Unraveling the Mysteries of Post-Exertional Malaise: Special Series from The Cohen Center for Recovery from Complex Chronic Illnesses at Mount Sinai

Dr. Raven Baxter 

Hi everyone. I'm Dr. Raven Baxter and I'm your host of this episode of the Raise the Line podcast. I'm a molecular biologist and science communicator and director of science communication at the Cohen Center for Recovery from Complex Chronic Illness at the Icahn School of Medicine at Mount Sinai Hospital. At the center, we work to advance treatment and knowledge of long COVID, tick -borne and vector -borne illnesses, myalgic encephalomyelitis, chronic fatigue syndrome, and connective tissue disorders like hypermobile Ehlers -Danlos syndrome. This series is covering post -acute infection syndromes. 

Today we're joined by doctors Rob Wust and David Putrino to discuss post -exertional malaise. So Rob and David, thank you for your time and joining us today to discuss this very important topic regarding post -acute infection syndromes. I would love for you both to introduce yourselves so that the listeners can know all about you. 

David Putrino 

I'm David Putrino. I am the Nash Family Director of the Cohen Center for Recovery from Complex Chronic Illness. I'm a professor here at the Icahn School of Medicine at Mount Sinai, and I’m thrilled to be here and thrilled to learn from Rob, actually. 

Rob Wust 

Yes, so my name is Rob Wust. I'm an assistant professor from the University of Amsterdam, the Vrije University in Amsterdam, where I particularly work on skeletal muscle metabolism and function and from a various range of diseases, healthy conditions, inactivity, but now also more recently on long COVID. 

Dr. Raven Baxter 

Wonderful. Well, thank you. It's nice to meet you, Rob. David and I work together at CORE. So I think we're both very excited to learn new things today. So full disclosure, I am a long COVID patient so I have a lot of familiarity with post -exertional malaise, particularly in my most severe condition where I was truly bedridden and could not do much without just completely getting knocked out afterwards. 

So, let's talk about the essence of post -exertional malaise and define it for the medical students. 

Rob Wust 

Yes, I think the key term of post -exertional malaise is that it's not just fatigue the people are feeling when they have suffered from long COVID or ME -CFS. It's really the worsening of symptoms, of general symptoms related to the disease or the onset of new disease, new symptoms after exercise. The exercise has to be above a certain intensity. 

And typically what happens is that the symptoms start within 48 hours. Often it's earlier already, 24 hours, sometimes a bit like almost at the end of exercise. But it's an onset. The onset starts after the exercise and it can last for days, weeks, or even months when you are very severely ill. And that essentially means that it's not just feeling fatigued, it's the whole plethora of symptoms that are related to long -COVID. 

Dr. Raven Baxter 

And it seems that PEM, post -exertional malaise, is a common thread throughout post -acute infection syndrome. Is that true? 

Rob Wust 

Yes, that's indeed true. And it's actually a very key symptom of the disease of long COVID and as well as this ME -CFS. And that's why they now think that the diseases are sort of under the same umbrella term of post -infectious diseases. What is really typical about post -exertional malaise or PEM is super specific for this type of diseases because we know from all the other diseases that we studied -- heart failure, diabetes, depression -- that exercise is good for you. Doing exercises makes you feel better, makes you feel healthier, makes your symptoms less. But it's the opposite essentially for long COVID patients, particularly if you go over this threshold all the time. 

Exercise below the threshold, the PEM -inducing threshold, we think that is good. So there is also this threshold thing that we need to keep an eye on when we try to understand the onset of PEM better. 

Dr. Raven Baxter 

Thank you. And just so maybe I can, from my perspective, help the listeners distinguish it from fatigue. So with post -exertional malaise, in my experience, I felt a complete body flushing. Like I know exactly when I'm about to have a crash and it would be completely immobilizing. That is very different from, hey, I just ran a mile. I'm pretty tired. The symptoms feel completely different. So can you lend any perspective to the things that we think are happening in our bodies when post -exertional malaise is happening? 

