We're going to get started because we have a very big agenda today. Welcome everybody to the management of major past related system disorders. We have a really good presentation today by a lot of speakers, so we're going to hold all our questions until the end. I'm Dr. Lynn Weiss, I'm the Chair of Physical Medicine and Rehabilitation at NYU Langone Hospital Long Island and Professor of Rehabilitation Medicine at the NYU Long Island School of Medicine. Our first speaker is Dr. Benjamin Abramoff, he's the Director of the Post-COVID Assessment and Recovery Clinic and Director of the Spinal Cord Injury Services at University of Pennsylvania Perlman School of Medicine. So I'll be teaming up with Alba and I'll kind of set the stage and kind of give a little bit of information about the scope of the problem, how we look at a patient that has long COVID related fatigue, and then Alba will let you know how we manage these patients. So what is fatigue? So fatigue can be very physical, it can be cognitive fatigue, I can't get through my day of work, concentration, it can be emotional fatigue, it's this feeling of weariness, tired, lack of energy, lack of motivation, it can be loss of physical endurance, which in some cases may be something separate, so I can't ride, I can do my day-to-day activities but I can't ride the bike, I can't go swimming, I can't do these activities that I used to. It can be mild, some of our patients that we see with fatigue following COVID report that they just can't get back to their prior level of like busy days and exercising in the morning and by the end of the day they just have to rest in the afternoon as opposed to doing those activities, or it can be severe, we have patients that have trouble doing their day-to-day activities, they need help from families to do activities that they previously did on their own, so it's a really wide spectrum. And what are the problems with having this fatigue? It can make people feel poor overall, it can affect their obviously emotional state, lead to anxiety, depression, it can interfere with social relationships, I have lots and lots of patients who are able to do their jobs on a day-to-day basis but they can't go out with their friends or they can't go to the movies or dinner, things that they used to do to get real pleasure before, it can worsen pain, it can lead to brain fog, so my patients brain fog and the fatigue seem to go hand in hand and so when patients have a lot of brain fog, oftentimes if we're able to address the fatigue, they both can kind of improve at the same time. Obviously school, employment, hobbies, all those can get affected by fatigue and how common is this? Well, it's extremely common during acute COVID, it's part and parcel of having an acute viral infection to feel fatigued. It's also the most common symptom of long COVID, ranges depending on the study from somewhere around 10 to 30%, that may even be a little bit on the high side. With patients who have long COVID, 80% reported fatigue as one of their symptoms, probably a little bit more common in hospitalized versus non-hospitalized patients who had COVID. Also individuals with long COVID report fatigue as the most debilitating symptom, it can lead to functional impairment. Some of the studies that looked at the prevalence of fatigue are limited by being observational in nature, lacking pre-morbid data, not having a control group, so many people who don't have long COVID are also fatigued on a day-to-day basis, lacking standardized assessments and selection and reporting bias in the studies that have been done. Do individuals with fatigue get better over time? So this is a busy slide, there's a lot on here, but you can see on the left, this is from hospitalized patients from Wuhan, China, it went from 52% at six months to 20% at one year. This is hospitalized, which may be a little bit different of a picture than non-hospitalized. And if you can squint on these studies on the right, you can see that on the top graph, up is better, less fatigue, there's a trend, kind of, again, if you squint towards less fatigue, and again, in the lower graphs, lower is better, less fatigue over time. So what are some of the risk factors for fatigue following COVID? Being female, and this is just in relation to the fatigue, not overall along COVID. Being female, being single, time since infection, more, so if it's earlier, closer to your time of infection, more likely to have fatigue. More symptoms, being sicker during acute COVID likely leads to increased rates of fatigue, and the presence of confusion, depression, dyspnea, or having premorbid heart disease, particularly in hospitalized patients, are all factors that are suggestive or risk factors for having fatigue following COVID. So when do you assess? When should you look at a patient following their COVID infection, and they say, I have fatigue? Because as I mentioned before, in the first few weeks, it's natural to have some residual fatigue and take a little bit of time to recover. So one thing that we, a lot of us, kind of discuss with our patients, if you're sick with COVID, you're fatigued, just don't, I don't think there's any hard evidence on this, but just take your time getting back, rest, fully recover as much as you can prior to going back to activities and work. We hear very common, hey, I was feeling pretty good, I thought I was over the acute infection, then I went back to the gym, or I went back to school, and I had a relapse of symptoms. So I try to, when my family, my friends say, hey, I have COVID, what should I do to prevent long COVID and long COVID fatigue? One of the things I mentioned is taking your time, doing it in a stepwise manner, getting back into activities. I think you should become a little bit more alert if you get to three or four weeks and your patient is still having fatigue. And at that point, I'd say, have your patient follow up with their primary care physician, check in, make sure that there's nothing else going on. And then if it's good to two, three months, that's when you're starting to get into long COVID territory, and you should think a little bit more in depth about how do we analyze this fatigue, how do we give our patients some resources to hopefully improve. So how do we assess it? So there is no objective measure of fatigue, which is different than weakness. And again, you can kind of look at these in separate categories. So you have to kind of dig in a little bit deeper. Ask about pre-illness functional status, medical status, were they fatigued beforehand, did they have chronic illnesses that might be contributing? We ask about the severity, again, is it mild, impacting just higher level activities? This might influence your rehab recommendations to the patient. Is it cognitive, physical, again, is it endurance, is it just this general tiredness? Are they falling asleep? What time of day is it? Is it constant, is it only in the mornings, is it only in the evenings? Again, this will impact your rehab recommendations in some cases. One important thing that I mentioned here briefly is assessing for triggers or post-exertional malaise, which I think I have a whole slide on. And again, what's their sleep pattern at night? Very important, because it may point you down a path in terms of your questions and evaluation. And then changes in function, something we all do as physiatrists. So post-exertional malaise, it's a key feature of ME-CFS and often long COVID. And this is described as having severe exhaustion after physical, cognitive, or mental activity. You can see on these graphs, it can start immediately following that activity, or it can be delayed. It can be delayed to that evening, it can be delayed to the following days. And if a patient goes through one of these episodes, which they often describe as a crash, it can last for even up to a week plus following their overexertion. So again, this is kind of the description of what that looks like. In patients who had post-COVID fatigue, 73% of the 80% of the patients who had fatigue reported episodes of post-exertional malaise. Triggers can be anything. Usually, it's some sort of physical exertion, but also stress, excess mental activity. All of these can lead to crashes in post-exertional malaise. So one of the main things that when you look at a patient who is presenting with fatigue following COVID that you want to look at is premorbid conditions. These are just examples, but did they have something that maybe increased following COVID? Did they have a history of MS? Did they have asthma? Did they have hypothyroidism? And these are also things you want to keep in your mind as kind of possible comorbidities. So you're looking for, is there another explanation for the fatigue beyond long COVID? Because some of these things can be treated in a way that we don't have a pathophysiologic, mechanistic treatment for long COVID. And then we also look at coexisting symptoms. And this is probably all the workup or assessment we do for long COVID fatigue, the most important thing. Do they have insomnia? Do they have sleep disordered breathing, which is so common, and a lot of patients don't end up getting assessed until after they have COVID, and it turns out they did have mild, moderate sleep apnea. And when we treat that, they feel better. Mood, autonomic symptoms, pain, cognitive dysfunction, dyspnea, all of these that exist can lead to increased fatigue. If they're very depressed, obviously could contribute to fatigue. So the post-COVID condition core outcome set has recently been released. It's an international consensus, stealthy process, made up of patients, families, researchers. They selected core outcomes, and they said that fatigue or exhaustion and post-exertional symptoms are core outcome measures, as well as physical functioning and work and occupation as other outcome measures. They recommended the fatigue assessment scale, fatigue severity scale, and the functional assessment of chronic illness therapy fatigue scale. And they also recommended the DePaul symptom questionnaire for post-exertional malaise questionnaire. And you can consider physical assessment measures as well, depending on the setup of your clinic and the time and in-person versus virtual. I'm running out of time, so I'll be quick here. Polypharmacy is really important to assess. Patients oftentimes self-medicate with over-the-counter medications, antihistamines or on anticholinergics, antidepressants. Just keep that in mind. They get started on numerous medications following their COVID infection, drugs and alcohol, supplements. How do you assess it? A lot of us do virtual exams as part of that first visit. One thing about those is it can be very helpful for our patients with fatigue, that they don't have to come in to a whole clinic appointment, and you can also assess the home situation a little bit. In person, obviously, you do kind of a thorough physical exam looking for other causes of their fatigue. Labs, imaging, it's really based on their symptoms. If they haven't had kind of a basic laboratory workup, I think in most cases it is appropriate. Usually by the time they see somebody in post-COVID clinic or a physiatrist, they've already been to their PCP and had some of this initial workup done. Typically neuroimaging is not effective and have a low threshold for sleep evaluation. Last slide. Is long COVID ME-CFS? I don't think they're necessary synonyms. I think a lot of patients with long COVID do fit criteria, though, for ME-CFS, and there are guidance