May Momentum Tuesdays 2022:

Interview Transcript with David Systrom, MD

Rebecca Handler, OMF Communications Manager:

Today we are joined by Dr. David Systrom, who is the newest Co Director of the Ronald G. Tompkins ME/CFS Collaboration at Harvard Affiliated Hospitals. So just to start off, I would love to hear more about what brought you to the field of ME/CFS research specifically and how you got started.

Dr. David Systrom:

Sure. So, with full disclosure, I am a lung doctor. I’m a pulmonary critical care physician, and I’ve had a special interest in exercise physiology for my entire career. Many years ago, we developed specialized exercise test called the invasive Cardiopulmonary Exercise test, which was originally designed to detect early heart disease, early pulmonary vascular disease to differentiate between heart and lung disease as a cause for exercise problems in cases where the clinician hadn’t been able to figure it out fully with tests for the patient at rest.

And we found this test very useful. But over time, slowly but surely, we came to realize that there was a subset of patients whose exertional intolerance was not explained by any classic heart or lung disease or a combination of the two. We began looking for other reasons, and Lo and behold, for the fair amount of serendipity, probably six to seven years ago, we began to systematically study these other patients and determine that many, if not all of them, met clinical criteria for ME/CFS.

Rebecca:

So, when you first started to see that, were you aware of chronic fatigue syndrome at that point, or was it something that was lesser known in the medical community at that time?

Dr. Systrom:

Oh, definitely the latter, yes. Aware also probably aware at the time of some of the controversies about case definitions. Many of them had been put through the wringer with experts, and there wasn’t a real consensus at the time. Nor are they totally to this day, all those things, I think, have gotten better about what the disease was, whether there was subset of patients with different types of problems that we could identify and maybe treat differently in the end. So none of that was readily apparent six to seven years ago.

And then I was very much aware that there was a large population of medical care providers who flat out didn’t believe there was such a thing as ME/CFS. And we’ll call them the naysayers for the moment.

In part, that was understandable. And that when we used all the time-honored things at our disposal history, physical exam, routine labs, cardiac Echo, cardiac stress test, pulmonary function test, chest imaging. Most often in these cases, they’re all negative. And that led to frustration both on the part of the health care providers investigating this disorder or these disorders and the patients, of course, as well. So, I was aware of the controversy way back in the day but have since become even more aware.

Rebecca:

That’s so important because I think there is still, unfortunately, a gap in that understanding. So I assume when these patients came to you, many of them actually weren’t diagnosed at all yet with ME/CFS.

Dr. Systrom:

That’s correct.

Rebecca:

So that must have been because ME/CFS is still widely a diagnosis of exclusion. So I’m sure that was difficult for them as well, just not having the proper answers, but everything, of course, coming back negative. So it is very difficult in the diagnostic process. And I think that’s still unfortunately, to this day, still something that many patients go through. And I know there is a statistic that says an average patient may take up to five years for a diagnosis.

Dr. Systrom:

All true. And then the diagnosis most often still is sort of a clinical one. It’s a framework to start with. But until we and others started taking a deep dive into the pathophysiology and increasingly the Omics plasma samples and whole blood samples, until we started doing that, we just were left with kind of a clinical framework to start with. But it wasn’t very satisfying in that it, yes, described the patient but didn’t lead to specific therapies or clinical trials that could be helpful for the patient.

Rebecca:

So that is such a huge gap. And I think that’s something we’re trying to fill at the Collaborative Centers, at the Open Medicine Foundation Supported centers.

So as the newest Co-Director of the Harvard Collaboration alongside Dr. Wenzhong Xiao, in what direction would you like to take the center in the better understanding and discovering of new treatments for ME/CFS and Long COVID and of course, the related multi-system, chronic complex diseases.

Dr. Systrom:

Great question.