Rob Wust 

Yeah, that's a very good question. Also a very difficult question because actually that's the key question that we all have is what really happens inside the body when this symptom develops? And the short answer is we simply don't know. To give you a little bit more perspective on this, I started working on this about two, two and a half years ago when we realized that exercise is not always good for patients with long COVID, particularly those that are diagnosed with PEM or post -exertional malaise. Before that, I think hardly anyone understood that this is something that can actually happen because, like I teach all the students in our medical school and our human movement sciences courses, exercise is good for you. Keep exercising. That's what everyone tells everyone. Go to the physiotherapist, do some exercise, keep active. It's good for healthy aging. It's good for chronic diseases. 

So we know that exercise is good for you, but this is such a specific condition where it's not, that understanding it really baffles exercise physiologists because you know it's completely against the general idea that is something that can be bad for you. Also scientifically, it's been a very underestimated or under understudied topic and only now we start to uncover all these aspects. 

Over the last two years, I spoke with a lot of different patients and they all have slightly different types of explanations what they feel when they go into PEM. Some people say it's more of a pain, other people say it's flushing, it's a fever, onset of fever. Lots of different symptoms come up. But for me as a scientist, it's super important to hear from patients what they say because that gives us indication of what is underlying mechanisms exactly and can we try to understand it better? 

And actually with the research that we have just done and we're currently still doing, we're just opening up this unknown box of what happens with PEM. What is the cause? What are the consequences? What is the phenotype? Can we do anything about this? Can we stop it? Can we reduce it? Can we measure it? We have seriously no clue.  That's what we are starting to work on and we do that with, of course, a lot of different people around the world. Different groups work on this, and we are just one of those. 

Dr. Raven Baxter 

Yes. So one of the things that is common to learn about when you're a person who's newly faced with this issue is how to do resting and pacing and that was particularly helpful for me because -- well, helpful and scary -- because it's sort of trial by fire. Like, you either under do it or you overdo it. There was really no like perfect baseline when you have PEM. and every day is different. So one day where you feel like, ‘I could have done a little bit more’ the next day, you're like, ‘I might've overdone it yesterday and now I can't move.’

So, David, how do you confront a patient who knows something's wrong, who is telling you, ‘it's harmful for me to move.’ As a physical therapist, knowing how important exercise is, what is your approach, because it seems like a catch 22? 

David Putrino 

I know it can seem like a catch 22 in terms of the general lens of medicine rehab. I probably went through a very similar training to Rob in terms of a lot of my clinical training back in the day was with exercise physiologists and being told about all of the benefits of exercise and being told, you know, exercise is medicine and so on and so forth. And I still believe exercise is medicine. 

But as with all medicine, there are conditions where it's contraindicated, as with all medicine, you dose appropriately, and as with all medicine, you understand that physical activity can be harmful to some. And Rob's work is so important in establishing this. Once you start to understand the pathophysiology going on in post-acute infection syndromes, and you start to understand that when you force someone with post-acute infection syndromes to exercise, or who have PEM, or if someone with PEM pushes themselves beyond their energy envelope, you set into motion a series of physiological changes that cause damage. 

So, once we start to understand that that is the pathology of PEM, once we start to understand that, you know, these folks are different, it starts to help you as a clinician understand, well, actually, I would never prescribe exercise for this class of individuals, this person who's living with this diagnosis. And it's not unprecedented. I really want to point that out. 

We know that exercise is wonderful for chronic diseases, however, we also know that there are conditions like Duchenne's muscular dystrophy -- a progressive illness where people's muscles break down. Now, if you apply this very blinkered mindset to it of, ‘well, you're losing muscle strength and your muscles are wasting, so we're going to get you to just exercise’ you will accelerate the decline of a person with Duchenne's. So I think we need to, when we're approaching post -acute infection syndromes, when we're approaching people who have severe post -exertional malaise, that's the mindset we need to bring. We need to understand that despite the fact that exercise is a good medicine for many conditions, there are, in fact, historical and pathological examples of, actually, if you apply exercise here, you're going to worsen things. You're going to make things much, much worse. And we need to very quickly establish PEM and conditions that have PEM as one of those conditions. 

Dr. Raven Baxter 
Thank you. So let's kind of set up a scenario. I would say that a lot of people may not have the vocabulary to express, ‘hey, I have post -exertional malaise.’ So if you encounter someone in your care, or maybe we could just put ourselves in the shoes of a general physician, someone comes into a treatment room and is like, I'm tired. Or I just don't feel good. 

