: Yeah, it is much less severe. And then, of course, we are vaccinated, and our immune system is trained. All of us have had at least one COVID infection so far. So the risk is much lower nowadays. On the other hand, we still have the risk of developing post-infectious diseases triggered by other viruses. During the last two to three years, we have seen quite a high number of other viral infections too. So we still see many patients with new infections triggering long COVID or post-infectious diseases. That's true this winter. That was true last winter. So we still get many patients developing these diseases.

SPENCER: Is there an estimate of, if you get COVID once today, what the chances of getting long COVID are from that?

CARMEN: Well, there are several studies and the numbers vary, but in the beginning it was about 10 to 20%.

SPENCER: Oh my gosh.

CARMEN: And now it's much lower. So yeah, probably with an average of 1 to 2%, I think that's a good estimate.

SPENCER: It's still pretty high. What do we think the current prevalence of long COVID is? If we look across society, what percentage of people have it right now?

CARMEN: There was a large review meta-analysis of the major cohort studies from Ziyad Al-Aly, who is a renowned epidemiologist in the US, and he came up with a number of 5% for 2023.

SPENCER: That's massive. One in 20 people have long COVID.

CARMEN: Of course, it doesn't mean that they are all severely sick, but it means that these patients have lingering symptoms. If we look around and the people we know, I think almost everybody knows somebody who has problems from COVID. I think it's a realistic number, at least, to say that there are a few percent of the population still suffering from long COVID.

SPENCER: Is it roughly static now? It's been about 5% for a while, or are we seeing that number tick up or tick down?

CARMEN: I think at the moment we have a static number. That's what the studies tell us.

SPENCER: What about ME/CFS? Do we have a sense of what percentage of people have that?

CARMEN: There were fewer studies about ME/CFS because, as I said, before the pandemic, there were a few scientists interested in studying ME/CFS. The estimate before the pandemic was about 0.15 to 0.3% suffering from ME/CFS. So in Germany, with 80 million people, that was estimated to be 150,000 to 300,000. That was quite a number, and now there is good evidence that those numbers have roughly doubled as a consequence of the pandemic.

SPENCER: Interesting. I would have thought it'd be even more than that. If 20 to 30 percent of people with long COVID meet criteria for ME/CFS, I would have thought if 5% of people had long COVID, you'd be seeing higher numbers. Is that not right, that 20 to 30% of that group with long COVID would not have any CFS?

CARMEN: Yes, that is what the results from several trials indicate.

SPENCER: Okay, got it. So that would suggest that maybe the numbers are higher.

CARMEN: Yeah, and it depends on which diagnostic criteria you use. When you use the IOM criteria, you have higher numbers of ME/CFS patients compared to the Canadian consensus criteria. There's a large German study using the Canadian consensus criteria, and there we had 10% of ME/CFS patients.

SPENCER: I know at least two different, unrelated people who currently still take great precautions to avoid getting COVID, meaning they make very significant changes to their life to avoid COVID because of concerns about long COVID. What would you say to someone who's doing that? This is being recorded here in 2026.

CARMEN: First of all, it depends on your personal risk. If you have had long COVID already, of course, you are at a higher risk of getting it again with another infection. Then I also would recommend, for example, to wear masks when you are in public transport.

SPENCER: You've had it previously. Yeah. So in this case, neither of them have had it previously.

CARMEN: We also have patients who are at risk because of immune deficiency. These are the patients we also recommend to be very cautious and to wear masks. To put it more generally, we know that there are people at higher risk. We know that females in general have a much higher risk. So 80% of our patients are female, and we know that obese patients are at higher risk. We know that patients with other immune diseases, like asthma and allergies, are at a higher risk. But the problem is, what would happen when you wear masks all the time? What we also learned from the years 2021 and 2022 is that by wearing masks all the time, later on, you have a higher risk of getting other infections because you do not continuously train your immune system, for example, with the respiratory syncytial virus, which became much more frequent in younger children.

SPENCER: So you might be actually weakening your immune system by doing.

CARMEN: So probably your immune system is not made to be protected all the time. If you are otherwise immunologically healthy, I would not recommend protecting yourself all the time. For example, I use a mask when I'm in contact with people who obviously have an infection. Or if I go on public transport and it's very crowded, then I take my mask to protect myself, but I don't use it all the time, and that's probably good advice on how to handle it.

SPENCER: We know that with COVID itself, age was an incredibly huge risk factor. Your risk of dying if you were 80 versus if you were 20 was almost unbelievably different. Is that also true of long COVID?