Well, I think our mandate, and this has been put into overdrive with the advent of PASC, or Long COVID, with so many patients calling their Congress people and asking for a systematic response in terms of NIH funding and related diagnostics and therapeutics. So, where I would love this to go rapidly is the development of hard endpoints that diagnose the disease where we can say as a group, okay, you have X. We have demonstrated these abnormalities. You can’t make them up. These abnormalities are not in your head. And believe me, when we do tell our patients this, we get appropriately emotional responses because many of them have been written off for so long.

So, we want hard endpoints: physiology and omics. And to a degree, I think imaging, especially central nervous system imaging, PET scans, MRIs, etc All of these things are hard endpoints. And they can tell us that patient X has not made this up, that patient X is not simply detrained or out of shape, that the answer is not going to be simply sending them off to the gym and telling them to work their way through it.

So that would be one better diagnostics and hard endpoints. And the other one, I think. And of course, there’s a congressional mandate with the RECOVER Project in Long COVID that I hope will in a way be transferred over to the quote “old fashioned ME/CFS,” clinical trials. So there’s been a dearth of clinical trials in both diseases. I think as we learn more about the diseases and they may, in fact, be very similar or even to a degree identical, Long COVID and ME, then I think we can be more intelligent about doing proper clinical trials, randomized, placebo controlled clinical trials with a real physiological basis and again, hard endpoints because of those clinical trials. So not only do we have a better diagnosis, or we hope to have a better diagnosis at play, we hope to use the diagnostic endpoints in clinical trials to determine whether drug X works or not. And these could be brand new drugs, or they could be repurposed drugs, which is really a fascinating area. FDA approved drugs, to a degree again, serendipity applied in an educated fashion to address both ME and PASC.

Rebecca:

Absolutely. I think that has a lot of promise, especially with repurposed drugs. If we can be able to find something that may work for ME/CFS or Long COVID patients, because as we know, new drug development is always a very lengthy process, so it would always be a little bit easier, perhaps if we could expedite it with the usage of drugs that already exist for these patients.

And so, to speak a little bit more on clinical trials… You and your group at Brigham and Women’s Hospital have evaluated more than 1,500 patients by performing something called an upright invasive iCPET to investigate this exertional intolerance or post exertional malaise (PEM). So I’m wondering if you could just explain a little bit about what you learned specifically using this iCPET testing method and why it’s important for researching these diseases specifically?

Dr. Systrom:

Sure. So, the invasive cardiopulmonary exercise test, as the name implies, is cardiopulmonary exercise test, which I should define a lot of places do the noninvasive variety some sort of workload imposed, usually on a cycle ergometer with an incremental protocol that takes the patient up to their maximum capacity. Although there are many variations of workload imposed, some centers use treadmills and there are some data on submax among protocols. But for the most part, I think the most information is gleaned with an incremental protocol where the patient has taken up over 5,6,7,8 minutes to their symptom limited maximum.

Along the way, the noninvasive part involves a mouthpiece, and the mouth nose clip, EKG leads, and a pulse oximeter. And the mouthpiece is connected to a metabolic cart. And that metabolic cart derives things like the oxygen uptake at the mouth and the carbon dioxide output at the mouth and measurements of minute ventilation. So, from those three variables, a fair amount of information can be gleaned about any patient with heart lung disease or ME/CFS, or PASC. You can determine how impaired the patient is from the time honored VO2 Max (that’s the maximum oxygen uptake) at the end of the exercise. So we expressed that as a percent predicted predicted values for Vo2 Max have derived from the patient age, gender, and an estimate of lean muscle mass, which in turn is derived from the height. So a fair amount of information can be gleaned from that.

We can say the patient is 50 percent of normal or more often in ME and PASC, it will be over 70, 75 percent of predicted. And I would hate to add that one should not stop there. on a symptomatic patient. One should not do a noninvasive test, to determine that their VO2 maximum is in a slightly depressed range, and simply decide this is detraining because there’s a lot more to be unearthed. One other comment on the noninvasive test is that more often than not, and especially seemingly in Long COVID, there is some evidence of hyperventilation. It’s not directly measured with an on invasive test, but there are a couple of measures, including something called ventilatory inefficiency minute ventilation divided by the CO2 output and expressed as a fraction or slope during the exercise. When that’s high, it’s compatible most often in these diseases with hyperventilation.

