Wearable technology and patient-led innovation

Emily Kate Stephens (0:07): Welcome back. This podcast is about bringing you the leading research and information from a range of different sources, but this week I am delighted to be able to share some research that the Visible community enabled to happen. Dr. David Putrino of Mount Sinai, along with some other incredible researchers, took the data from over 5000 Visible users who opted into the study, and uncovered really useful information about how wearable data can help us manage complex illness. In this interview, Dr. David Putrino explains their findings, along with some of the other studies that he and his colleagues in this expansive research community have been carrying out in recent years, and share some of the insights of what we have learnt about these complex illnesses on this journey. Dr. David Putrino, an absolute pleasure. I'd love to talk to you today about your latest studies and the work that you've done most recently. But what I would be really interested in hearing from you initially is where do you think we are in the spring of 2025 in terms of our understanding of these complex chronic illnesses, Long Covid specifically, but now looking at that as a broader part of these complex chronic illnesses, including ME/CFS?

David Putrino (2:41): Yeah, I think that right now, 2025, I'm feeling more and more hopeful as we move forward, and the reason for that is because when we started to address the problem of Long Covid in 2020, and subsequently started to learn about things like ME/CFS more deeply, infection-associated chronic illnesses. These were things that we had heard about peripherally in our research and clinical training. We certainly did not have a lot of domain knowledge. We certainly didn't have a detailed understanding of just how complex the pathobiology could be, and just how intricate and challenging these conditions were, and so in 2020 we were kind of a one trick pony. We were thinking about things in terms of this is autonomic nervous system dysfunction. These patients have postural orthostatic tachycardia syndrome, which basically means that they're unable to regulate blood pressure and heart rate as they change positions, and they have all sorts of systemic challenges as a result of that. And we were going down that road. We've seen POTS before. We've seen dysautonomia before. We're going to treat it like that. And when we initially saw that our approaches were certainly helping some people, but they weren't helping everybody. We started to deepen our collaborations outside of our own specialty, and we started talking to people like Akiko Iwasaki from Yale University, who's an amazing immunologist, to understand how Long Covid and other infection-associated chronic illnesses affect the immune system. We started talking to people like Amy Proal, who's an amazing microbiologist, and started to understand how persistent pathogens and reactivated pathogens could be at play. We met Resia Pretorius out of South Africa, who was studying microclots and all the ways that Long Covid was a vascular disease, and how other infection-associated illnesses might be vascular, and we started talking to gurus in the field of metabolic science and understanding how mitochondrial function was compromised and how energy delivery and energy production is really a challenge in these folks. So we were learning a lot and in the first couple of years, we were still running clinical trials, but our clinical trials weren't so successful. We would try something out, and it wouldn't work so well. Maybe some people got some benefit, but most people said that they felt the same or maybe a little better, and so we just kept moving on from different interventions. I feel really the reason I feel optimistic right now is, alongside all of these connections and collaborations we made, we also published a lot of papers. We published a lot. Yeah, we did a lot of research, and it's

Emily Kate Stephens (5:35): Amazing the number of collaboration that some of those people that you've mentioned, but also there are so many other people who have been working, particularly in the Long Covid space, and then you've brought in this ME/CFS sort of team. But these people, as you say, you've got all these multiple papers that cross over. That's the wonderful thing. You see these different names on the papers, and they are all cross disciplines, all coming together to collaborate.

David Putrino (6:00): Absolutely, and it's crucial. I often get asked by people, "What's the cure for Long Covid? What's the treatment for Long Covid? And my answer is always that is an inappropriate question. The appropriate question is, "How do we break Long Covid and ME/CFS up into the 10 to 20 different subtypes that it clearly is, and understand the complexity, and then begin to develop precision treatments for those subtypes.

Emily Kate Stephens (6:33): It's really interesting because going back to two two and a half years ago, when we first, it was actually Akiko Iwasaki who first subdivided these elements that you've just actually referenced, this autoimmunity, the microclots, and how are we going to bring all of this together? And actually, what you're saying is now two years on, it's rather than necessarily us converging, we're developing more of an understanding of how these are diverging or how the different people with the different symptomatologies possibly are actually presenting differently because they are suffering from something different. Is that what you're suggesting?