and research that's been done in that area long before long COVID. So I kind of think of PASC as this umbrella that incorporates conditions like ME-CFS. Thank you. And now to continue our discussion of fatigue, we have Dr. Alba Azola, who's the assistant professor and co-director of post-acute COVID clinic at Johns Hopkins in Baltimore, Maryland, right here. Thank you. Hi. Thank you so much for the opportunity to present on fatigue. So I'm going to briefly start by going over, just aim it here, okay. I have no disclosures, but I am going to speak on off-label use of certain medications, including Naltrexone and Mestinon. Like Ben was mentioning, not all fatigue is created equal. There are several different types of presentation, those with a mild post-viral to more post-exertional malaise. And it bears repeating, screening for post-exertional malaise on patients presenting with fatigue is needed. It really going to impact the plan of care and how you're going to rehab this patient. So really teasing out their triggers is going to be important. So we can start with the treatment for fatigue with energy conservation strategies. And this is helpful in all types of fatigue, even those deconditioned from being months in the ICU to those that have post-exertional malaise. So learning about pacing, prioritizing, planning, and positioning, it's principles that we know as physiatrists and can really be implemented in this patient population. So when we're talking in fatigue with post-exertional malaise, there's some caveats to implementing pacing in this particular population. And it's really important to understand what are the threshold to having symptoms, what specifically for that patient triggers the post-exertional malaise. Sometimes patients can find physical cues or use biofeedback with monitoring. The physical cues, I have patients that say tinnitus, like when they have the onset of tinnitus, it's when they know they're going over their energy envelope. Some other neurologic symptoms or brain fog can be another cue. We want to assess their activities and how they're performing those activities. So we want to know that we can explain to them to break up those tasks. They can do things, but they need to learn how to break them into smaller portions, take rest in between, what things absolutely need to get done, prioritizing, all the four Ps are in this part of the treatment, and how to get it done with the energy they have on that day. Right? It's important for them to learn to assess their energy battery every day and plan and prioritize according to their level of energy that day. And one key thing is creating space for recovery. Patients tend to have good days and bad days, like Ben mentioned. In the good days, they may feel called to do more than usual, and they try to do the extra trip to the grocery store or take their kids to the pumpkin patch, and this leads to fatigue crashes. And it's important for them to understand that they need to leave a little bit of that 30% of their battery to be able to sustain and not experience a crash. There's many tools that you can provide to your patients. This is from the World PT Day. It's an activity diary. I use this often. With the brain fog, they forget exactly what they did a couple days ago, and like Ben mentioned, these symptoms can be prominent 12, 24, even 48 hours after they have done whatever triggered that crash. So keeping track of their activities during the day, it's really useful for them so that they don't get into the Corona Coaster, which I like to call with my patients. So it's always about getting off of the Corona Coaster and minimizing those crashes. We definitely see an overall decline of function when people are riding the Corona Coaster. It's just, I've seen patients go from walking into my clinic to being homebound because they're unable to really implement this pacing strategy. So this is their medicine, and they really need to understand that that's the most important thing they can do. Spoon Theory also talks about energy management and patients like that. We can support with parking placards, reasonable accommodations for work. These people want to continue working. That's what they really want. And there are many ways, depending on their occupation, that you can support them with accommodations that can help them reintegrate to the workforce. We can also refer to OT and PT, especially for coaching. Virtual has been very important in that because they can see the home environment and they can coach them on how to energy conserve. And rehab psychology, just like we do for spinal cord patients, TBI patients, stroke patients, these patients have impairments that have limited their lives significantly. And they need tools in their pockets to be educated on coping skills to manage their new impairments and process that. So that's really a key piece to their treatment plan. Dietary patterns and hydration. Just want to highlight, I'm not married to any particular one, but many patients found omega-3s, turmeric, and vitamin C helpful. I just want to highlight that it's important to know what this medication's side effects are or whether they're metabolized. Turmeric is metabolized in the liver. It's important to know how much dose their patients are using. There's a lot out there on the internet with high dosing for several different things that could be actually toxic levels, for example, B6 toxicity. I have seen it in my patients. And it's important to collaborate with sleep disorders if they have one, mood issues. All of those need to be co-treated as well. Now I'm going to talk about some of the medications that we've been trialing, again, off-label. A lot of this I learned from the ME-CFS and dysautonomia population. The level of evidence is weak, but it's evolving. There's several randomized controlled trials on low-dose naltrexone being run at the RECOVER study. At least from my anecdotal evidence and what people have been seeing, there's some good response to it. And I'm going to talk about the mechanism of action. So there's two potential mechanisms of action. One is increase in production of endorphins. That can help a lot with the pain symptoms, the myalgias, the arthralgias. The second mechanism is a decrease in expression of inflammatory cytokines. So the low-dose naltrexone will bind to TLAG receptor 4 in neuroglial cells as well as immunologic cells and decrease their expression of the cytokines. So patient selection, fatigue, fibromyalgia, and they cannot be on opiates. Dosing, this I got from Dr. Peter Rowe, and you can go through it later, but start low and go slow. I see a phenomenon of a sweet spot. So a patient that's doing really well at 2 milligrams and wants to try 3 often has to go back to 2 because they may not see the same improvement in symptoms. So there's kind of like a slow titration that's required to find that specific dose that helps. Limit side effects include vivid dreams and insomnia. This can be quite distressing. If that happens, we dose in the morning, and that tends to help with those symptoms. And several, a very small portion of patients can have reduced appetite, nausea, headaches, and flu-like symptoms, but it's pretty well tolerated overall. If they have liver disease, this is contraindicated. It's processed in the liver. At normal commercial available doses of 50 to 150 milligrams of naltrexone, you can see an elevation in LFTs, but at dosing of 1 to 4.5 milligrams, it's really not common to see an elevation in LFTs. And that's how I figured out that turmeric was metabolized in the liver because my patient had an elevation in LFTs, and we were going to stop the LDN, but then we figured out that she was taking high-dose turmeric. So it's important to review all those things. Prose is inexpensive, about $20 to $30. It's not covered by insurance, but again, it's accessible to most people, well tolerated, and improvement in a significant amount of patients. It's not a magical wand that's going to make everything go away, but people find it helpful and increase functionality. The only pain in the tush is that you have to find a compounding pharmacy that can make that. Important to keep in mind that compounding pharmacies utilize different mixes to prepare the formulation, so you want to make sure that there's no things like lactose or milk protein products. I've had patients that are allergic to that, and those are used in the compounding process. So it's important to know what is in the compounds. And for those patients with fatigue and dysautonomia, first thing, we have to manage orthostatic intolerance. I'm sure that will be covered in a different talk, but we consider trials of mestinone or pyridostigmine with very, very, very careful patient selection, very, very, very careful. So the evidence is weak, but it's evolving. There's several small randomized controlled trials in the ME-CFS population. A prominent figure in this area is Dr. David Systrom from Harvard. He's published quite a bit on this. And we know that mestinone is an acetylcholinesterase inhibitor that works at the neuromuscular junction in patients with myasthenia gravis. But there's also acetylcholine in different nerve endings as a neurotransmitter, and particularly in the autonomic nervous system. So overall, in the autonomic nervous system, it increases parasympathetic drive and decreases sympathetic tone. I have no time, so I'm going to leave this for you guys to review, but there's a lot of tips on how to dose it, titrate it, and the definite contraindications. And that's it. Thank you. Now we're going to move to breathing disorders in PASC, and our first speaker is Dr. Jason Malley. He's the director of the Long COVID Clinic Clinical and Research Program at Harvard Medical School and assistant professor of medicine. Great. Thanks so much, everyone, for coming. So I'm going to talk today, along with Matt Bartels, about breathing discomfort and respiratory issues after COVID. I'll talk about kind of the first half of assessing this, and then Matt will talk about the rehabilitation approach and treatments. So the goals are really to understand the respiratory complications that we're seeing and how we approach these pulmonary and breathing discomfort complications, and then identify appropriate next steps for treatment, and ultimately talk about the rehab approach. These are conflicts unrelated to what we'll talk about today. So this is a typical patient who is someone young, previously very active, and comes in after having COVID-19, having persistent symptoms, including breathing discomfort or shortness of breath. This is someone who managed their illness at home after four days, felt better, and then over the coming weeks to months began to notice he couldn't get back to running. He could actually barely walk around his house without feeling that his breathing was uncomfortable, and was describing the breathing as if it felt the breaths weren't satisfying, no matter what effort they put in. If you ask patients, this is a very common way people describe their shortness of breath after having COVID-19, and at times feeling tightness. And this is just a recent study, just to point out that respiratory complications, at least in this large study that compiled over 50 individual studies in over a million patients, they found this cluster, or this specific area of respiratory symptoms, was the most common reported in these studies. Fatigue was another very common symptom, and again, cognitive impairment, another very common