And that’s known to be a feature of at least a subset of patients with ME and very commonly seen in Long COVID. The other is an entitled CO2, and its response to exercise when those numbers are low at rest and even lower yet with exercise.

That’s another hint that the patient is hyperventilating. And again, this does not mean it’s all in the head. It’s a poorly understood phenomenon, but it’s ubiquitous, certainly in PASC and a subset of patients with ME. So that’s a non-invasive test. It’s useful. It’s very useful to start with, but again, if there are mild abnormalities, please don’t write the patient off as having nothing wrong with them. So the invasive portion is where we leave most of the insights into the pathophysiology of exercise intolerance in both ME and Long COVID. And that adds to the noninvasive test.

Two catheters that are placed in our cardiac cath lab before the test. One is a radial artery catheter, and the other is a pulmonary artery catheter placed with the help of ultrasound and fluoroscopy in the cath lab through the internal jugular vein. So those two catheters are placed and at our institution, the patient is pulled around the corner into the exercise lab and then up on the bike and everything properly set up and they peddle away for, again, five to perhaps eight minutes. And we got a phenomenal amount of information. So the additional information that we get from the catheters, combined with a non-invasive test is measurements of blood vessels or vascular pressures. That systemic blood pressure, and that’s pulmonary artery pressures and pulmonary venous pressures. And then importantly, the filling pressures for both the left and the right part, the right atrial pressure and the pulmonary capillary wedge pressure. Turns out that that has been a phenomenally revealing area. Filling pressures are quite low and almost universally low in the 1,500 patients that you mentioned that we’ve studied with ME and then more recently Long COVID. Then there’s one other category of measurements made with the catheters. And the big one is Fick cardiac output Dr. Fick put this on the map 100 years ago. If one measures the Vo2 with a mouthpiece, and then the difference between the arterial and the mixed Venous oxygen content, divide the Vo2 by the difference between those two, you have a fixed cardiac output. It really is pulmonary blood flow in most cases without any shunting of blood, abnormal shunting of blood. And I’ll get into that in just a second. The pulmonary blood flow matches the systemic blood flow, and we can quantify it and determine every minute what that number is. And then at maximum exercise, what percent predicted.

It is. What we’ve discovered, in addition to the preload failure, that’s the low filling pressure during upright exercise. And I’d emphasize upright. If you do this supine on a cath lab table, you will miss the signal with gravity as the enemy, as it were, what we can see, low filling pressures.

We call that preload failure. So that’s part of it, and the other part with both ME and Long COVID, it’s evidenced that at least in a subset of patients, a very high pulmonary blood flow, but evidence of low systemic blood flow. Now that pattern has been known forever, both on the cardiac cath lab table, but also in exercise testing with intracardiac left to right shunting.

So, with a simple defect and congenital heart disease, pressures tend to be higher. For instance, in the left atrium and systemic blood well, oxygenated blood, is pushed preferentially over to the right side and around and around in the lung circuit, it goes. That’s the definition of left to right shunting.

And we have found the very same phenomenon without any evidence of the intracardiac left or right shunting in a subset of patients with ME/CFS. The paper was published in CHEST last summer with Philip Joseph as the first author. And then we have found the very same thing in Long COVID. So it seems to be a dual abnormality of peripheral blood vessel tone and blood flow that underlies at least a fair amount of the exercise intolerance in both diseases.

We measure that with low filling pressures, both sides of the heart, but especially the right atrium. And then the additional problem in a subset of patients that seems to be more frequent in women than in men, and something that we’re investigating that appears to be peripheral. We know that there’s no intracardiac shunting based on the resting right heart catheterization and some oxygen measurements done traditionally there. It all seems to be in the periphery.

And the final part of this is that there is at least a loose association with autonomic nervous system dysfunction. And in about 45% of ME patients with the vascular abnormalities, we can demonstrate with a skin biopsy that there is either definite or probable evidence with nerve density or neurite density in the epidermis of the skin of something called small fiber neuropathy.