David Putrino (7:15): Yes and no. I would say, and again, herein lies the complexity. I would say that one goal is to understand how someone with an autoimmune variant Long Covid might look different clinically from someone with a mitochondrial variant Long Covid. The other challenge that we face is that some of the most prominent symptoms: cognitive impairment, fatigue, post-exertional malaise. Because we don't have good literature and we don't have good vocabulary for describing these symptoms, beyond I feel extremely exhausted, or if I exert myself, I feel worse. It's very hard for us to understand what might be driving these symptoms. Cognitive impairment can happen because you have POTS. Cognitive impairment can happen because you have mast cell activation syndrome and circulating histamine. Cognitive impairment can happen because of autoimmunity, and it can happen because you have neuroinflammation occurring. And trying to get to the bottom of you have cognitive impairment. Why do you have cognitive impairment? And then let's treat you differently based on the reason why is such an important piece of the puzzle. Because what I frequently am seeing in the Long Covid space and the ME/CFS space is let's run a randomised controlled trial where everybody gets the same treatment, no matter what, so long as they have that diagnosis, they get the same treatment. Well, depending on where you recruit from, you can recruit a whole bunch of people who have Long Covid, not because they had a mild, non-hospitalized, non-severe acute Covid infection, and now have very severe Long Covid symptoms. You may recruit a large number of people who had severe acute disease and have a Long Covid diagnosis because they have lasting lung damage from that severe acute disease, and they still met diagnostic criteria for Long Covid. So, being a lot more careful about how we identify who comes into our studies, and then following more closely who responded, who didn't, and why they may have responded or not responded is really, really important.

Emily Kate Stephens (9:36): It's down to that subjectivity of so much of it as well, isn't it? Because also, I know that we have got sort of PET imaging. We've got MRI scans showing differences in the brain, but so much of the reliance on our self-reporting and how people perceive their symptoms to be also influences the way in which they're treated and the way in which their symptoms vary. So it's. I mean, we're human, so it's that subjective nature of all of it that needs to be broken down. So your most recent study, I think it's still in preprint.

David Putrino (10:16): We're still under review.

Emily Kate Stephens (10:19): If we talk about that point that I just made-that things are subjective and things are so reliant on patient feedback. You have recently done a study, which is, I believe, the biggest, one of the biggest studies of its kind. Which, rather than reliance on solely patient feedback, you have actually looked at biometric data, which therefore takes the onus off what we are reporting in terms of the patient, and actually enables you to look at this data and relate that to the symptom sets. Would you be kind enough to give me an overview of the study that I'm talking about, which is looking at heart rate variability and heart rate, but it's using smartphone technology.

David Putrino (11:12): Yeah, absolutely. So, to our knowledge, this is the largest study of its kind in people with complex chronic illness who were engaging in regular, even daily monitoring of symptoms, as well as capturing their heart rate and their heart rate variability through the Visible app to have physiologic data alongside their self-reported symptom data. Basically, what we were able to show across these thousands of individuals who contributed hundreds of days of data was that we were able to, with fairly good accuracy, predict who was going to experience a crash, so a sudden worsening in their symptoms, versus people who were not and who were just going to maintain a steady level of symptom levels. What was really particularly interesting about this paper was, although physiology, you know, heart rate and heart rate variability were quite predictive of crashes and worsening of symptoms, things like people's self-reported feelings of depression and anxiety were not, indicating that for the longest time, with infection-associated chronic illnesses, people have been told that okay, your symptom fluctuations-they're probably anxiety. This is probably all in your head, or at least partially in your head. What we were showing in this study, alongside the very exciting findings that we can actually be predictive of a crash, we were also showing that feelings of anxiety and feelings of depression were not predictive of a crash. This is a really great paper to show that as we start to look more closely into physiological signal, I think that we're really going to start to see that we can link a lot of continuously acquired physiological signal to people's symptoms.

Emily Kate Stephens (13:02): I just think it's really, really fascinating that it's validation. I think what you have found here in this study for patients, it is validation that it's not something imagined because what you're saying is you saw these changes in the heart rate and the heart rate variability actually in advance of the symptom changes, and the thing that takes away is that idea that it's just how people were feeling. There's that physiological marker before, not just during. Before, talk to me about well. Actually, I think first of all, what we should do is explain what is heart rate variability for those that don't know, and what can it tell us the fluctuations in it. What can it tell us?