area. And respiratory complications generally is referring to shortness of breath, but some people can have cough. In terms of what could be going on in the lungs, people's natural instinct is to look towards the lungs to see, is this explaining why someone's shortness of breath is occurring after having a respiratory virus? Most people, actually, that we see, they don't end up having any findings on their pulmonary function tests or chest imaging, but there are some patients who they'll have a persistent impairment in their lung function, or persistent injury to their lungs. So this is one study that looked four months out for patients who, in small groups, were hospitalized or not hospitalized for COVID-19. And this is a measure called DLCO diffusion, which is a way of looking at how well gas enters the lungs, basically air from the atmosphere getting into the bloodstream through the lungs. And it's very sensitive for injuries that persist after infection. So it will go down, your diffusion of gas will go down, if you still have injured or inflamed lungs. They found that this group, less than the lower limit of normal here for DLCO, hospitalized patients, 70% of them four months out, still had measures of impairment in this gas diffusion four months out from the hospital. Whereas non-hospitalized patients, most people had normal lung function, including their DLCO. But a third of them, almost a third, 31% who weren't hospitalized, did have impaired DLCO. So it's worth looking, certainly, at full pulmonary function tests for people after COVID-19 who are having shortness of breath, because a reasonable percentage, even people with mild illness or who weren't hospitalized, could have this impairment in diffusion, which is a potentially subtle sign of ongoing inflammation, either in the lungs or in the blood vessels of the lungs. This is another example of the type of disease you could find in the lungs, though, again, is less common except for after severe disease. These are forms of inflammation, persistent changes that look like pneumonia but are actually due to continued inflammation in the lungs, in some cases treated with steroids. So this was a study of patients four weeks after being in the hospital for COVID-19. They followed up with them systematically and found that 39% had persistent respiratory symptoms, primarily were still short of breath after leaving. And of those with respiratory symptoms, most people had normal PFTs and imaging. But 43% had, oh, sorry, most people had impairment in PFTs and imaging. 43% had no evidence of issues, so the majority did have some abnormality on their pulmonary function tests. And of those, 18% had persistent CT changes. So on top of pulmonary function tests, CT scanning or chest imaging is another kind of initial step to look to see is there a persistent change in the lungs, an injury that would explain the shortness of breath. This is just one final study on potential mechanisms of shortness of breath within the lungs themselves, which looked at patients who underwent chest CT with images both on inspiration and expiration. And this is something done to look at the very small airways of the lungs, which can become inflamed and air gets trapped. And you can see a difference between inspiration and expiration CT scans. This air trapping suggests bronchiolitis, inflammation of very small airways. And it's kind of an asthma-like syndrome. In some patients, it may respond to inhalers. In others, unfortunately, it doesn't, but it often improves with time. Occasionally, people take oral steroids for this. And the investigators in this study assessed patients who had presented to a clinic for shortness of breath after having COVID-19, so it was a select group of people. But they found that air trapping was one of the more common findings in this group compared to a healthy control group. And this can only be seen on inspiratory-expiratory paired CT scans, so it would be missed on a traditional CT scan. So now to begin what we focused on for this statement that was about the assessment and treatment of breathing discomfort and respiratory sequelae as a collaborative, the key aspect of assessment really is to understand someone's initial illness and where they are now. So initial illness, how severe it was, really tells you first how likely is it that they're going to have one of these findings on chest CT. People with severe disease who are on oxygen or in the hospital are much more likely to have a persistent injury in their lungs. People who had mild illness are much more likely to have normal testing on PFTs and chest imaging and have some other explanation for their breathing discomfort. And then where are patients now? So if a patient has gone from being very short of breath in the weeks after COVID-19 to having some shortness of breath but with much more exertion, so they're able to do a lot more, their shortness of breath has improved over the course of weeks or months. It's a lot more reassuring than someone who has had persistent shortness of breath that's been unchanged and much more likely to suggest some sort of injury to their lungs. And then the basic assessment is really you examine the patient. You ideally can walk them around while measuring their pulse oximeter. And if you have available, do full pulmonary function tests. And these are a very good screen, again, to see do I think it's more likely this person has a persistent lung disease or do they have another cause of shortness of breath, like a muscular cause, a cardiac cause, deconditioning, many other aspects of shortness of breath. And we're trying to triage high likelihood of lung disease versus high likelihood of some alternative explanation. The evaluation that we focused on discussing for this paper was really to first have some objective way to assess what they're experiencing in terms of severity of shortness of breath and what people can do functionally. And there are a lot of different scales. These are some examples which measure either the experience and severity of dyspnea or what you can do functionally, what you're able to do physically during the daytime. This gives you a baseline. It also lets you then when you follow up a patient who may still, they may be having a bad week when you see them, but you ask them how they're doing in terms of this compared to six months ago and you realize that they've really made a lot of progress. I think in patients with long COVID, it's really every two to three month assessment because you can't look week to week. People aren't going to really notice a major difference. But when you look back with them six months, they say, oh, I'm completely different than I was six months ago, but still not back to where I want to be. As I mentioned, pulmonary function test is key. And imaging, which can begin with x-rays, but actually based on more of the recent studies like the one I showed, I think CT scans, especially inspiratory, expiratory CT scans are valuable for people who continue to have shortness of breath that's not improving and have other red flags either on exam or on pulmonary function tests. And cardiac evaluation is really up to judgment. If someone has discomfort besides shortness of breath with activity, chest pain, tightness, sweating, other symptoms that make you worry that this is cardiac ischemia, then you should pursue that. But generally, I don't routinely pursue that in people who have no other concerning aspects, but just have this persistent breathing discomfort after COVID. One of the steps after finding potential abnormalities is to have someone see a pulmonologist and people come to our clinic. I see patients for kind of every symptom of long COVID, but happen to be a pulmonologist. Certainly if people have abnormal pulmonary function tests or chest imaging, they may have one of those conditions that you need to either follow closely over time to see if it's improving, like scarring in the lungs or inflammation, or consider steroids or other treatments. Certainly people who have an abnormal pulmonary exam or they continue to have shortness of breath or they're having episodic shortness of breath that might suggest an asthma-like syndrome, they could see a pulmonologist. And then especially people who have unexplained desaturation with activity. Some people come to the clinic, they look fine, but then they have an assessment at their first physical therapy session and the physical therapist tells us that they were actually desaturating into the 80s when they were at their peak activity. And then we have to really pursue more work because that suggests to us there is some impairment in gas exchange and probably persistent injury to their lungs. So I'll pass it off to Matt with that and have him go over the treatment. Thank you. And by the way, he is not a physiatrist, but he's an honorary physiatrist now. So now to continue with breathing disorders, we have Dr. Matthew Bartels, who's the chairman and professor at Montefiore Medical Center. All righty. So welcome, everybody. So yeah, now we're going to talk a little bit about how do we apply physiatric and other treatments to some of these patients and how do we get them to work and improve their function. These are disclosures. None of them are actually particularly pertinent to this talk. So the treatments. For patients, once again, that we have these clear abnormalities on PFT, imaging, and oxygenation, we actually coordinate with their primary care doctors, their pulmonologists, and we maximize their medical treatments. But these patients actually can often progress well with our traditional pulmonary rehabilitation. Unlike a lot of the other conditions that we're treating with long COVID, it seems to be that, fortunately for us, pulmonary rehabilitation exists in a lot of the modalities we have. We can apply pretty much unmodified for the patients. But there's some real considerations that we have to include in our treatment of these patients because they do have some specific abnormalities. And they have some specific things with the comorbidities, such as fatigue, that make us have to modify how we progress. But for stable deficits, and these are the patients that we were just discussing or just hearing about that, you know, they don't really have progressive changes and they just have a stable level of dyspnea, you can go with progressive mobilization as tolerated, once again, with respect to fatigue. Because if we try to do a traditional really push-hard program for a person who also has concomitant fatigue, they can actually have relapsing problems. Supplemental oxygen, that is the drug that we use here. This is a proven treatment and it works really well, and don't be scared to use it. There's also a lot of concern with patients who may have an obstructive component that you might cause oxygen retention. That's true at rest, but not with exertion, because when you exercise, the exercise is a driving factor that will make you breathe hard so that you don't actually retain CO2 and have all of the bad consequences of having that elevation. So you use as much as needed. Up to six liters nasal cannula PRN during therapy and activity, up to 100% non-rebreather. So we can have some patients that we sometimes put on, not fortunately most of our COVID patients, but that they're on six liters nasal cannula plus 100% non-rebreather, so they're getting 20 some odd liters of oxygen. If it's needed during the activity, because what we really want to do is improve their function and