What are some things that they say that you might flag, that you would wanna dig deeper in? And what specific questions should doctors be asking their patients in the treatment room? 

David Putrino 

Yeah, well, I would say first and foremost, speaking for our clinic, we use scales. If someone tells us they're fatigued, I want to know how fatigued they are. I want to know what activities make them fatigued. I want to know how long that fatigue lasts. I want to know if anything else accompanies the fatigue.  And so we use scales such as the fatigue severity score for post -exertional malaise. We screen for post -exertional malaise using the DePaul post -exertional malaise screener. These are well validated scales that can identify fatigue and post -exertional malaise. 

And yes, you're 100 % correct, Raven, many, many individuals with post -acute infection syndromes don't know quite what's happening to them. It's a very scary period. They will tell you that they're fatigued, or they will tell you that something's not quite right and you need to, as a clinician, understand well what that is. 

The simple concept that I try to teach to anyone who's looking to work with folks with post -acute infection syndromes is step one is that you need to differentiate between what is fatigue, which is this general feeling of, exhaustion or tiredness that is present; what is exercise intolerance, meaning you try to exercise and something physically stops you...you can't complete the exercise task; and what is post -exertional malaise? Which is, as Rob beautifully defined -- and I won't go and redefine it -- but essentially you exert yourself and then for days or even weeks after that exertion, even though you can engage in that initial exertion, you pay for it with worsening symptoms or even onset of new symptoms. 

So clinically, that's the first thing that you need to understand because you can take a different path based on what emerges. We've had people who have come to the clinic, who told us that they had fatigue. But in reality, when we dug a little deeper, actually they had exercise intolerance. And when we did a deeper dive on their symptoms, we learned that they had vocal cord dysfunction that was stopping them from exercising and just making them feel generally a little bit more exhausted because they were having difficulty with getting air into their lungs and oxygenating their tissue. And as soon as we addressed the vocal cord dysfunction, everything else cleared and everything else was fine. 

But if we had said to that particular individual, “Well, you should rest because you're fatigued or you should pace because you have PEM,” they wouldn't have gotten any better. and in fact, they may have deconditioned. So, the first thing is differentiating between those three situations and understanding what each one might indicate in your differential diagnosis. 

Dr. Raven Baxter 

Thank you. Now, I want you all to remember this, because I have ADHD and I'm going to forget, but I want to talk about the mitochondria. But before we do that, I want to talk about mobility aids, because that was something that was really important for me personally that I had to figure out on my own. Shower chairs -- chairs everywhere, actually -- so that I could walk around and sit whenever I needed to and not sit on the floor because getting up from the floor is hard when it's hard. Rollators actually were really great too because you can roll and sit. Canes...like they have canes that fold into chairs. Really just retooling your entire living environment to your new normal. Even if it is a temporary new normal, having mobility aids is important. 

If you wanna do laundry, have a chair by the washer and dryer so that you don't have to stand and bend and do all of that. It just takes some of that extra exertion off your plate. If you have to make food in the kitchen, put a chair in there. I had a rolling chair, actually, like a desk chair that I tried to roll myself in because I didn't know how to get a wheelchair, and honestly, no one could push me and I couldn't push myself in a wheelchair. 

I also couldn't get out of the house because I had to go upstairs. I was like in a sub -basement level. You might become actually housebound depending on how bad your post -exertional malaise is. So, telehealth appointments were extremely important for me because even making it to the car was impossible. I couldn't drive for months, let alone get up the stairs to get to the car. So the patient's lives might drastically change because of post -exertional malaise. And I think just offering some insights into how they can even temporarily make their life a little bit easier is really important. 

There was one other thing: exertion. For me in particular, exertion wasn't just physical. It was also like audio-visual. So, a lot of the time I walked around with sunglasses on...wait, walked around (laughs) laid around! I laid around with sunglasses on and earplugs. If I needed to watch or I wanted to watch something -- because I was basically housebound, I couldn't interact with anyone so I needed something -- I'd watch documentaries, but I couldn't do it without sunglasses and earplugs in because it would actually exhaust me to do otherwise and it would result in a myriad of other symptoms that we won't even get into. 