David Putrino (13:58): Absolutely, heart rate variability is a metric that we can take from measuring somebody's heart rate, and effectively, heart rate variability measures the amount of time between beats of the heart. So, counting the amount of time between beat number one and beat number two and beat number three, and tallying all of that up and averaging it to try and understand how regular is your heartbeat. We always think about heart rate in terms of okay, my heart is beating, my pulse rate is 60 beats per minute, and so what that means is that in one minute your heart is beating 60 times. But what people may not be aware of is the fact that although yes, it is true that your heart is beating 60 times in that one minute period, those heartbeats are not equidistant apart. There is some level of variability between each heartbeat that can be measured, and that's what heart rate variability is. What we've learned over time is that a larger heart rate variability, so the more variability and variation there is between that sort of beat to beat time duration, generally speaking, the healthier you are.

Emily Kate Stephens (15:15): Which is interesting because it's almost the opposite to your heart rate. So, I think that takes a moment for people to get their heads around that you are wanting, you're hoping to have a higher heart rate variability.

David Putrino (15:27): Yes, it can sometimes feel a little bit. It can sometimes feel as though it doesn't make sense. It feels as though it should be the opposite.

Emily Kate Stephens (15:36): Yeah, counterintuitive.

David Putrino (15:38): You would want a very steady heartbeat, steady and rigid. However, when we think about heart health and when we think about longevity, what this all comes back to the autonomic nervous system. I mentioned that earlier, and the autonomic nervous system is this part of your nervous system that does all of the things that are supposed to be under autonomous control. We've heard of autonomously driving cars, and well, there are parts of our body that are also under autonomous control. For instance, we don't think about getting goose pimples or goosebumps on our skin when we get cold. Our body just does that. We don't think about sweating when we get hot. Our body just does that to cool us down. We don't think consciously about changing our blood pressure when we go from laying down flat to standing up straight to make sure that our brain is still getting a good blood supply. Our body just figures that out, which is really clever when you think about it, and quite precise. And so the autonomic nervous system controls all of that for us, and it's broken into two parts: the sympathetic nervous system, which is called our fight-flight nervous system. That's the part of our autonomic nervous system that really dials up if there's a threat, or if you have to run away from something or fight something. And then there's the parasympathetic nervous system. We call that the rest and digest nervous system, and that's the part of the nervous system that is active when we're calm, when we're laying down to go to sleep. It's active when we're trying to digest food. All of these things. What we want for optimal health is to be in that calm state, and when we're in that calm state, that parasympathetic state, our heart rate starts to get a little bit more irregular because it doesn't matter so much if your body is not getting consistent large amounts of blood to every single cell. You can relax, you can be calm. The tiger's not there that you have to run away from. Everything's okay. Whereas, if you're pushing more into a sympathetic nervous system response, then when you're getting ready to fight or run, what your body wants is it wants blood flowing to every muscle fibre that you can possibly get, and so what our heart rate does is it becomes incredibly regular, and every heartbeat is equidistant apart because you absolutely want your heart going as quickly as possible, and you want to make sure that you know blood is getting everywhere it should, and it's getting a regular supply so that you can utilise everything at your disposal.

Emily Kate Stephens (18:20): So what you're seeing in people with a lower heart rate variability is a prevalent sympathetic nervous system response, and that takes us back to the whole autonomic dysfunction that you referenced at the beginning. This overriding sense that people with some of these chronic conditions have been pushed into a stressed, a fight or flight, fight flight or freeze response. Not necessarily continually, but more of the time than is necessarily easy for our body to handle.

David Putrino (18:59): That's correct. So, when our body is in a sickness state, it will tend toward sympathetic nervous system overdrive, which will mean that it's in a highly stressed state. And when I say stressed, I mean physiologically stressful. I mean that we're putting a lot of extra work on our organs. We're putting a lot of extra work on our hormones. We're putting a lot of extra work on our immune system, and all of that leads to heart rate variability that is relatively low for that person. And I say relatively low because we're all a little bit different. And what is a low heart rate variability for some people may not be so low for others, but when we measure one person's physiology regularly every single day, we can identify these dips in heart rate variability, and we can say, "Hey, something's happening here. We better inform the person and make sure that they're okay.