we will overcome whatever the oxygen deficit is. And that's mostly related to the DLCO deficit we see in a lot of our long COVID patients. So the rehabilitation therapies, traditional pulmonary rehab, it's not as available as we would like, but it is now paid for and it is reimbursed through Medicare, at least through the duration of the public health emergency. And so far through the end of 2023, we're hoping that legislation will make it that it continues to be paid for in perpetuity, because we're going to continue to see long COVID patients. COVID is still out there. I know we're, most of us running around without masks, but there, if you look at the numbers, there are still significant numbers of people who are getting COVID and they may actually have long COVID symptoms. Other things you have to look at is at home programs, because a lot of the patients may not have such severe disease that they need a pulmonary rehab program, or it may not be available. We do at home or modified programs using physical and occupational therapy. So what other things do we do? Breathing exercises. Some patients have respiratory muscle fatigue. Why? Because they were intubated for a prolonged period of time in the hospital. That needs to be built up, just like other muscles decondition, the respiratory muscles can do that. That can be done through educational resources such as at home and or in-person training. We also do a lot of training in education when we have patients come through pulmonary rehab. They learn how to use their supplemental oxygen. If they're on inhalers or they're using other medications, they have to know how to time them and how to rescue those. So in case they get, if they have that little asthmatic component, they can rescue those so that they don't actually get themselves into respiratory distress. But those patients who don't have supervised rehabilitation, there's often the ability to do phone or telemedicine backup, and there are now new programs of telemedicine, which is also now brand new and available, and we'll talk a little bit in a moment. So you instruct patients with chronic productive cough and airway secretion clearance. It's not a very prominent factor in most COVID patients, but we do see some patients who had a pre-existing bronchiectasis or a pre-existing component of a productive respiratory disease that now is exacerbated by having COVID on top of that, so we want to make sure the secretions are cleared. And the pharmacologic therapies, most of the oral steroids, bronchodilators, are not routinely recommended for the breathing discomfort in the absence of having something documented further, and we just heard that there are some people who may have some bronchiectasis or some very small vessel disease, small airway disease that may actually respond to bronchodilators, so maybe that would be indicated. And there have been a lot of patients that have been tried for those persistent ground glass capacities on steroids, but in my experience, the majority of them don't really change with that trial of steroids. But it is worth to do it, but if it doesn't succeed, don't keep on doing it, because remember steroids have a lot of adverse side effects that we are trying to avoid. So when do you get your pulmonary therapy? When they have fatigue with post-exertional malaise, because then you really need to work very closely at pacing, and it's hard to do this at home. You can't just say exercise, and they don't know how to moderate themselves. If they're waiting for further workup, and they don't really have a progressive appearing disease, you can go ahead and start them on the pulmonary rehab. Don't delay the exercise program for the completion of the workup, because most of the times there's not going to be something that dramatic in the workup that's going to miraculously change their disease, but the workup will help you to modify the program, but you can at least get it started. Consider looking at the physiologic subjective responses, and that's where those ratings of perceived exertion, such as the Borg scale, are very important. Because as a person's having a good day or bad day, they can do more or less exercise with the same perceived exertion, so that they don't over-fatigue and over-exert themselves in the process. The other thing is PFT abnormalities. We talked a little bit about that. It's really important if a patient is progressively getting worse or not improving in a way that you think that they should, that maybe getting repeated PFT is useful, but don't do it rapidly. Wait several months, because these patients are not having day-to-day changes so much as they're having progressive quarterly changes. I've had patients that it's taken them up to 18 months to actually maximize their recovery, so it's a very slow and gradual process. But if they stall in that recovery, then I may consider actually getting a pulmonary function test. I'm not going to spend a lot of time on this to go through this algorithm, but this is in the PASC statement, and it walks you through how you can actually assess your patient. Look for the pulmonary etiology, break it out into whether or not there's pulmonary disease on top of the thing or not, and then looking to also make sure that you assess that there might be a cardiac abnormality. I'm not talking about this, I think Dr. White said might, but we're going to be looking for possible cardiac abnormalities, because a fair number of long COVID survivors have also had myocardial injury, and that is something to always keep in the mind, because the heart and lungs are connected, and if one is failing, it's going to affect the other. Now a little bit about supplemental oxygen. I said use as much as needed, and kind of think of the patients into two groups, group one and group two. Group one, I think of as they've got an intrinsic pulmonary limitation, they have resting oxygen, resting desaturation or hypoxemia at rest, and they have an intrinsic limitation that's within their lungs. These are pretty obvious. These are the patients that need oxygen at rest. They also get very desaturated at night, and they also show desaturation with exertion. The group two are the ones that slip by the radar many times. They look pretty good at rest. They have a reasonably normal saturation, but they desaturate significantly with exertion, and those patients need to also be put on oxygen. They also are patients who may have desaturation, but may have a concomitant problem, such as right heart failure or other heart failure, pulmonary hypertension, cor pulmonale, and they also can be seen because they have erythrocytosis. They have elevated blood counts, and they're not cyclists who are training for the Tour de France. So what you do for those patients is make sure you get the oxygen. How do you detect them in your clinic? I often will get the patient when they walk in into the clinic, and they're on room air. They have to walk a couple hundred feet to get into the office. I throw the pulse ox on them the moment they walk in the door, and I often find out that they're desaturated, and they didn't even know that they were doing that, but they did feel fatigued with every bit of activity. Of course, your oxygen is down at 85%. You're going to feel awful. So exercise guidelines. Focus on monitor progressive aerobic exercise with strengthening, as well as posture, breathing exercises, and flexibility, two to three times a week for two to three months is what we aim for. Education, education about the medication use, oxygen use, how to try to titrate the oxygen, and often these patients are improving, so we work with them at home to titrate the oxygen to the point where they're off. So my goal with a lot of my long COVID patients, as opposed to my other pulmonary patients, is to try to eventually get most of them off of supplemental oxygen, and it is a reasonable goal for, I'd say, at least 80% of the patients that I've been treating. There's also a lot of emotional support, because this is very hard to live through, and disease-specific education about long COVID. Now, performance testing. A brief thing about this is six-minute walks and other field tests are great to assess function. We do it on a regular basis, every month or every several months, so that you can see the progress that the patient is making. It gives them gratification to see that they can do more and they desaturate less. And the other thing is the really severe patients with concomitant pulmonary hypertension and or heart failure, they need to have this kind of cardiopulmonary exercise testing for safety. And I'm running out of time, so I can't go any further. Thank you. Thank you. Next, we're going to be talking about cognitive dysfunction in past patients, and first we have Dr. Jeffrey Fine, who's the Vice Chair at Rusk Rehab and Associate Professor of Rehabilitation. Oh, you're going to go first. I'm sorry. First, we have Dr. Felicia Ambrose, who's Professor and Vice Chair of Research and Faculty Development at Albert Einstein College of Medicine. So thank you for the invitation and for everyone to come in so early today to listen to our presentation. Jeffrey and I are going to be talking about the cognitive dysfunctions seen in PASC, the evaluation and management. So there has been over 620 million cases of COVID worldwide about with 1% mortality. But very early on in the course of this pandemic, patients started complaining of persistent unexplained complaints. And one of the main complaints at that time was brain fog. This was second only to fatigue. Initially, the medical response was very mixed. We thought that it could be a post-ICU syndrome, although many of the patients were never admitted in an ICU or a hospital. They thought it could be a PTSD. After all, the world went into a global lockdown. There was social isolation, maybe a little bit of depression, or maybe COVID never cleared up. And then there was also the question was, is this psychosomatic, psychological, fed by the media, social media, a form of mass hysteria? What the patients complained about was mostly problems which centered around executive function, attention, and language. And it's been difficult to actually get a true sense of the prevalence of the cognitive complaints, because even the definition of PASC is actually not really settled. The exact symptoms, how long it has to be, how severe, what are the criteria for qualifications. And it varies from organization to organization, country to country. In the U.S., CDC defines it as more than four weeks. In the U.K., it's over 12 weeks. The WHO requires you to have it for at least two months. So then we are comparing apples to oranges in many circumstances. But overall, PASC is thought to be about 10% to 25%. Some of the early research was actually led by the patients. Hannah Davis and group, they publish in Lancet. And this study that they looked at around 3,700 patients, actually mostly the participants were members of the COVID support groups. They didn't do any cognitive testing. But their numbers were like problems with memory was about 70%, with language was around 40%. But when other groups looked at this in a more systematic way, the COVID and cognition group from the University of Cambridge did a lot of publications in cognition in the COVID group. These were smaller groups. These were patients who were admitted with formal neuropsychological testing. They also found somewhat similar numbers. Most of the symptoms were thought to be associated with older