So, that is another aspect of exertion that people don't usually factor in because we talk about exercise a lot. Stress was very hard on me. Like any type of emotional anything. I couldn't talk on the phone. I just couldn't do anything. I actually had to balance like, if I want to do laundry today, I can't call my mom on the phone. Like it was that much of a tightrope balance between having a crash and being completely debilitated for the next two days or not. So, yeah, it's really hard on patients. So any insights you can offer the medical students is really going to be helpful. But let's talk about the mitochondria. 

Rob Wust 

Can I first....before you continue with the mitochondria? 

Dr. Raven Baxter 

Yeah! 

David Putrino 

Yeah, I'd love to comment as well. 

Rob Wust 

I think this is really important to comment on this because your condition that you'd explained to us is super important for clinicians to understand. They need to realize what patients are going through and stories like this really resonate also with me, with listeners because the patient story is important also for us to understand what actually disease is like and what impact it has on daily life activity. Because on the outside, you cannot see it. 

Now, when you go to a GP as an ME or long COVID patient, you look like a normal person. You can't measure anything wrong in the person because there's no blood test. There's no echo or ECG type of measurements that we can do to diagnose this PM. And as a result, you may look perfectly fine, but the next day you crash when you are back home again, and the doctor thinks, “Well, she looked actually pretty okay.” But actually the day after you're completely crashed and maybe that lasts for a whole week. 

I think that's super important to realize that what you see in front of you as a doctor is not the same as what happens when that person goes back home and how much you have had to sacrifice to go and see that doctor. So it's that realization also for students that there's no diagnostic criteria. We cannot diagnose it properly. It's a hidden symptom because it doesn't happen at the spot when you talk to people. It happens the day after and the week after. So I think that's super important to realize this. 

And I mean, that threshold of where you get the PEM is really patient dependent. I mean, your story, to me, sounds pretty serious and pretty severe. There are also people that have a sort of a mild symptomology where the PEM threshold is higher and that can change over time. It can change with the patients. I think that's super important to realize as a physician and as a physiotherapist. 

David Putrino 

Absolutely. And I think that a lot of what you shared is so important for medical students to hear. I want to shout out resources that are on Long COVID Physio website because they have pacing guides in multiple different languages that address exactly this issue of use of mobility aids. 

It’s important to understand that pacing is not just taking it easy. Pacing is a sacrifice. Pacing is an acknowledgement of, if I do these things, it's going to use this many units of energy, and if I do these things with a wheelchair or with a shower chair or with a walking aid or if I go to the airport and use the disability services that the airport provides versus being stubborn and walking through that airport, because I don't want to appear disabled, -- which is stigma, of course -- your life is going to be a lot easier the next day as a result. So pacing absolutely needs to utilize mobility aids and then education about pacing. And I think this is a nice segue into mitochondria. 

You know, just as you said, exertion is not just physical exertion. We often have to have these conversations with patients about anything that your body is doing that is increasing its energy consumption has the potential to cause a crash. So cognitive work, you know, is a huge challenge. We're recording this podcast while the UniteToFight Conference is going on, which both Rob and I have had the pleasure of speaking at. Already on Twitter, we can see patients saying, I love the first day, but the cognitive exertion of following the talks has caused us to crash. So cognitive exertion...the brain uses a lot of energy. Cognitive exertion will cause crashes. Emotional exertion will cause crashes. Having a tough conversation with a partner or a family member will cause exertion. 

But other things also cause exertion. Digestion causes exertion. And one of the conversations that I often have with patients, they'll tell me, well, I eat so healthy. I eat all of these things, but I feel really exhausted after I eat. And we talk about things that are hard to digest, you know, like leafy greens, for instance, are really hard to digest. And patients will sometimes say to me, you know, it's the craziest thing. I ate like white bread with butter and I don't get any symptoms. But if I eat a kale salad, I feel exhausted after eating a kale salad. And I'm like, yeah, because it's so easy for your body to digest white bread. You know, it's a simple carb, right? But a kale salad is high in fiber and these leafy greens take a lot of energy to break down. So even the diet that you eat when you're in a crash might have to change to something that is easier to digest and gives you more energy at a cheaper cost.