Emily Kate Stephens (19:54): And that goes back to your point of everyone being different, everyone being individual. You have to look at you can't just. That the marker of heart rate variability is X, you have to look at what that person's is compared to that person's on the next day and the next day. And I guess one of the problems is that we don't necessarily have knowledge of what our heart rate variability was before we got these complex chronic conditions. So you just have to measure it from the point at which you start.

David Putrino (20:20): Exactly, and I think it's important to note that one of the findings of the study was that we were very good at predicting crashes from physiological recordings like heart rate and heart rate variability within subjects. So, looking at the person's own data, but our predictive algorithm was less accurate when we were taking data from one person and trying to apply it to somebody else. So this really was a very interesting finding because it tells us once again the need for precision medicine, the need to treat every single person as their own data set to understand how they're doing and how best to help them, and again, the clue is in the name, right? We call them complex chronic illnesses because they are complex and they require a personalised approach and they require a precision medicine approach.

Emily Kate Stephens (21:15): Because presumably, people come to you and say, "Okay, so from the data that you found, how far in advance of a crash are you seeing the heart rate or the heart rate variability differentiating from the norm? And you're going to say it completely depends on the person. Is that right?

David Putrino (21:35): That is correct. Yeah.

Emily Kate Stephens (21:36): So there is no across the board five days in advance of a crash, you need to start doing X. You have to look at every single person as an individual.

David Putrino (21:47): That's correct. Yeah.

Emily Kate Stephens (21:49): Okay. What did you see with the? Obviously, we don't need to explain heart rate in the same way that we did heart rate variability, but the changes in the heart rate in advance of you measured it in terms of crash fatigue and brain fog. That's correct, isn't it?

David Putrino (22:03): That is correct. Yeah.

Emily Kate Stephens (22:04): So, what was the heart rate doing?

David Putrino (22:08): Paradoxically, you know, compared to the heart rate variability, what we saw was that when heart rate was increasing and was experiencing periods of increases and fluctuations, that it was more predictive that someone was moving into a crash or a period of bad fatigue or bad cognitive symptoms. Once again, this makes physiological sense for us in terms of what we know about what a body does when it is entering a period of physiological stress. But this was the first study to capture in such a large population of people with complex chronic illness.

Emily Kate Stephens (22:45): It's absolutely fascinating. So your heart rate's going up. Your heart rate variability is going down. You did what you called a seven day data predictor. You looked at data over a seven day period. Is that right?

David Putrino (22:57): Yeah, that's correct. Well, we collected data from many many days, but we analysed 5000

Emily Kate Stephens (23:07): Readings. You did this on the basis of 55,000 readings.

David Putrino (23:12): That's correct. Full respect to Annie and Mike and Abbey and Rory, the data science team on this, it was such a dizzying amount of data, and not just 55,000 over 55,000 really describes the number of days of data. But then on top of it's multi-dimensional, so it's not just 55,000. It's 55,000 days, but then they're capturing 30, 40, 50 variables per day. So now we've got 55,000 times 30. You know, so there was over a million data points that were being analysed by this team again, which is just so incredible, such an incredible achievement from the Visible team and from the community. I've said it as a clinical trialist who's worked for a couple of decades in running clinical trials across many communities, I never ceased to be amazed by the passion and the level of just resilience of the complex chronic illness community to sit there and document as perfect research participants, just with this overwhelming drive to figure out what's happening in their bodies. These are folks who have been told over and over again, nothing's wrong. We can't see anything wrong, and it translates to folks who are just incredible and just really passionate about being great research participants, working in collaboration with anyone who's willing to help and take them seriously, and the data really reflects that. The fact that we were able to get so many people,

Emily Kate Stephens (24:53): And that's amazing. Them documenting it has actually put this here in black and white that there is something physiologically wrong. You might not have that biomarker from some peripheral blood draw, okay? But there is data in your body that is quantifiable and that can be then seen by physicians to say yes, there is something going on. The third element that you looked at in this study, was the respiratory rate, and the really interesting thing about that is that you did not necessarily find that the respiratory rate was a predictor of the crashes. But you've done another study. Was it back in 2023 or maybe 20 beginning of 2024.