population. And this group actually looked at the younger population, people under the age of 60, and found similar numbers as well. They also found that people who had neurological symptoms were more likely to have post-COVID cognitive complaints. This is a very interesting study, I thought. One of the issues we have with these studies looking at prevalence is that people who actually participate in these studies usually believe that they have PESC. So that is a confounder. So in this study, this was done in England, they partners with BBC2 and called it the Great British Intelligence Test. And they did not mention COVID in any of their promotions. And they had people sign up for this. They had cognitive testing done formally. But they also collected a lot of medical information about their demographics, pre-existing medical disorders. And then they asked them about COVID itself. So they had about over 80,000 people who participated with a mean age of around 46. They took all adults. So it was a wide range. And about 12,000 had COVID, which was a positive. They had a positive test. And they compared the two groups, those with COVID and those who did not have COVID. And they adjusted for the age, gender, education, income, racial groups, pre-existing medical disorders. And they found that globally, there was a difference between the two groups. Those who had COVID scored much lower globally. And these areas were mostly in verbal reasoning, multistage planning, and spatial attention. And even people who had a mild COVID also showed a difference. Overall, among the patients who had COVID, about 25%, 24% actually had residual symptoms that fit into the post-COVID. And this is probably the most objective test study on prevalence. The many mechanisms that have been proposed for why there's these cognitive complaints following COVID infection. And they range from inflammation to direct injury to the brain and neurons by the virus itself. None of this have actually been proven. And so it's definitely a lot of work to be done in this area. When you're assessing a patient with a history and physical, you're going to have to do a very thorough general medical examination and general neurological examination. And history with particular emphasis on sleep disorders, psychological issues, and past medical history. As it's been mentioned before, many of these have interact with cognitive symptoms itself. They can either cause new cognitive symptoms or they can worsen ongoing symptoms. To look for the cognitive domains itself, there are several cognitive tools that we can use. The MoCA is the most commonly used. It has the advantage of having the visual-spatial-executive domain, memory, verbal fluency, and attention. The things that the patients were complaining about. It's a quick test. It takes about 10 minutes. It's available in multiple languages for the people with lower education who have low vision or are blind. It can be used in a virtual setting. It's more sensitive than the MMSE for picking up mild cognitive impairments. The downside is it requires training and certification, and there's a cost associated with it. The MMSE is a much older test. It does not have a visual-spatial component to it. There's a lot of bias against education and your language and mathematical abilities. It is very poor sensitive to mild cognitive impairment, and there is a low ceiling as well. If you're a high-functioning person, a small decline is not going to pick it up. The St. Louis University Mental Status Examination covers all of the domains. It's probably maybe a better tool to use in these circumstances. It takes about 7 to 10 minutes. It's sensitive to mild impairments, and it's superior to the MMSE. They have education-based norms, so if you're above high school or below high school, there are different values to be used. The MINICOG is a very, very brief test, and it only looks at memory and planning. If you have no time, then this might be what you want to do. You give three words to the person, and there's a number of variations available. Ask them to draw a clock, and then ask them, and then follow it up with the three-word recall. The short test of mental status is kind of a compromise. It does look at all of the domains. The executive function is not examined very thoroughly, but it is quick and maybe a compromise. If the patients have more than—if you screen positive and you're interested in doing more, there are many other tests to look at each cognitive domain. But at this point, it's probably better to involve a speech therapist or a neuropsychologist. And I'm going to pass it on to Jeff to talk about investigations and treatments. Thank you. Now we have Dr. Jeffrey Fine, who is Vice Chair of Rusk Rehab and Associate Professor of Rehab Medicine at NYU Hospital, Brooklyn. Okay. Good morning, everyone. I just want to say before I start, it's been an absolute professional pleasure to work with everybody on this collaborative. Really quite fulfilling, and I appreciate the work of everybody who's on the panel today. So this is work that we've done as part of the collaborative, where we have shared the work with CDC and presented as part of their provider outreach, and this presentation represents an extension of that, including an appendment of information that we've reviewed since the publication of the statement. I don't have any disclosures. These are objectives, and this is the consensus guidance statement that we're referencing. Millions have suffered from COVID, and many still struggle with fatigue, activity intolerance, and cognitive symptoms. PASC is a post-infectious, post-viral syndrome that likely represents a final common pathway for a phenotype of a post-infectious immune and neuronal dysfunction. All these conditions we've heard about now repeatedly have overlaps with PASC. I do think that they are related to one another in regards to post-infectious dysregulation. The cognitive symptoms are the most common symptom following COVID. Problems with reasoning, problem solving, attention, memory, as we've heard, and patients present to our PASC clinics to address these problems. Now Dr. Ambrose addressed these mechanisms of the proposed pathophysiology related to long COVID, and ultimately some have some evidentiary base now that we'll look at in the next few slides. It does not appear to be a global increase in brain blood barrier permeability, although there may be focal changes in the permeability, and it does not appear to be intrathecal replication of the virus. It does not appear to be a viral infection of the brain. That's an important thing to recognize. This comes from an article by Baldrini who outlined these proposed mechanisms. Essentially the infection of... The viral infection... We may not have an absolute viremia in every case of a patient that's infected with COVID, more likely in just the severe cases, but the virus's presence in the vasculature produces an endothelial injury. We've heard obviously about ACE2 receptor and TEMPRSS2. The effect of the virus sort of binding and infecting the endothelial cell is that it disrupts the nitric oxide synthetase and produces the predilection for a lack of vasodilatation in the microvasculature and microthrombi. Additionally it may thin the basal membrane and produce permeability of systemic inflammation to transmit mediating factors across the barrier to then drive activation of central inflammation. Not just in the brain. So this is in the periphery too. So peripheral nerves are subject to this same phenomena. Okay, so what's the evidence that this is actually occurring? So a couple of studies that were published since we did our consensus statement that for patients with COVID... This is an interesting study of patients where they studied serum brain biomarkers. So in the blood of patients that had COVID. And the evidence is that for patients that demonstrated cytokine storm and evidence of autoantibodies, they demonstrated evidence of non-traumatic brain injury based on the elevation of serum biomarkers of brain markers. Now here's the data. So the way to look at this slide is on the left. The most left graph on the acute and the subacute data points represents acute infection and 30 days. On the left are healthy controls. And on the right, as a control group, are patients who have severe traumatic brain injury. A condition of which we know there's significant neuronal injury. So if we look at the three samples, we look at GFAP, which is a marker for astroglial injury. We look at NFL, which is a cytoskeletal injury. And total tau, which is a reflection of loss of microtubular stability. We see a stepwise increase from patients that have mild, moderate, and severe COVID in the acute and in the subacute phase. Clearly different than healthy controls. And for patients with severe COVID, approaching the parameters that are associated with severe brain injury. So chemical evidence that there's a non-traumatic brain injury happening that we can measure in the blood. This study, a remarkable study. Important study. Everybody should look at this one. In the UK, they have something called the Biobank. Where they're studying their population as a whole with a lot of different parameters. And it just happened to be that prior to COVID, they had patients that had done cognitive testing and had MRIs completed pre-infection. So they had then 401 COVID patients that were part of this study that then got COVID and they were able to then aggregate the functional MRI and their cognitive testing post-COVID. So you had patients that were now studied at a baseline before COVID. An important distinction. Because it's hard to differentiate when patients present how much deficit they had before. So what was important? They did demonstrate in those 400 patients in aggregate that there were significant reductions in gray matter in the perihippocampal gyrus, which is associated with memory encoding. And the lateral orbital frontal cortex, which is the initiation of choices. And if you look at the graphs on the bottom, the orange represent the patients with COVID. The blue represent the control patients in the trial. And you'll see the volumes are diminished in those brain regions. A second measure looking at diffusion indices is a measure of injury. A higher diffusion index represents injury. It was also demonstrated in the COVID patients as well, involving the olfactory nucleus, the olfactory tubercle. These are part of the pathways that go from olfactory bulb to entorhinal cortex. And in their sub-analysis, it demonstrated that the secondary, second-order neurons that transmit to the limbic system, amygdala, also had demonstrations of diffusion index injury. So this is not from viral infection of these structures. It's from viral infection of the support cells of the olfactory neuron, not the neuron itself. And then finally, on their cognitive testing, this is trails A and trails B. These patients in the COVID sample took longer to complete the task, another cognitive demonstration of impairment. So an important study that was pre-post imaging. So this comes from the guidance statement that all patients should be screened for cognitive symptoms. And Dr. Ambrose reviewed the screening instruments that we use for that, and we're going to review a few studies that look at that in more detail. Patients should have a thorough neurologic exam. Patients should have a medication review, and we'll review their medical conditions. And we're going to take a look at a few of