You know, a hot room causes you to sweat. That's energy. Your body has to work to produce sweat. These things can cause a crash. So anything that causes energy can cause a crash. So, a comprehensive pacing plan educates the patient about how to avoid energy consumption and think about it as an efficient or inefficient engine. Like, what are the sort of like subtle energy leakage strategies that can also cause you problems? And so, yeah, that's a good segue into mitochondria. 

Dr. Raven Baxter 

I am really laughing over here because I, at my worst of this, was eating salads every day. And I was like, I gotta get my greens in. And I would crash immediately after eating these foods. And one time I face planted into my salad because I crashed while sitting at the dining room table. I could laugh now, but like, I really thought I was doing good things with that salad and now I'm like, that explains a lot. So okay, that puts things into perspective. 

Rob Wust 

It's important to realize that indeed, what David nicely mentioned is that everything costs energy. So it's easy to dive directly into this mitochondrial aspect because that's where energy production is taking place. The question is, however, is that then the real culprit? Is that where the problem starts? If that is the case, then we can say, well, maybe that's where we need to start looking into. But there are also, for instance, genetic metabolic diseases where there are these mitochondrial dysfunctions occurring that in some cases they are very similar symptoms as long -COVID patients. 

So patients that, for instance, cannot burn down any fats, they have very similar crashes when they do physical exercise and they can get into conditions like rhabdomyolysis, which is the breakdown of muscle, severe breakdown of muscle after exertion. But those are very specific genetic metabolic diseases where there's only maybe, you know, a few patients in every country in the world and so they're very infrequently studied. But there is some overlap in the symptomology between long COVID patients and genetic metabolic diseases, for instance, that now spark our attention. Is there indeed something wrong with the mitochondria and is energy production the real problem here? 

The problem that I have in terms of scientific understanding is that -- and this is where the key problem occurs in this field -- yes, if there is a problem with the mitochondria, we all know that exercise should make those mitochondria better and that's just not happening here. So, while we know when we see mitochondrial dysfunction occurring in diabetes, heart failure and also for other chronic diseases, we always say, do some exercise because that's good for you. It's good for the mitochondria. It makes them stronger. It makes them produce more energy, makes them better connected to each other. And it's less oxidative damage to the muscle, et cetera, et cetera, et cetera. 

But in this condition, it's the exact opposite, where that exercise makes that mitochondrial dysfunction worsen and makes the problems worsen. So the obvious treatment that everyone thinks of when we think about mitochondrial dysfunction is not happening here. And that's where the sort of problem occurs with understanding this disease and this particular symptom is that maybe yes, there is something wrong with mitochondria, but what is it then? And how can we fix it? 

Dr. Raven Baxter 
Okay, so because general audiences will also hear this interview as well, pretty much everyone can say ‘the mitochondria is the powerhouse of the cell.’ We have to acknowledge this. But like, can we walk it back a little bit and just explain the function of the mitochondria and then the dysfunction of the mitochondria. 

Rob Wust 

So mitochondria are organelles inside every cell. You actually inherit them from your mother because the egg cells, they're the only ones who contain mitochondria. So it's maternally passed on to you. And it has its own DNA, actually, that's an interesting phenotype. It has its own DNA because it evolved from a bacterial ancestor. That's maybe a little bit off topic here, but it's important to realize that they are the main source of the ATP production of the cell. 

So ATP is the main energy current that we use for contractions of muscles, but also for nerve conduction, conduction of brain function... everything that we do in our body resolves around energy and that's where the main energy source is taking place. So they are also the locations in the cells where fats and sugars are being burned down and that turn into energy. A little bit of that conversion of energy is turned into oxidative damage. So there's a bit of damage occurring all the time when this conversion occurs. We don't really know actually how much of that percentage is and what are the cause and consequences of dysfunctional mitochondria. 

But one of the ideas is that if your mitochondria do not function properly, is that there is also a problem with the energy production, of course. It slower and it's not so efficient and you make a lot of heat, for instance. Heat production is one way to tell when mitochondria are not functioning properly because you essentially lose energy, but you don't turn it into this ATP current. So, for the large part, that’s the production and the function of these organelles. 