Just briefly on that, the small fibers have a lot of functions. It’s been known forever that they mediate pain, so they’re very much the same as the pain fibers. They’re unmyelinated small fibers that are in multiple organs, but especially in the skin where we can sense pain. But more recently, largely neurology has come to recognize that they play autonomic nervous system function as well, sympathetic, and parasympathetic function. And what we think we’re seeing in ME and in Long COVID is this association between the absence of the nerve fibers on the skin biopsy and then blood vessel dysregulation, both venous and arterial during upright exercise.

At least the hypothesis is that this is post infection, most often in ME, and of course, all the time in Long COVID, post infectious, likely autoimmune dysautonomia or autonomic nervous system dysfunction. And in turn, we get abnormalities of blood vessel tone and blood vessel flow, especially during upright exercise. I know that’s a mouthful, but that’s exactly what we have found over the last several years.

Rebecca:

Well, I think that is such an interesting finding, especially something that I’m curious about is how does Post Orthostatic Intolerance play a role in this? Is this something that you see with these patients, or is it separate from ME/CFS?

Dr. Systrom:

Yeah, it’s very much related. If one drew a Venn diagram of these disorders, there would be huge overlap amongst ME/CFS and POTS, for instance, and less frequently, orthostatic hypotension during an upright tilt table test. And we are in the process of trying to marry our exercise findings Both with vascular dysregulation and just Parenthetically the hyperventilation that we see during exercise to Dr. Peter Novak’s findings at Brigham, who does the tilt table test and measures along the way. And most patients ended up carbon dioxide level pressure pressures, which go down a subset of patients, meaning there’s hyperventilation during upright tilt table test, and then he Additionally measures brain blood flow with transcranial dopplers.

He can show on a subset of patients with chronic fatigue and more recently Long COVID that when he puts them in the upright position, yes, there are symptoms, there’s the orthostatic intolerance, and yes, there’s hyperventilation, just as during exercise. And additionally, he can show that brain blood flow, perhaps read component, is decreased in the locations during the upright tilt table, and a large percentage of them have classic criteria, meaning heart rate changes. So large overlap, not perfect. I think, having done work and seen the results of folks who have had previous tilt-table tests and done our exercise test, I think that we end up catching more preload failure, more evidence of dysautonomia with the exercise testing than the classic tilt table test diagnosis of POTS, but there is substantial overlap.

Rebecca:

Thanks for explaining that a little bit. I always think it’s interesting to see all the different pieces of the puzzle and how they interact with each other, because I know that’s such a common comorbidity with many patients with ME/CFS and also now with Long COVID.

So, something else that I think is a huge hindrance to research in general is obviously just funding into ME/CFS specifically. Which brings me to a question. So if money was no object, obviously it always is with this disease, what would you like to do towards finding a cure for

ME/CFS and these related multi-system diseases?

Dr. Systrom:

Yeah, I think the two areas are the ones we touched on just briefly earlier, and that is money spent to better define these diseases and better understand the symptoms that result in the clinical diagnosis or the case definition. So, I think largely speaking, those categories are the ones I mentioned.

So, the pathophysiology of exercise intolerance because fatigue in Post Exertional Malaise is ubiquitous and orthostatic intolerance and exercise in the upright position is very common. So the exercise testing, I think with the invasive component to it, opens a lot of doors, a lot of light on the pathophysiology.

But maybe two comments on that. One is we need to do more than just describe the pathophysiology. We need to take perhaps those hemodynamic subsets that we’ve identified and then properly design clinical trials that address the problem.

So for now, what we’ve been doing is we’ve been and others have been, borrowing some from the POTS literatur and drugs that have been found useful in orthostatic tachycardia syndrome and orthostatic Hypotension and dysautonomia and using those drugs and then determining if it makes the patient better. So that’s one approach using exercise and borrowing from another area such as POTS.