these. Now, ultimately, as part of the guidance statement, we looked at a lot of literature that had to do with what is the medical workup for patients that have reversible causes of dementia. Now, there's no biomarker for PASC. Maybe we'll get there, but there's not one currently. So it's important when patients present to your clinic that you help to rule out other conditions that could plausibly explain their symptoms, autoimmune disease, thyroid disease, smoldering infection. So part of the workup is to look at some of these factors that can contribute to reversible cognitive impairment, look for factors that may represent a persistent infection or smoldering inflammation that has not yet reconciled, a reactivation of a latent Epstein-Barr virus or CMV, and to look for the presence of either an unmasked or new autoimmune syndrome. With every infection, we produce some autoimmune antibodies. There's a molecular mimicry against our tissues. And it's clear when we look at patients with PASC that one of the factors that is a risk factor for the predilection of PASC is the presence of autoantibodies. In regards to imaging, so patients need a thorough neurologic exam. In terms of imaging, most patients do not require CAT scan because it's going to be normal in most patients. It's not necessarily going to add to the management unless you're trying to rule out a more important central neurologic problem, a subdural hematoma, central vein thrombosis, a subdural hematoma. So ultimately the neurologic conditions statement, consensus guidance statement, has been submitted to PMNR and will be in publication shortly. And it goes into a lot more detail about these referral patterns. These are the tools that Dr. Ambrose talked about. So you may say these are screening tools. They don't have to be administered by a neuropsychologist or they're resolved enough to isolate the deficit. This is a study where it demonstrated the MoCA clearly showed problems with attention, executive function, and language in a series of 46 patients. In a meta-analysis looking at multiple studies, 27 studies looking at 290 individuals, you see the forest plot on the bottom. The MoCA is effective at identifying these patients' cognitive impairments. Now our recommendation as part of the consensus statement was that even if patients screen negative with the screening tool but have positive symptoms of cognitive impairment, we still do make a referral. This is another study from Mount Sinai that Dr. Tabakoff presented last year for data using the NeuroQL. Again, demonstrated that 63% of past patients demonstrated at least mild cognitive impairment, most a moderate impairment. So referrals. As we refer patients, this is referring to the providers in your community that have expertise in managing this. So this is either going to be neuropsychology or if not available, then psychology, speech therapy, occupational therapy. We'd look at medications to deprescribe with the primary care doctor that may be contributors to cognitive impairment, and we focus on lifestyle interventions like sleep hygiene. Treatments for the cognitive symptom that your neuropsychologist may recommend. Here's sort of a short list of things that may be effective. Day planners, digital tools like To-Do List, Evernote are popular with our patients. How are we doing? Okay, all right, so we're on time. So just briefly, sleep hygiene, super important. It's part of the metabolic clearance of metabolites in the brain, and refer to a sleep specialist. There are medications that you can use. These are sort of the CBT insomnia approach to sleep management. They're practical for everybody. Make the bed for sleep. Medication polypharmacy reduction. Look at the BEERS criteria. Those are from the American Geriatric Society about reducing potentially harmful medications that contribute to cognitive impairment in elderly patients. These are patients with vulnerable brains, so we want to reduce or eliminate these categories of medications. Lifestyle interventions to reduce vagal tone and reduce autonomic hyperarousal can be quite helpful for these patients. And actively manage medical comorbidities that can contribute to cognitive impairment. So 50% of the cases of Alzheimer's dementia are attributable to these seven conditions. Part of our active treatment plan should be managing and helping the patient to self-manage these conditions to create a healthy environment for their healing brain. Future directions. The PASC Recover Initiative is an NIH-funded grant that's looking at the long-term trajectory of patients with COVID and long COVID PASC, including interventions that are effective to bend the curve to help improve recovery, as well as create phenotypes that drive then more specialized treatment plans for patients with sub-phenotypes of COVID. All right, thank you. Thank you. Our last section is going to be on cardiac disorders in PASC patients. And first we have Dr. Jonathan Whiteson, who's the vice chair. Second. Oh, second. First we have Dr. Carmen Terzek, who's the Director of Cardiac Rehab and Professor of Physical Medicine and Rehabilitation at the Mayo Clinic. Thank you, good morning. And I don't have anything to disclose. Those are the learning objectives, but you can check it. I think you have access to that. And I think I always like to start with the most current data. And this is from this morning. So you can see. I don't have to repeat that. We know the impact of the disease and what is coming. I mean, this is just the tip of the iceberg. So what is the incidence of myocardial injury in COVID-19? So this is more in acute phases. And I like this paper. It was one of the first paper in the beginning of the pandemic. The majority, as you can see, the information came from China at that time. And the incidence of myocardial injury went from 1% in some of these data to 100%. And those are hospitalized patient during the January, February, March peak. It was not the peak, but the most dramatic part of the pandemic when we didn't know exactly what was going on and how to treat them. So what are the areas? I mean, what is the cardiac injury that we can see, the acute cardiac injury? And basically involve any cardiovascular system, the heart, peripheral vascular, central, central neurohormonal, autonomic control, the cardiovascular system, and the conduction system, or every single aspect of the cardiovascular system. And in general, having reported the MIs around 7 to 40% in this patient. Acute heart failure, arrhythmia, as you can see the number, myocarditis, pericarditis, venous, thromboembolism, all of them during the acute infection. And what is the pathophysiology? So what happened in those patients? So there are many, many theory, and we are trying to understand more and more what really is the cause. I will say that probably it's a combination of all of them, the severe sepsis, the hypoxemia, the cytokine storm that we know, the coagulopathy macro and microvascular that we see, and the endothelial and microvascular inflammation and dysfunction. And in this regard with the coagulopathy, there are several papers, and I would like to bring this study, that show significant megakaryocyte associated with fibrin and microthrombi were identified in the cardiac microvasculature of many patients that die with COVID-19 during the acute phase. So there is a strong support that thrombosis, and microthrombosis may underline myocardial injury during the at least acute course of the disease. And there is also theory about direct myocardial invasion, and I think that we talked some about that in the central nervous system, it's a controversy. So there have been some detection of the virus in the heart, but some of them may or may not be associated with cardiac injury. So there is a total of five cases in this report that confirmed the infection, those cases were associated with myocardial injury, but the majority of the case, no. So it's not very clear if there is a direct association between the invasion of the virus to the heart and the disease. So other mechanism also, beside the one that I mentioned before, include the supply demand imbalance, and you can see this in many patients, not only with COVID-19, but patients that are in the intensive care unit with severe sepsis or multi-organ failure, so you can see also myocardial injury. So as I said before, probably it's a combination of many of these mechanisms. So this is in the acute phase, so what happened in the post-acute of the past? So here the patient, what we have seen, a significant number of patients three months after the acute infection, they are presenting with symptoms that may include chest pain, palpitation, shortness of breath, orthostatic intolerance, impaired activity tolerance. This is in symptoms, but patient also presented with syndromes, so myocarditis, new myocardial infarction, 4%. It's not so high, but it's significant. Arrhythmia, left ventricular, right ventricular dysfunction, heart failure, exacerbation of previous heart failure, and this is preempted, 52% in some reports. And some non-specific finding on imaging, not associated with heart failure, but finding in imaging such magnetic resonance of the heart. And what is the cause, or what is the mechanism of that? We have some hypothesis about the mechanism during the acute phase, but what about about past? And we don't know, we think that it's a long-term tissue damage, that it's unresolved inflammation, the inflammation continue, that it's autoimmunity, or it's an autonomic dysfunction that is happening in the heart. So we know that many of these patients show myocardial abnormality, until 78%, with or without symptoms. And what is very important, that this cardiovascular manifestation in past can be present in people without previous history of cardiovascular disease, like 529% of patients. So we see that it's exacerbated in patient with previous cardiovascular disease, but we see it's a new manifestation on many patients. And this is data from us, from the Mayo Clinic, it's not published yet, but this is very important, as we're trying to understand the mechanism of cardiovascular symptom past, and this also can be discussed with people with short-term breath or lung issue, but what we saw in the stress test, when we did a VO2 max stress test on those patients, that there is a significant relation between the peak VO2 in patient with lung COVID. So patient with lung COVID have the incidence of pain, or they show in the stress test, that they have very low peak VO2, compared with patient that didn't have a history of COVID infection. So what is the mechanism of that, that what this patient have a very low peak VO2, and some of these patient were compared with previous stress test that they have prior to infection that were within normal. So we don't know, it is the condition is, is impairing VO2 extraction, impairing our cardio output, we don't know exactly what is the mechanism, but this is a significant finding. The other thing I would like to bring is the arrhythmia. So we have seen significant number of patients that are developing an arrhythmia, and this is a nice study that was done using six hospital in Norway, and where patient that were intubated and they stay in the ICU, and they show that there is significant number of patient with this arrhythmia, that three months after the infection. And the majority of this arrhythmia are more common, the most common one is atrial fibrillation. And this is where it's important that many of these symptoms beside the