David Putrino (25:43): 24 was the resonant breathing study. 22 was the hypocapnia respiratory rate study that we published. Yeah.

Emily Kate Stephens (25:52): So the thing is that whilst it might not be an indicator, you have also got your name on this study about resonant breathing that shows your respiratory rate, your breathing can influence your symptomatology. So, whilst in this study you didn't necessarily find it to be a predictor, it is a huge player in terms of what you can then do with your heart rate and your heart rate variability, I believe.

David Putrino (26:23): Yeah, absolutely. When we first started seeing people with Long Covid, and we were trying to figure things out, so just early 2021, my team works a lot across a lot of communities. So we work with folks who are living with stroke or spinal cord injury, ALS, and then we work with elite military performers and high performance sports. And I was talking about the patients that we were seeing with a colleague of mine who was a former military operator, and he did a lot of work with pilots, fighter pilots, and he was listening to all these symptoms, and he was like, "This really sounds to me like low carbon dioxide, and I was like, wow, that's interesting. I really didn't think about that direction, and so we started testing carbon dioxide levels in our Long Covid patients, and not everybody, but a fair percentage had low carbon dioxide. And the first thing that we got told when we said low carbon dioxide levels was, oh well it's probably because they're hyperventilating so they're breathing too quickly so we and that led on to probably because they're anxious and probably all of these things so we got annoyed by that and of course we did a study and in the study what we were able to show was that yes, absolutely. These folks have low levels of carbon dioxide, below normative levels, so like abnormal. But also, their respiratory rate was normal. So, although their respiratory rate did not deviate from what our control group had, their carbon dioxide levels were much lower. We've since published on metabolic reasons why what's happening to their mitochondria that might lead to low levels of carbon dioxide. But in the meantime, we also said, okay, well, who cares why? How do we fix it? And breathwork was incredibly instrumental in helping a lot of people with some basic symptom management techniques that could increase carbon dioxide levels, which is not usually what you hear. You don't usually hear that you want to increase carbon dioxide levels, but in this case, we did, and also decrease sympathetic nervous system activity in such a way that people really derived a lot of benefit from this breathwork,

Emily Kate Stephens (28:43): Which is amazing, isn't it? Because you gave an explanation previously about the autonomic nervous system and how all of this system of our body operates automatically. However, breathing is a function of the autonomic nervous system. We don't need to think about breathing, for example, when we're sleeping or actually the majority of the time, but it is one element for the autonomic nervous system over which we actually have agency. We can change our breathing pattern in a way that we can't really do with a lot of other parts of our autonomic nervous system. We can change our respiratory rate. We can change our breathing pattern consciously, and is that one thing, or tell me what can influence heart rate variability? Is breathing one of the major things that we can use? Because I know you don't want me to come and say what's the cure, what's the treatment for Long Covid, but in terms of the information that you found from this study, it gives us pointers to things that we can actually do to try and regulate those boom and bust cycles.

David Putrino (29:54): Yeah, absolutely. Certainly, breathwork is something that can regulate autonomic nervous system activity; it can regulate heart rate variability, and it can help to optimise heart rate variability. So many of our patients have disrupted and pathological sleep, and what we know from literally decades of literature is that if we can correct sleep, particularly slow wave sleep, when it comes to autonomic nervous system function, but also all phases of sleep, your heart rate variability is going to improve and increase. And then there's many other things that we can be doing to improve heart rate variability that are lifestyle related. So, pacing and energy conservation super important for improving heart rate variability. This sounds obvious, but I'll say it out loud. Infection prevention and avoiding reinfection is so important, especially for people who are already struggling with Long Covid, to prevent changes in their heart rate variability. And then what we're now looking into are more targeted therapies and interventions for specific problems that we're seeing and problem sets that we're seeing in people with Long Covid. And we're measuring heart rate variability to see if, as people's symptoms improve, their heart rate variability also improves.