I think another area where in 2022 money would be well spent is further exploring Omics. So that’s plasma and even whole blood signatures that might identify patients with ME and with Long COVID and even better subsets of patients who have different signatures. We’ve begun to make some forays into this area with Ron Tompkins helping OMF, we have data back and are writing up four different papers.

One is on the inflammasome and its special activation, meaning special activation as a result of acute exercise in ME, and hopefully going forward Long COVID. So we have a multiplex that we ran with the help of NIH. It’s largely so-called trail related pathway that represents the inflammasome and inflammatory cytokines that are listed by Acute Exercise.

So that’s one of the areas. And we have two different lines of evidence using proteomics and one line of evidence using metabolomics. And of course, there are others.

There is transcriptomics, there are macrovesicles we know in the blood and even some emerging evidence that the red blood cells both in ME and in Long COVID are abnormal. They’re abnormally large, they’re stiff, they may not get through capillaries normally and their interactions with the endothelium of systemic blood vessels may be abnormal.

So this may be one of the underlying reasons for abnormal oxygen extraction during maximum exercise in both ME and Long COVID. Lots of lines of evidence that are using either plasma or full blood and cellular elements to better understand some of the vascular dysregulation. One other area I didn’t mention is that there is a differential diagnosis for impaired oxygen and extraction during exercise that we found within invasive cPETS.

One of them we’ve talked about is left to right shunning. The other possibility is intrinsic mitochondrial dysfunction in the limbs scalable muscle and that can give the very same findings of impaired oxygen extraction as left to right shunting. And this is a relatively uncharted territory for both ME and for Long COVID. But there is some evidence, little bits, and pieces historically.

For instance, a virus can hijack the genetic material in the mitochondria and make it dysfunctional. And then there’s certainly some evidence that as a result of infection, either fire infection or latent infection that’s reactivated and the resulting inflammation that the mitochondria suffer oxidant damage or oxidative stress and maybe the mitochondria become dysfunctional. So this is very different from the not totally different but a different Genesis than the genetic forms it’s acquired. It’s dysfunction, but it results in the very same symptoms we think of fatigue, perhaps post exertion malaise and perhaps they even influence the autonomic neuropathy that we’ve been talking about because ripple nerves are high energy tissues. They rely on adequate mitochondrial function. Same goes for, I’m not studying this in particular, but focus on the neurology ring. Mitochondrial dysfunction is another area that I think might beg for clinical trials because the treatments available and perhaps pending or mitochondrial dysfunction are totally different from the treatments that are usually directed at just one angle.

Rebecca:

I think that’s such an important area of research. Mitochondrial dysfunction as well as your work is just so important because post exertion malaise specifically is just a hallmark symptom of ME/ CFS. And I know it’s also found prominently in long COVID patients as well. It’s something that we’re hearing more and more about.

So this work that you’re doing to investigate this specific symptom I think is just key to a lot of the heart of this disease.

Dr. Systrom:

Well, thank you for that. I should probably mention we have completed one randomized clinical trial with a POTS drug, as it were in ME/CFS, in one of our cardiopulmonary journals called CHEST. So it will see the light of publication very soon.

And it was a study of 50 patients with ME/CFS randomized to placebo or Pyridostigmine, which is Mestinon. And this is an example of off label use of what one could view as a POTS drug. The POTS doctors have used it forever. It’s a myasthenia gravis drug. It improves the concentration of acetylcholine and the synapse between nerves and myospena, between the nerve and the motor end plate.

And what we found in the study, we basically took ME/CFS patients at the case definition. They did a clinically indicated invasive CPET, and then if they had evidence of the vascular dysregulation I mentioned on the first test, they were randomized to receive placebo or 60 Mg of Pyridostigmine, and then they were asked to cycle again approximately 50 minutes later with the catheters still in place. And what we found was evidence that with Mestinon, the right atrial pressures were higher. During the second test, the cardiac output was higher at peak exercise. The VO2 peak was higher at peak exercise.