arrhythmia patient also have persistent dyspnea and fatigue, where, and associated with any echo fissure of cardio dysfunction. So the echo basically was normal. Now this is a global echo, we were talking, I was talking with Alva this morning, that we do, when we do a stress echo, we can see some regional anormality, anormality but those patient were, the patient that were present in this study, they just have a general global echo. And sometimes you don't see any change. So this is a nice paper you had the opportunity to read it, I like a lot. And this, they evaluate the long-term of cardiovascular outcome on COVID-19. In patient, you see the VA health system, look at the amount of patient, 150,000 patient were evaluated. And they use 5.5 million control, so, and six million of historical control. So this is very, very good data. And they evaluate this patient, they follow this patient at one year. And they saw that there is a two-fold increase in incident cardiovascular event. And the majority of them were a cerebrovascular disease, this dysrhythmia, pericarditis, myocarditis, heart failure, and thrombotic disease. And this important disease was present in patient not hospitalized, but increase in a great patient that has severe disease, initial disease in the acute phase. And it was present in old age group and in younger patient without risk factor, for example, obesity and diabetes. So that is a very important aspect to consider. So what is the initial evaluation when we have the patient? And I like to stress that it's very important to partner with our colleagues in cardiology when we see this patient. But let's say we have a patient that show some palpitation, shortness of breath, have some vague cardiovascular symptom. So it's very important, first of all, to understand the symptoms, to review their COVID-19 past medical history, hospitalization or treatment, to review the risk factor of cardiovascular disease that the patient may have. Previous test, cardiology assessment that may have in the past, and the current cardiovascular history. And it's important also, as we discussed in the previous presentation, to review the medication, focusing on those one that were prescribed for cardiovascular condition. And other medications, some other medication can be prarythmic. And also, it's important to do basic laboratory and cardiac test, if the patient haven't had any recently, to diagnose, treat and exclude any other condition like pulmonary, serious pulmonary condition, thromboembolic, cardiac complication. Some of the tests, as you can see here, basic test, stress test, I think will be important as well. And again, as I mentioned before, partnered with our colleagues in cardiology will be very important to assess this patient, specifically the symptoms, severe or are progressing. And with this, I'm going to leave Jonathan to talk about what do we do with this patient. And our last speaker is Dr. Jonathan Whiteson. He's the Vice Chair of Clinical Operations and the Medical Director of the Cardiopulmonary Rehabilitation at NYU Rusk Rehab. Thank you so much, Lynn. Thank you, everybody. And yeah, what do we do with these patients? First of all, we gotta remember that these patients don't come only with heart disease or only with lung disease or only with fatigue or only with cognitive issues. They have everything. So don't lose sight of that, that while we split the talks up, these patients have everything going on. So they are complex. I have nothing to disclose. This is my outline. I won't read it for the sake of time because I'll get the hook. And so, but I think we've all been mentioning and I think it's really important to understand about post-exertional. I'm gonna call it post-exertional symptom exacerbation. Forgive me, I'm a little bit of a rebel. I don't love the term post-exertional malaise because these patients don't just have fatigue when they overexert themselves, but they have other COVID symptoms that exacerbate too. So forgive me. But post-exertional symptom exacerbation is something that we have to look out for. So individuals with cardiovascular disease, of course we want them to be active. Even people without cardiovascular disease, we want them to be active with risk factors or otherwise healthy. We want you to exercise. And exercise is a prescription, a dose, frequency, intensity, et cetera. And we should all be exercising. But those, as you have heard, who have COVID, who may have post-exertional symptom exacerbation, we have to be very careful in terms of recommending activity, progressive, and exercise. So we need to do a full thorough evaluation and then we need to decide whether we're gonna say they can do self-monitored exercise, whether they go into a cardiac rehab program because they have cardiovascular disease, and are they gonna be able to go back to perhaps athletic and sports performance. So how do we try and understand post-exertional symptom exacerbation? I'm gonna give you a little breakdown of how I review this in terms of if you have somebody who is active and has some fatigue or tiredness post-exertion, if it seems to correlate with the dosage of exertion, it seems to be within your experience, within their experience. If it doesn't last for more than two or three days, then we may call this something that's expected. Just like when you go and do some unaccustomed activity, you're gonna feel a little bit of tiredness or fatigue or some stiffness. We call it deconditioning, counseling, reassurance, education, I think is really important to your patient who has PASC. They have been on the websites, they have been listening, they know about post-exertional malaise or post-exertional symptom exacerbation. They are worried, so reassurance is important in this mild symptom exacerbation. But what if it's more persistent? What if it's more severe? What if it really truly is a part of ME-CFS? What if it really is more significant? Patients are describing a crash. It's lasting days or weeks. It's out of proportion to the pre-symptom exertion. Well, then they most likely do have this post-exertional symptom exacerbation. We have to be careful and we need to reduce the dose of activity or exercise really to the point where they're not feeling symptoms in the moment and their symptoms of post-exertional symptom exacerbation truly resolve and then very slowly and very individualized get them to add a little bit of activity. It could be about walking a New York City block. I know not everyone lives in New York City, but I just have that in my mind. It could be climbing a flight of stairs. It could be literally walking five minutes. That's it. See if you can tolerate it and if you can, for a week or 10 days and then slowly increase, but a really slow progression. There are few but still significant numbers, still people who have such severe post-exertional symptom exacerbation that just being upright, just walking around at their home, they're gonna have significant symptoms and these people present a real challenge. We really have to get them to reduce their level of activity and very slowly and maybe in a physical therapy environment, get them back to low levels of activity and slowly, slowly progress over months, not over days, not over weeks, but over months so that they can recover. So how do we measure activity performance in individuals with cardiovascular disorders in PASC? You've seen these mentioned before, 30 seconds sit to stand, two minute step test, six minute walk test. These are standardized. They're objective. They can be done in a clinic. They can be done by you, by your nurse practitioner, your physician assistant, a physical therapist. It doesn't take long, but it's good to get a baseline understanding of their activity. If they can't complete those tests, they are significantly impaired and for sure need to be evaluated by a physiatry. Don't forget, a lot of these statements that we put out are not just for physiatrists but for family practitioners and primary care doctors. So partnering with those doctors to make sure that these kinds of patients are referred through to you so that you can manage them and take care of them. Other standardized tests, and again, Matt and I, sort of we mirror each other. Heart and lung disease live hand in hand. I'm not sure if I can say that. Chest in chest. And so we will do standardized exercise stress tests and cardiopulmonary exercise testing. It does give us metabolic equivalence which correlates very well with daily life activity tolerance. And it also helps us to understand if someone is gonna have a post-exertional symptom exacerbation. You really do get a sense later that day, the few days afterwards. And this has helped me differentiate patients who do have post-exertional symptom exacerbation from those who don't. And it does affect, obviously, how you're able to progress them. But the CPET also allows you to differentiate between heart and lung disease as well. And repeating these standardized tests at intervals can help understand not just baseline but how patients are progressing. So after we've completed our evaluation then we want to recommend either exercise on their own, general rehabilitation or cardiac rehabilitation. So those who can tolerate a self-guided home exercise program if they have really minimal symptoms or no post-exertional symptom exacerbation. If they have PASC and cardiovascular risk factors and do not qualify for cardiac rehabilitation. Again, a lot of education. Teach them how to do a self-monitored exercise program. Monitor their heart rate response or perceived exertion. And follow the 2018 physical activity guidelines. Who may warrant or need more general rehabilitation under the guidance of a physical or occupational therapist. Those who have more significant symptoms with cardiovascular disease. They may not qualify for cardiac rehab. But those who do but yet have more significant PASC or post-exertional symptom exacerbation. Put them through a general rehabilitation program first. Harden them a little bit. Get them to the point where they can tolerate progressive aerobic exercise. And make sure that those patients are also referred through to you. You should be guiding that general physical therapy. That prescription should come from you. So what about cardiac rehabilitation? Well they have to have qualifying diagnosis. I'll go over that in a bit in the next slide. And make sure that you educate your colleagues. The other professionals, yourselves, your patients. Less than 30% of patients who qualify for cardiac rehab are actually referred through. It's a tragedy of modern medicine. But we need to do better by educating people. The program includes an evaluation by a physician who's trained in cardiac rehabilitation. A pre-cardiac rehab exercise stress test. 36 sessions of physician monitored progressive aerobic exercise. Starting at 31 minutes. That's the minimum that's allowed for insurance reimbursement. Progressing up to hopefully 60 minutes. Education, support, and a repeat of the stress test to monitor outcomes. In terms of the diagnoses that qualify many patients who had acute COVID who were stressed. Or those who have a more chronic COVID. They may have had an acute coronary event. An echocardiogram that shows new wall motion abnormalities is enough to support that. Those who've had coronary interventions. Either bypass, stent, angioplasty. Those with new onset left ventricular dysfunction with ejection fraction less than or equal to 35%. And those who've had other