They also have some other functions. They are involved in some hormone productions in your kidneys, they are also involved in communication with other organelles in the body...so there is a little bit more to mitochondria as being the sole powerhouse of the cell. It has a few more other functions. And that's why I think also if there is mitochondrial dysfunction, you need to specify on what part of the function essentially the dysfunction occurs. 

Dr. Raven Baxter 

I love this. You heard it here, everyone. Mitochondria is more than just ‘the powerhouse of the cell.’ We need to give it more credit.  

Rob Wust 

Exactly. 

Dr. Raven Baxter 

Thank you. So I've seen something floating around in this space called a theory of ‘metabolic trap.’ Do you know about this? Can you talk about that and what the theory is there? 

Rob Wust 

It's an interesting theory actually and it's been going around for some time in the ME -CFS field. It's a very complicated biochemical pathway. That's where essentially I have to try to explain it in simple ways where certain metabolic enzymes are constantly turned on essentially and they turn on the production of certain substances. In this case, the main focus of this metabolic trap hypothesis goes around tryptophan and kynurenine, where there's a constant production of kynurenine and that's actually very neurotoxic. So it affects your brain function. And one of the ideas, for instance, is that exercise reduces that circulating kynurenine and that therefore it improves cognitive function in healthy normal conditions. That's why one of the reasons why we think exercise is good for patients with depression, for instance, is it helps to get rid of that kynurenine.  

The unfortunate situation is that in acute or long COVID infections, this pathway is continuously activated in immune cells. We published a study recently on this topic where we think that when this pathway is continuously activated, it can sort of impair immune cell function, but it can also relate to cognitive changes that we see in patients with long COVID -- brain fog, depressive feelings, et cetera. The only unfortunate thing is that we don't really know how to break that positive feedback system and how it occurs in the first place. Because if we know how it occurs in the first place, we can do something about it. And if we block it, does that then solve all our problems? That's the main issue that we don't know. 

David Putrino 

I would add to that, you know, often when we think about what are the drivers of complex chronic illness and post-acute infection syndromes, a lot of the time, we do sort of stumble back to two main theories. You have been infected with something that has persisted, so there's persistent pathogen in your body. Or your body thinks that there is a persistent pathogen, right? Regardless of if the pathogen is persisting, your body is certainly behaving as though it is. Those are basically the two theories. They're not mutually exclusive. They can occur together. 

So viruses, the way that they replicate is they infect us, they latch onto our mitochondria and they leach energy in order to replicate because viruses do not have mitochondria of their own. So now in any cell that they're infecting, your cells’ mitochondria are producing energy for that cell, but it's also producing energy for that virus. So, you get an increase in all of the waste products associated with energy production. One of the theories as to why mitochondrial dysfunction may be ongoing is that virus never went away, and these viruses are continuing to sort of jump between cells and so on and so forth. 

One thing I do want to point out is a lot of people actually have experienced a milder version of post -exertional malaise without knowing that they have, which is when we get sick with viruses. When you're actively, acutely ill, many people will have this relatable feeling of you sort of wake up and you're like, maybe today I'm actually better and you sort of push yourself too far. You try and convince yourself, OK, I'm finally over this terrible virus. I'm good. You push yourself too far and then you crash. And in some cases, you may even crash for a couple of days because you really pushed out outside of your energy bounds. You weren't ready. And now the virus has kind of resurged because you depleted your energy stock. 

So it's worth mentioning that many people have experienced this before in acute illness, it's just they haven’t experienced that chronically over months and years and decades. So it's a very reasonable theory to suspect that persistent pathogens might be at play at creating this chronic situation of mitochondrial dysfunction, in which case, if we can correct the mitochondrial imbalance, it may be a band aid, but it will be something that you have to keep doing until you address the persistent pathogens. 

Similarly, on the other side of things, if your body just thinks that there is a persistent pathogen, it's a high inflammatory state, which will cause your cells to expend more energy than they need to, which then leads to energy deficits that occur much, much more easily. So again, you will have to address that energy differential with mitochondrial supplementation and things of that nature. But that may not solve the problem. 