CARMEN: Well, we have other risk factors. The risk of dying the older you are is most likely due to a weaker immune system, and we also know that men are at a higher risk of dying because men in general have a weaker immune system. The opposite is true for long COVID; we have younger patients with a stronger immune system.

SPENCER: Oh, I see. So we think it's because the immune system is overreacting, so it's sort of the opposite of what was happening when a patient is dying of COVID, where a weak immune system causes you to die, but an overactive immune system might cause you to get long COVID. Is that accurate?

CARMEN: Yeah, exactly.

SPENCER: Oh, that's fascinating. That's kind of flipped on its head. What about vaccines? Do we know that they reduce the chance of getting long COVID?

CARMEN: Yeah, we know it. There are many studies providing proof that they reduce the risk. Unfortunately, it's not 100%. That was the hope, that you could protect yourself very efficiently, and the numbers are about 50%. The risk reduction is about 50%, which still is a lot. And we know, of course, that vaccination also protects from the more severe causes, so the recommendation is to get vaccinated if you are in a risk group. That means if you are above 60 years old, you should get vaccinated. We also recommend vaccination to our patients where we know they have a higher risk of developing long COVID, especially the patients who already have long COVID or ME/CFS, who have a risk of disease deteriorating with another infection.

SPENCER: Has it been shown that people with immune issues prior are much more likely to get long COVID?

CARMEN: Yeah, if you have a more active immune system, or if you have a certain type of immunodeficiency. There are several forms of immune deficiencies we know which are associated with a higher risk of developing long COVID.

SPENCER: And suppose you get long COVID, what is the progression of it? Does it tend to slowly get better over time? Does it kind of just stay static for many people, and do most patients eventually recover after a certain number of years?

CARMEN: Well, we have different courses, as you describe. In some patients, it gets better. In some patients, it may get worse. Some patients get sick, so they have COVID, and then it's a continuum into long COVID. Other patients recover. Often, they go back to work or back to sports, and then they get worse again. We see fluctuating courses; some have better months and worse months. Of course, we have patients who recover, especially early during the first month of the disease. Unfortunately, we also have those with the severe and chronic form.

SPENCER: So it sounds like a really wide range of possible outcomes. Let's say someone gets long COVID. Do we know the chance that three years on, they're completely better?

CARMEN: Well, it's difficult to say because long COVID is so different from patient to patient, and we do not have good prognostic factors yet. We also tried to find prognostic factors. We started in 2020 a large observational study for long COVID and ME/CFS patients, and one marker that came out as being prognostic is hand grip. That is an indicator of how strong your muscles are, and if you have a low hand grip early on in the disease, you have a higher risk of a severe and chronic course.

SPENCER: That's a funny metric, because that's also been found to be very linked to longevity and other things. But I think we assume that it's not a direct link. It's some kind of indicator, right? It's not like if you make your hands really strong you're going to improve.

CARMEN: It's an indicator of your metabolic health as well, which is influencing the strength of your muscles. So if you just regularly train the strength of your hand, that does not necessarily mean that you live longer.

SPENCER: Do we know at least if the majority of people with long COVID will eventually get better? Or do we not even know that?

CARMEN: Well, when we look over the last three to four years in which we have followed the patients, those patients we follow in our cohorts are those who either have developed ME/CFS or at least have a form of long COVID that goes along with fatigue and exertional intolerance. There, we found that those with ME/CFS have less than a 10% chance of recovering over this time, and those who do not fulfill the criteria have a higher chance of getting better over time. But still, there is also a high number who remain sick. There was a recent study published from RECOVER, the US group studying long COVID, and they also showed that there is approximately a group of 5% of patients who stay chronically ill for years.

SPENCER: Yeah, sometimes people will refer to chronic Lyme disease as one of these conditions that they'll kind of group in a similar category. In fact, funnily enough, I was actually diagnosed with chronic Lyme disease when I was a child, and I went through intensive treatment where they gave me antibiotics for a month intravenously, which my understanding is that's not even considered. Many people consider that not a legitimate treatment now, but anyway, that was my own experience. But I'm curious, would you group chronic Lyme disease in the same sort of set of disorders? Or do you think that's really just unrelated, something different?