surgeries. Including valve and heart and heart lung transplants. Healthcare disparities. This is rife in our medical world. In our living world. And certainly in PASC as well. And black Hispanic individuals have lower referral rates to cardiac rehab than white and Caucasians. Black and Hispanic and other racial and ethnic minorities are more likely to have COVID-19. More likely to have severe COVID-19. More likely to have underlying pre-existing cardiovascular risk factors. More likely to have cardiovascular disease. Remember it. Look for it. Think about it. Treat appropriately. Females as well. Underdiagnosed. Undertreated for cardiac disorders. And as well discriminated against when it comes to referral for cardiac rehab. Really important. If that's the only take home message you get from that, from me, great. Myocarditis. And this is something that's very significant. And this is one of the more significant contraindications. And certainly the one that's truly relevant to PASC. People with myocarditis cannot go through an exercise program. And anyone with ongoing myocardial dysfunction or low ejection fraction. They need to be evaluated. And we're talking about at least three months. More likely six months. That we're preventing or stopping people from doing an exercise program. In terms of when patients are exercising on cardiac rehab. These are the reasons to terminate an exercise session. But there's a reason to terminate cardiac rehab program in general. And that's if they're developing post-exertional symptom exacerbation. Heart and lung live together. Monitor the oxygen saturation. There's a whole separate guideline on breathing disorders as others have already talked about today. In terms of athletes and return to play. This is very significant. Elite and professional athletes. They will be guided by their governing federations and the physicians involved. And most of these individuals, if they have any kind of cardiac symptoms, are gonna be getting cardiac MRIs. Because this is their livelihood and their life. And this is what they're gonna push for. So they need to be taken care of specifically. In terms of those with abnormal lung cardiac workup. They should be restricted from training. And have further cardiac evaluation. This should say the American College of Cardiology. I guess I was thinking about us, the American Academy. So forgive me, ACC. But they have given some guidelines. I'm not gonna go through this slide in detail. But this is well worth reading. If you take care of athletes. Whether they be professional or weekend warriors, et cetera, college, collegiate athletes. This is, these are important guidelines. And in terms of returning athletes to play. If they have ongoing symptoms. If they have new symptoms. If they've required hospitalization. It's a triad testing of EKG, cardiac troponins, and echocardiogram. Athletes who have been diagnosed with myocarditis. They have to have an echo. They have to have halter monitoring to look for those arrhythmias. They have to have EKGs prior to returning to support. They can only go back to training if ventricular dysfunction is normalized. If the biomarkers have normalized. And if they don't have any signs of abnormal heart rhythm. They should be reassessed periodically through the few years following the myocarditis. And they should absolutely be followed by their sports medicine clinicians. I don't put much in red. But I think this is really, really important. If you have active myocarditis. If you allow someone to exercise. And they have an arrhythmia. And they die. That's a problem. So we have to be very, very sure that individuals who have myocarditis. Symptoms of myocarditis. If they want to go to exercise. If you are concerned. Get a cardiac MRI. Because you have no legs to stand on. If you allow someone to exercise with myocarditis and they die. Sorry to end on such a down note. But it's good to protect your patient and yourself as well. This was the publication. And I'll thank you very much. Thank you. I really want to thank our panel of experts. That was a wonderful presentation. And we covered a lot of material in an hour and a half. Unfortunately, I don't think we have time for questions. Because there's another, it's 9.29. Maybe get one question in. Is there another, is there one question? Oh, we can go five minutes? Thank you. Great. Oh, perfect. I'm Dr. Javier from Puerto Rico. I just want to know if there's any, on long COVID, if there's any measurement of a continuous elevation of IgGs or any complement in the cascade to be able to monitor their chronic fatigue? At this time, there's not clear clinical significance for... Could you repeat the question? Oh. Yeah, the question was whether there are biomarkers to track and follow that correspond with clinical presentation of fatigue. The short answer is no. The long answer is we are definitely... there's a lot of evidence emerging on this. There are certainly much work being done. And I think that we would probably get to that point, not in the very distant future. But at this point, a lot of this information that some patients get for a lot of money that they pay for the specific test, there's no clear clinical significance to their $500 test that they dished out. Thank you. Yeah. No one else is lining up. Ron Garbo from VCU Autonomic Clinic. Thank you for your work. I do... I don't want to be hyperbolic, but your work, I think, is truly historic when we look back at the history of medicine. And the wellness community doesn't know all the things that we're going to unravel. So... But I want to... And I don't necessarily need an answer, but I do want to draw a distinction between cardiorespiratory synchronization inducing that versus respiratory muscle training. And I believe cardiorespiratory synchronization should come first, because there are some dropouts with respiratory muscle training. And... But the reason I do that, as soon as I say a certain word, you get into the buckets conversation. So I personally believe whether you're talking about pulmonary, cognitive, or hypervigilance from psychological disorders or autonomic dysfunction, that heart rate variability biofeedback is a foundational starting point that encompasses all these. But as soon as you say the word biofeedback, oh, biofeedback's not covered. I don't want to compare it to other biofeedbacks. Nothing else compares to it. Let's compare it to respiratory muscle training and put it, I think, in front... I believe in front of it and $200, $300. I think everybody should have access to a device we monitor remotely and access to coaching. Thank you. Thank you so much. I'm going to respond not to the statement or the question. I think it was more of a statement than a question, and no one is disagreeing with you. But I will say, this collaborative is not closed. This collaborative is wide open, and if you have thoughts and you have ideas, join the collaborative. Your input, your thoughts, your suggestions are so valuable. So speak to any one of us. Speak to Kavitha. We will give you the information on how to join the collaborative. And I'm saying that to every... No, no, I know you are. But I'm saying that to everyone. Please participate. Your opinion counts. Good morning. I'm Jerry Kappel from Gaylord Hospital. Recently joined the collaborative from more of a community setting in Connecticut. I'm seeing more and more patients now with long COVID who are getting reinfected with different variants. So I'm wondering from the group with the different clinics around there and recommendations, are there any changes that we see coming for patients for whatever reason are getting reinfected multiple times with variants on top of their pre-existing long COVID or is it too early to tell? So there's a paper out from the VA data looking at long COVID and reinfections. And the symptoms definitely worsen and there are more symptoms with each reinfection. I think the paper quotes about... I can't remember the exact numbers, but they do second and third infection and they see a relationship and increase in symptoms, neurologic, cardiac, fatigue. All of those symptoms exacerbate after a reinfection. I guess my question was more, should we do anything different for this group of patients or just use the same guidance even though they're getting reinfected and potentially sicker? I would say from my experience with reinfection happens, they're able to implement the strategies that we've been teaching them after their first infection, which actually really helps cut down the time of the crash or those symptoms that they're experiencing. So I think just reinforcing what we have... what has worked and being able to implement that. I love seeing patients that were first waivers and now, you know, get reinfected and I'm able to... they're able to implement the tools quickly and recover and rehab better. So that's what I would say about that topic. Thank you. I don't know if anybody has any other comments. I'll just add that, you know, those people who were infected and were either sicker or they had not been vaccinated and certainly with the original variants seem to have had a more difficult time, seem to have had, you know, greater incidence of Long COVID. We asked the question at our program at NYU, does this mean that now people are vaccinated and now that we're an Omicron variant and so on that we're not going to see Long COVID? Absolutely not. We're still seeing Long COVID. They're still showing up even though they've been vaccinated, whether it's their first or their fourth infection. So I think the bottom line is we're still learning. There's so much still to learn. This is so dynamic. Agreed. Thank you. One more question. Is there any specific changes in the sleep-wake cycle of the patient and if they go into the different stages of sleep, either after REM, if they stay in delta wave or they go right into alpha wave? Is there any evidence of that? You're on. You're the pulmonologist. By the way, while he's coming up, I just want to put in a plug for the third session for treatment and evaluation of TASC patients, which is tomorrow at 8 a.m. Yeah, no. Thank you. So sleep is... I would say universally I don't think I've met a patient who their sleep is not affected among their other symptoms of Long COVID. There are patients who have more typical illness associated sleep issue, which is insomnia. They lack sleep, difficulty falling asleep, waking up during the night. But then a striking thing is also patients who have hypersomnia. They sleep far longer than they used to. And sleep for most people is like a fingerprint. It's very consistent. Um, our studies so far, we've found people who have different patterns of sleep architecture than you would expect. We generally don't have a baseline, a pre-illness polysomnogram to compare it to, um, but we suspect that there are changes in sleep architecture that could underlie daytime fatigue, brain fog. People essentially have as if they are chronically sleep-deprived for a couple of years now with their long COVID symptoms, even though they may actually appear to have a longer duration or normal duration of sleep. So there are some medications I definitely think getting people into... Any other questions? All right. Well, thank you very much for waking up early and coming. APPLAUSE

cognitive dysfunction

long COVID

prevalence

memory problems

executive function

underlying mechanisms

inflammation

treatment

lifestyle modifications

cardiac manifestations

research

diagnosis

collaboration