Emily Kate Stephens (31:21): You did a study previously. Actually, it didn't involve Long Covid patients. I think it was predominantly looking at stroke patients, but maybe there was one fibromyalgia patient in there looking at vagus nerve stimulation. But I think that was actually implanted devices. Is that another thing that we could look at that vagus nerve stimulation in terms of improving our heart rate variability, and can you just talk to me a little bit about the role of the vagus nerve when it comes to our autonomic nervous system regulation?

David Putrino (31:52): Yes, so when it comes to the autonomic nervous system, the vagus nerve is probably the most important part of the autonomic nervous system. It is this long nerve that runs from the brainstem down into every organ in the body, and it is incredibly important for carrying out a lot of the functions that the autonomic nervous system is responsible for. Vagus nerve stimulation is a technique that can be invasive, meaning that we can implant a device that wraps around the vagus nerve and stimulates it, or we can use non-invasive techniques such as placing an electrode on the ear and stimulating the vagus nerve from there, because the vagus nerve also innervates portions of the ear. What we do know is that vagus nerve stimulation can regulate vagus nerve function. So, if the vagus nerve is overactive and is causing too much sympathetic nervous system activity, vagus nerve stimulation can suppress sympathetic nervous system activity and therefore upregulate parasympathetic nervous system activity, which is very, very important for helping to stabilise heart rate variability if it's out of balance. We are currently just finishing a trial on vagus nerve stimulation in Long Covid, and what I can say anecdotally from this is we're going to have to go deep into the responder analysis because certainly some people were helped, but other people it didn't do so much.

Emily Kate Stephens (33:23): What were you looking at as markers in that? Were you looking at the heart rate variability?

David Putrino (33:28): We were looking at heart rate variability. We were looking at various different blood and saliva biomarkers, and we were also just looking at symptom reporting from our patients. And again, certainly some people benefited greatly from vagus nerve stimulation, but other people not so much. And this was a placebo-controlled trial, so we were able to see how people who received placebo vagus nerve stimulation how their symptoms changed as well. So we're probably going to learn quite a bit from this study in terms of who responds and who doesn't. What I can say is, it's definitely not a cure-all, and there's a lot we need to learn. Not everyone may have the same vagus nerve anatomy, so stimulating in the same place on the ear on everyone may not be the right move. We also don't understand dosage as well as we would like to. We had a dosage parameter that we based off of what other people have studied in other conditions, but what do we do in Long Covid and other complex chronic illnesses? Should you be stimulating all day? Should you be stimulating just once per day? Should you be doing it three or four times per day? These are all open questions, and we have a lot to learn.

Emily Kate Stephens (34:33): Does it need to be completely different for every person based on their symptoms and their physiology? There are so many,

David Putrino (34:40): And can continuous tracking apps like Visible and others can these be the tools that allow us to personalise interventions using more sophisticated techniques like machine learning and AI.

Emily Kate Stephens (34:53): That's your area, isn't it? You're director of rehabilitation innovation. So you are this is feels. Like you've really, really found your place working with these huge data sets and working with innovation because one of your things is that you try to create these real-world working things to help people with their health conditions in terms of creating apps and creating games and creating ideas that can just help people in their day to day, rather than being completely intangible or completely medicalized.

David Putrino (35:28): Yeah, I think our team in general, we try to be very pragmatic. Very early on in my research career, I realised how frustrating it was to publish a paper saying, "Hey, this experimental therapy is promising, and as soon as you publish the paper, you would get 100 phone calls from people with that illness saying, "Hey, can I access this technology? And you would have to say, "Oh, I'm sorry, we finished the study, and the technology is not accessible. And that really bothered me. And so the work that we do now at Mount Sinai is very much focused on the idea that if we run a clinical trial and the technology is promising and the technology helps in any way, we implement that technology. We move from being clinical researchers to implementation scientists, so that we can say yes, you absolutely can access this technology. We're going to provide you with access to it, because otherwise people just have to wait far too long. The national average in the United States is 17 years to get access, easy access to a new technology.

Emily Kate Stephens (36:35): Oh my goodness! I thought that the drug cycle was bad enough that sort of 10 year thing, but 17 years.

David Putrino (36:45): None of our patients have that sort of time, nor should they have to.