CARMEN: Well, I would group it into these diseases, but there are some specific things about chronic Lyme disease, because we know that there is a group of patients where it can persist, the Borrelia burgdorferi, which is the bacterium causing the disease. And these patients can be treated by antibiotics, though it can persist in the skin or in joints and then it's treatable. And then there's another group of patients where we have no evidence of persistence of the bacteria, but who still are very sick, and this probably is more likely what we see with ME/CFS or long COVID, where we have a disease which was triggered by the infection, but which becomes independent of the initial trigger.

SPENCER: And I guess in this case, it's a bacterium rather than a virus. But for that group, are the symptoms fairly similar?

CARMEN: The symptoms of Lyme disease are also very similar. So they also suffer from severe fatigue and cognitive impairment, malaise, so this is similar.

SPENCER: Before we wrap up, I just have a few more questions for you. What advice would you give to someone who has long COVID or ME/CFS today? What should they do?

CARMEN: Well, I get this question asked several times.

SPENCER: I'm sure you do.

CARMEN: The problem is that we still have few specialists, so many patients need to rely on their primary care physician. At our center, we have a website on which we provide a lot of information for patients and physicians. We have guidelines on how to diagnose and treat ME/CFS, and we also have guidelines for long COVID. I recommend that patients tell their physicians where they find this information, and I tell the physicians that they should proceed symptom-wise. Ask your patients what are the most worrisome symptoms and what would you like to get treated first, and then do a stepwise treatment. Self-management is important too. For those suffering from post-exertion malaise, the strategy of pacing is very important. That is not so easy to understand and handle. There is also information material available on our website, but I'm pretty sure you can find it at several US institutions and self-help groups in the US. There are also strategies that may be helpful, like certain breathing techniques and relaxation techniques. You may also find strategies to handle certain intolerances. Many patients also suffer from allergies or food intolerances. There is a lot you can do, and there is a lot of information available. There are many well-informed patient organizations for these diseases, and I recommend that you also look to have contact with these patient organizations to get information. Of course, there are a lot of social problems that come along with having such a severe disease and being sometimes unable to work full-time. It is also very helpful to exchange with these patient organizations to find a way to handle this.

SPENCER: We'll put links in the show notes to your website with that information. Suppose that it's not you who has long COVID or ME/CFS, but one of your loved ones — your child, husband, wife, or mother — what would you advise in that case?

CARMEN: Well, it's a difficult question because it's always challenging to handle diseases in your family. What I advise my patients is that we would like to treat everybody in a clinical trial. If we have no curative treatment to offer at the moment, we should try to treat as many patients as possible in clinical trials. One prerequisite is, of course, that we have the financial support to do these trials. We are now in a situation that has much improved. I think the situation is similar in the US; there are also several research centers here now performing clinical trials. What I recommend to all patients is to participate in these trials, even if you receive a placebo, because that is typically done in a clinical trial. Only half of the patients get the drug; the other half gets the placebo. We still learn a lot. If this drug is effective and you just received the placebo, you will benefit from the effective drug in the end because there will be a next trial, or it will be licensed in the end. That is what I would try to offer every patient, not only my family.

SPENCER: And then, how about on the psychological front? Because I imagine it can be quite difficult. Your loved one might be essentially disabled from one of these conditions. Do you have any advice there?

CARMEN: Yeah, that is really terrible to see how much these young patients suffer. We even have children suffering from these diseases. To help these, we try to build a network to offer psychological and psychotherapeutic support for everybody. In Berlin, we received funding to build a care network, so we work together with primary care physicians who develop experience in treating these diseases, and we also work together with a network of psychotherapists providing social support for these patients. We hope that in a few years, we will have such a structure in Berlin that every patient developing long COVID or ME/CFS gets an early diagnosis, receives adequate symptomatic therapy, and gets adequate support, and that we can, in the end, cure all these patients.

SPENCER: That's a wonderful goal. Final question for you, suppose you had unlimited money to run one study? What's your dream study that you wish you could run on these relevant questions?

CARMEN: Well, I'm pretty much convinced that a subgroup of these conditions is autoantibody mediated, and we have very effective drugs nowadays. Actually, my dream is coming true because we received funding to run these studies, so my next hope is that we get these studies done as fast as possible. These are quite demanding nowadays, to do clinical trials, with all these regulatory and data protection rules. But if we can conduct these trials as quickly as we hope, then we may have results by the end of next year.

SPENCER: Wow, that's fantastic. Great news. I'm really excited to see how that turns out. Hopefully you'll find a cure. That would be incredible. So Carmen, thank you so much for coming on the Clearer Thinking Podcast. This was so informative.

CARMEN: Yeah. Thank you very much.