That was the primary endpoint. And interestingly, if they received placebo, all those things were worse. So we think this was just a single acute dose of 60 milligrams of Mestinon.

And we don’t clinically, most patients who respond to Mestinon with ME/CFS do so over weeks to months, even at higher doses. But the biological signal was there and it was statistically significant.

So we think we had a window into the pathophysiology of the disease and that kind of overriding abnormally low sympathetic tone by enhancing the sympathetic tone through what’s known to be a cholinergic center, sympathetic ganglia We think that what we did was tighten up the venoconstriction, improved preload, and therefore VO2 peak with a single dose. So it’s a proof of concept. The effect size was not great, but again, it was a single acute dose of Mestinon. So I’m not aware of anything quite like that in the field.

We’re excited about it.

I think it at least helps codify the notion that vascular dysregulation is that way in ME/CFS, and it deserves diagnosis and treatment. The other perspective, randomized, placebo-controlled clinical trial we have ongoing is an $8 million study of mitochondrial dysfunction at the Brigham of single site study funded by a Pharma company named Astellas from Japan. It is ME/CFS, but PASC was not excluded. We have already included some patients in the study who have long COVID. And it involves two very difficult to get needle muscle biopsies of the thigh frozen and sent appropriately to Baylor for evaluation of mitochondrial function. And I would emphasize that we take that approach in ME and PASC is very important again, because most of these patients don’t have genetic forms of mitochondrial myopathy. And the study is ongoing. It was powered by 40 patients. We enrolled 27 of the 40 over about six months, and we’re looking to complete this and run our stats on it. It involves two invasive cPETS at baseline and then at the end of six weeks of treatment with PPARD Delta modifier. It’s proprietary, but it’s thought to act favorably on fat metabolism by the Mitochondria. So we don’t know what patients have gotten yet, but stay tuned.

Rebecca:

Thank you so much for explaining that a little bit more. We’ll be really interested to hear as research comes out and more information is gathered from the sample collection and from this data,

Dr. Systrom:

We would agree, of course. We are by no means the only ones in this field and a special shout out to others who have been at it for longer period of time, and I mean addressing the infectious underpinning of ME/CFS, the immunology and to a degree, some of the things we’ve talked about. I think we’ve got some tools that we found very useful in other diseases at our disposal and again with a bit of serendipity, being able to apply it to ME/CFS and PASC and I think we’ve got some insight.

But you asked me earlier where I would love to see an infinite supply of research funding go?

And that would be to the folks across the country and really across the globe who have taken the diseases, ME/CFS and PASC, seriously, who have addressed these diseases with their own infrastructure, their own laboratory infrastructure. And I’m hoping that we can move this rapidly to better diagnostics and better therapeutic units with proper clinical trials.

So, it is going to take a village to better understand these diseases and to learn how to treat them properly. Of course, I am very much aware, largely through Ron Tompkins consortium, and a special shout out to him, he’s dearly missed and really did establish the notion of teamwork in this area. But what I’ve come to recognize is that both clinically and on a research basis that we have to bring together really all the specialties and subspecialties of medicine.

And I am continually impressed that there are areas of expertise that come from the neurology ranks, ranks, the immunology ranks, infectious disease, special shout out to Donna Felsenstein at Mass General, Peter Novak at Brigham Faulkner, Rheumatology, pulmonary, Cardiology. And we all really have to be talking to each other to make progress.

The silos should be broken down. And I think that was Dr. Tompkins’ vision, and that’s something that I hope that we can carry forward.

Rebecca:

Absolutely. And we really appreciate you stepping in here to help carry out Dr. Tompkins’ legacy because this meant so much to him to see that these patients were able to have improvements in their health care and in their lives overall. So thank you for joining not only Open Medicine Foundation’s scientific advisory board, but stepping up to the role as Director at the newly named Ronald G. Tompkins Harvard Collaborative. It means a lot to these patients on a global scale, myself, being one of them, I know it’s exactly what he would have wanted.

Dr. Systrom:

Well, thank you so much. It was a pleasure to talk with you today.