Emily Kate Stephens (36:49): One other study that I just wanted to ask you about was a 2024 study that you did that looked at neuropathic pain in Long Covid patients and looked at the differentiation of pain types of pain in specifically in Long Covid. I was really interested by this because is not all pain neuropathic pain in terms of it is all something that is generated is an afferent signal from the brain assumed to be from some kind of stimuli. I think this is a really, really important area. Is this idea that neuropathic pain? People are dismissed as this pain is in their head. This pain is in their brain. All pain is generated from the brain, and therefore we should completely lose this narrative that pain is not somehow real, or that pain is not somehow as important or justified as what other people describe. Talk to me a bit about the difference with neuropathic pain.

David Putrino (37:55): Yeah, so this is an interesting topic, and it's a good one to talk about. So in that study, what we showed was that many individuals with Long Covid have new onset pain. They did not have chronic pain before their acute Covid infection, and then after their acute Covid infection, pain is now just a part of their life. And chronic pain. We wanted to dig a little bit deeper into the sort of chronic pain that people are experiencing, and so we used a questionnaire that really categorises pain as neuropathic or non-neuropathic. Now, non-neuropathic pain tends to be the nature of the pain tends to indicate that it is more local and inflammatory. For instance, if you have a joint injury, you're going to score on this particular scale as having non-neuropathic pain because it's localised to a joint area. It has a certain quality to it. It's a hot pain, and it hurts to touch, and it hurts to put weight on, and it doesn't hurt so much if you take weight off it, and all of those different things. And then you have neuropathic pain, which is pain that is as a result of a nerve misfiring. Now,

Emily Kate Stephens (39:13): Right,

David Putrino (39:15): You're absolutely correct that all pain signals, whether it be non-neuropathic or neuropathic, all pain signals are 100% created by the brain. So there are areas of the brain that not only tell us how much pain we should be in, but also how much we should care about the amount of pain that we're in. Which we can get, we can go down a rabbit hole some other time. But it's all very fascinating, and you know, and pain is a very fascinating topic. But if we zero in on the people who have neuropathic pain, yes, neuropathic pain is sometimes considered to be all in the head or somewhat psychological. That is 100% incorrect. And anyone who is trying to peddle that has a very strong misunderstanding of what neuropathic pain is. In many cases, when we talk about neuropathic pain being nerve pain generated by misfiring of the nerves can misfire for all sorts of reasons. If you lose a limb, you will get neuropathic pain more often than not because the nerve will try to grow back, and when it reaches the end of the residual limb, it will sort of just tangle up together and not be able to sort of go out and innervate the rest of the missing limb. And as a result, it will that tangled mess of neurons will start to misfire, and it will give you not only pain sensations but all sorts of unusual sensations that make you feel as though your limb is still there. That's called phantom limb pain, and that is a class of neuropathic pain. Another way you can get neuropathic pain or nerve pain is through autoimmunity and autoantibodies that are irritating the nerve and telling your nerve that it should be firing off pain signals, which can be, as you might imagine, incredibly painful and very, very real. Actually, a fascinating finding that I'll point you to is in 2024 we pre-printed a paper which is still under review with Akiko Iwasaki's team, and in this preprint, what we showed was that when we take IgG, so when we take antibodies from people with Long Covid and inject those antibodies into mice, the mice start to get sick. And what we saw even more interestingly was when we actually started to break down the groups of people with Long Covid into groups by their symptoms. When we injected the mice with IgG from people with Long Covid who had neuropathic pain, the mice go on to develop pain disorders. So this tells us that autoantibodies, functional autoantibodies, are most likely present in that IgG, in those antibodies that we're injecting, and they're attacking the nerves of the mice, and they're going on to cause pain. So this is once again, this is just more evidence that what we're dealing with is clearly biological in nature. But not only is it biological in nature, but it's also the technique for what we did there is called a passive transfer. We can passively transfer it on to a host animal,

Emily Kate Stephens (42:31): And it just highlights that differentiation between the symptom sets or between the way in which people are actually experiencing the pain.

David Putrino (42:42): Exactly.

Emily Kate Stephens (42:44): Why is that still in preprint? It's just under review.