But those are two theories -- and I'll stress that they're theories -- as to why the mitochondrial dysfunction might be ongoing that really push us toward addressing some of the drivers that may be occurring upstream of the mitochondrial dysfunction that we're seeing. 

Dr. Raven Baxter 

Thank you, David. I'm learning so much. I'm just in a constant state of knowledge acquisition in this podcast. But we're heading towards the end here, and I want to get into solution -esque questions. When I talk about diseases to people they're focused on prevention and management. So, the questions I get are, what can I test and what can I eat? They're usually asking me about supplements and diets and tests. Now I know the answer to this sort of, but I would like to just pose...can you eat something that might alleviate the symptoms? What are some things that even though there are a lot of unknowns with post -exertional malaise, I would imagine that the physician and the patient would both want some sort of sense of control over this. So is there anything that people can do to manage their PEM besides resting and pacing? 

David Putrino 

So, what I'm about to say, I mean, some of it is evidence based and some of it is not evidence based. But the reality is we need more research in the space to better understand. There's a lot of questions that I would love to sort of throw at Rob on this topic as well. But like, in terms of testing, from a research perspective, there are things like two -day cardiopulmonary exercise testing (CPET), which will tell us about preload failure of the heart and oxygen extraction and give us really good information about someone's exercise capacity. But I 100 % would not recommend that for the average clinical patient. 

Rob Wust 

Can I just quickly interrupt here? Because I think this is an important thing that you highlight here is that this two -day exercise test is the way to diagnose PEM or post -exertional malaise. The issue is that then essentially you make a patient go through the PEM two times and you actually make it worse. So you could actually push back patients a lot in their recovery period by doing this test and I think that's something that should not be done by clinicians because there is just this fear that a patient will go back into remission for weeks. It takes a long time for him or her to recover back to their stable pre -exercise levels. 

One of the things that we now do in collaboration with a sports physician is to do a submaximal test. So you don't go all the way to the maximum exertion, but you only go to the first ventilatory threshold, as we call that at the stage where things are getting a bit harder. So maybe at that moment, that first initial step tells you something, ‘okay, this is probably the area at where the PEM starts to occur.’ So that also gives the clinician and patients maybe better indicators of, ‘you can go to this far, but not further.’ And that gives you like day-to day-hints with using heart rate monitors to say, ‘okay, my heart rate cannot go over 115 or 120 or so.’ And maybe that gives also a base, like pacing, a bit of advice based on exercise testing. But definitely don't go all over that threshold to induce PEM and definitely not on a two day exercise test. That's my, extra bit of information on what David mentioned. 

David Putrino 

Yeah, I totally agree with that. One of the things that we're currently researching in our lab in addition to submaximal monitoring is understanding the utility and the value of looking at resting metabolic rate as well. So, that is a test where we have people sort of just sit in a dark room for 15 or 20 minutes and we measure how much energy their body is producing. And we have some data that we're getting ready to publish at this point showing that the overwhelming majority of people with post -acute infection syndrome who come to our clinic will be producing 20 to 30 % on average more energy at rest than controls that are controlled for their height, weight, age, and gender. So at rest, their body is just churning more energy to just exist. 

We're hoping that that might -- because resting metabolic rate can be calculated quite simply without risking harm for patients who have energy envelopes and can be and have PEM -- be a useful marker. And then from there, you know, beyond pacing and lots of education around rest and the importance of rest, there are some supplemental protocols that have evidence. For instance, we sometimes recommend combinations of things like alpha lipoic acid and CoQ10 because there is a beautifully conducted placebo controlled RCT that showed that folks with long COVID derived benefit from that particular combination of mitochondrial supplementation. 

But the reality of the situation is that we have not done nearly enough research into the benefits of mitochondrial supplementation to be able to say this patient should get this combination of mitochondrial supplementation. So often there's a bit of trial and error involved in actually finding something, a combination of mitochondrial support and antioxidant support that can actually make a patient feel better. 

However, I did want to point out the fact that there are well -conducted studies that show improvement with these mitochondrial supplements in comparison to a placebo. So the point being that mitochondrial supplements are something that can be helpful to a large proportion of patients, but we need much more research to understand the nuances and the intricacies of prescribing the right mitochondrial support for the right patient. 