David Putrino (42:50): Great question. It is. It is the peer review takes so long. We're very frustrated about this one because this is the sort of paper that really settles a conversation, right? If I can inject an animal, and the animal starts developing a clinical syndrome after it gets an injection of something. That should be game over for anyone who wants to say that this is not a biological illness. And it is quite frustrating that it's been sitting in peer review for over six months now. Wow.

Emily Kate Stephens (43:19): You're probably quite excited about that paper eventually getting published. What else are you excited about currently in this space in terms of the research that you're currently working on? In terms of what you are seeing other people, I mean the list of your collaborators is amazing. What are you seeing amongst that community, that is really exciting for you right now.

David Putrino (43:44): I mean, we are personally feeling very bullish and very excited about our rapamycin clinical trial, which will be starting in just a few short weeks. Rapamycin is an immunomodulating drug, and at low doses, it can correct a lot of the immunological issues that we have been seeing in Long Covid patients and publishing in Long Covid patients. So we're really excited to start this trial and get it moving. We think it's going to bring a lot of hope to patients, and we're going to understand a lot more about how it affects people.

Emily Kate Stephens (44:18): And that is a repurposing of a drug, what is it currently used for?

David Putrino (44:22): Rapamycin is currently used as an immunosuppressive drug in high doses.

Emily Kate Stephens (44:27): Okay,

David Putrino (44:28): For people who go through an organ transplant, so you get an organ transplant, you don't want your body to reject the organ. You take rapamycin at a high dose, and it suppresses your immune system and helps to prevent that rejection from occurring, however, at low doses, its effect on the immune system is actually quite different. At low doses, rapamycin seems to dial up certain elements of the immune system that can fight off pathogens, either persistent pathogens or pathogens that may be reactivating in the body, and it also dials down a lot of needless inflammation. So,

Emily Kate Stephens (45:05): Wow!

David Putrino (45:05): When you think about what is happening in the bodies of many people with Long Covid and other complex chronic illnesses, it's almost the perfect drug to address many of the issues that we've been publishing about. So, getting the clinical trial has been phenomenal.

Emily Kate Stephens (45:21): That's amazing, and that also brings in two elements that we did not touch on when we were doing our various lists of autoimmunity and mitochondrial dysfunction, and that's the role of inflammation and the role of viral reactivation. So you have hopes that the rapamycin will actually try and alleviate some of that cycle that people are going through if they have a reactivation of latent viruses.

David Putrino (45:45): That is correct. So we think that rapamycin could help the body fight off these reactivations. We also the other area that I was going to say that I'm excited about is we're also planning a number of combination antiviral clinical trials based on anecdotal clinical data that has been showing very strong effects for people with Long Covid by addressing the viral reactivation. So not necessarily the persistence of SARS-CoV-2, but the ability of SARS-CoV-2 to reactivate other viruses and using some of these antivirals to suppress that, and as I think I mentioned right at the beginning, I don't think that any of these solutions are going to be the be all and end all for all people with complex chronic illness. But I do think that as we understand how each of these tools can modulate symptoms in different subtypes of people with Long Covid, we're going to get more and more tools in our toolkit to use in combination together to help people live a better quality of life.

Emily Kate Stephens (46:48): I think that is a wonderful point on which to end. That is just fantastic. Thank you so much for your time today.

David Putrino (46:56): No worries. Thank you for having me, and hope for many more of these.

Emily Kate Stephens (47:05): It is really exciting to be able to contribute to the scientific fields in some way, and as Dr. Putrino, along with many of the other doctors and scientists that I've spoken to, have repeatedly said, the generosity, curiosity, and passion of this cohort of patients is quite incredible. The willingness to participate in the process and progress is no mean feat when you're suffering from one of these illnesses. So, such a huge thank you to all those of you who contribute to every scientific study that takes place. Each of you is pushing the research and the agenda, but not just for yourselves. It's for the entire community, and that's really quite remarkable. As always, please feedback. Let me know what you thought of this episode of the study of the information, and keep feeding back to me about what you'd like to learn about in future episodes. Thank you for listening to Make Visible. Please do like, follow, or subscribe to listen to our next episode, where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible, a group of scientists and engineers whose lives have been affected by energy-limiting health conditions. We're building wearable technology that's helping 100,000 people measure and manage their complex chronic illness. To find out more about what we're working on and how Visible could help you, visit our website at makevisible.com.

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