Rob Wust 

Yeah, I think I completely agree with this, David. It's a very difficult field to get a clear answer, ‘this is the compound that you need to take.’ I think being nice to your mitochondria is always a good idea. If you're ill, if you're not ill... I think it always improves your health. I'm not a doctor, so I cannot prescribe drugs and I cannot say ‘take this and you will feel better’ but what I've heard from anecdotal evidence from patients and people contacting me is sometimes NAD supplementation seems to work in some cases. I see David nodding. 

There is a very small study done some time ago about creatine supplementation, and it also reduces fatigue a little bit. So yeah, there are some smaller studies where there is a marginal increase or decrease in symptomology in patients. 

The issue is a little bit that I think it's not going to take away the root core of the problem and that's where we are trying to make people feel better and maybe increase the PEM threshold by just a little bit so you can do daily activities better and shorten the duration of the PEM. I think that's also super important. If you do not suffer for a week, but just a day that I think helps a lot in terms of daily life activities for patients. 

But until we know exactly what the key mechanism is of the disease and being able to change it, we are not able to make people completely healthy again with mitochondrial supplementations, particularly if they're in supplements. I mean, we of course, are also looking for ways to treat patients in a different way but supplementation is the easy answer, of course. If you smoke, for instance, the first answer is ‘do not smoke.’ Keep a healthy diet. Use omega -3 fatty acids...those are all small things that can be beneficial for mitochondria. But we don't know how much it really changes the disease progression. That's, I think, the problem that we are facing at the moment. 

Dr. Raven Baxter 

Rob, how close are we to getting more concrete answers to the drivers of this? 

Rob Wust 

Well, for people with ME -CFS who have suffered from the disease long before the COVID pandemic started, there was hardly any research done on this, in this field and people were just the lost ones out of society. With the COVID pandemic, we had this open up a lot of extra research in this field, because certainly a lot more patients became ill. I mean, everyone knows at least someone in their general area that suffers from this disease and that has sparked a lot of additional interest in science on this field. I didn't work on this topic before COVID started, for instance. So for me, I'm a new scientist in this field. And there are so many other people that are trying to find answers to pathophysiology as well as the treatment options. 

So while it may take a while to really understand the core problem of the disease, therapies are still being tried. What does work? What doesn't work? And we kind of hope that soon there will be maybe an off -label medication that can be used that will alleviate symptoms a little bit, that are gonna be on the market quickly and are easily available to patients. But I do think that there's a lot of research that came into a massive current and rapidly increased the search for treatments and I'm quite positive that at some point in the future, we will find a treatment that will at least alleviate symptoms. It may not completely get rid of all the symptoms, completely solve the problem, but alleviating symptoms I think is already, that’s the first big step forward. 

Dr. Raven Baxter 

Thank you. And so in our final minutes of the podcast, I would love to leave the medical students with a piece of advice. Whatever you think is most important for them to know or do or incorporate into their practice. If there's anything that comes to mind or to heart, please share. David? 

David Putrino 

My parting words would be that PEM is a frequent symptom that accompanies post -acute infection syndromes. Usually, upwards of 90 % of people will report PEM as part of their chronic illness experience. And although we don't quite yet have the perfect biomarker or blood test, all of what we've been discussing here -- the metabolic changes, the drastic responses to exertion and exercise -- this literature exists. It is robust. It's real. And so when a patient tells you that exertion harms them, believe them. 

You don't need a blood test to start to enact pacing strategies and then start to research mitochondrial supplementation and antioxidant supplementation that may help that patient and work with them to find, you know, the constellation of interventions that really gets them to experience their best possible function. 

So, my parting message is believe your patients. My parting message is work with them as a partner to go outside of your scope of what is perfectly known, embrace a little bit of uncertainty and that is how you're going to do justice to your patients. 

Rob Wust 

I couldn't agree more, David. 

Dr. Raven Baxter 

Well, thank you both for your time. I think that this was such an amazing, rich conversation and I'm sure that the students will learn and benefit from this. So, thank you both for your time, and we'll see everyone in the next podcast. 

David Putrino 

Thank you, Raven. 

Rob Wust

Thank you. Bye bye.