It didn’t take David Systrom long to take on long COVID. Systrom – the Harvard pulmonologist whose invasive exercise tests are redefining how we think about chronic fatigue syndrome (ME/CFS) – didn’t lead this study but helped design, analyze it, and write the paper. The study was led by Yale pulmonologist Inderjit Singh. Like Systrom, Singh is one of the few pulmonologists who has his hands on an invasive exercise machine.
“We are one of the few centers in the world that performs invasive cardiopulmonary exercise test (iCPET). We primarily perform iCPET for patients who have unexplained shortness of breath or fatigue. So, these are patients who’ve had all the routine investigative testing, all of which do not explain their symptoms.”
Singh appears to be coming to long COVID (and ME/CFS) in the same way that Systrom did: by coming across people with mysterious fatigue and/or shortness of breath. Instead of directing them to the nearest psychologist – as most pulmonologists apparently do – Singh appears to have taken them on.
It’s hard to overstate how important the long-COVID exercise studies are both to people with long COVID and/or ME/CFS. Exercise, after all, is, in one form or another, recommended for most diseases and conditions. Until ME/CFS came along, few people had considered the possibility that exercise could be a) fundamentally harmful; b) or instead of making you stronger, it could make you, in a very fundamental way weaker; i.e. it could actually impair your ability to make energy.
These studies present the opportunity not just to better understand these diseases but to rethink fundamental assumptions that have been made about human biology – assumptions that have undermined the efforts to understand ME/CFS and other diseases. A recent study, for instance, exploring exercise intolerance in rheumatoid arthritis, found some intriguing similarities to ME/CFS.
Persistent Exertional Intolerance
The title of the newest study, “Persistent Exertional Intolerance After COVID-19 Insights From Invasive Cardiopulmonary Exercise Testing“, adds a nice qualifier: the exertion intolerance isn’t temporary – it’s persistent, and exercise isn’t the issue – it’s exertion – a much, broader, more inclusive and descriptive term that hearkens back to a proposed name for ME/CFS (Systemic Exertion Intolerance Disease (SEID)).
The study was small (just 10 people) but it contained long-term (for long COVID that is) patients – all had come down with long COVID about a year before. The one person to see the inside of a hospital room was hospitalized for a short time.
One of the graces of the invasive cardiopulmonary exercise test (iCPET) is that, unlike non-invasive CPETs, it takes just one invasive test to uncover some rather dramatic problems with energy production in ME/CFS.
The results were familiar. The limited ability to exert oneself was not a cardiac issue but was found somewhere in the periphery; e.g., something was happening in the blood vessels and/or the muscles.
- The “Markedly reduced aerobic capacity” (peak VO2 <80% of expected) – indicated that the long COVID patients were unable to produce normal amounts of energy. (Aerobic capacity involves the use of oxygen via the Krebs cycle to generate energy. It’s the main source of energy for the body.)
- High blood oxygen levels at the moment of peak exertion – indicated that the lungs were delivering sufficient amounts of oxygen to the blood but the oxygen was not getting taken up in normal amounts by the muscles.
- Increased oxygen saturation found in the venous blood – cinched the former finding. Since the veins direct the blood back to the heart after it has gone through the muscles, the blood oxygen levels of the venous blood should be much reduced. The higher levels of blood oxygen found in the veins of the long-COVID patients indicated their muscles were not taking normal amounts of it up. Because the mitochondria use oxygen to produce ATP they weren’t able to produce as much energy.
- Hyperventilation – Carbon dioxide (CO2) is a byproduct of energy production which is removed via breathing. CO2 is toxic in high quantities but healthful at the proper levels. Rapid and deep breathing (hyperventilation) removes too much CO2, and results in narrowed blood vessels and symptoms like fatigue, cognitive issues, etc.
- Significantly reduced left-side filling pressure – Systrom’s ME/CFS studies indicate that not only are the blood oxygen levels increased in the venous blood but that leaky blood vessels are causing some of the venous blood to disappear – resulting, if I have this right, in reduced left-side or diastolic filling pressure.
It was truly all of a piece. The reduced aerobic capacity made sense given the finding that the raw material of energy production – oxygen – was not being used up. Either the oxygen was not getting through to the muscles in normal amounts or, if it was getting there, the mitochondria were not taking it up.
Deconditioning Rears Its Head
“By using iCPET, we provided a comprehensive and unparalleled insight into the long term sequelae of SARS-CoV-2 infection that is otherwise not apparent on conventional investigative testing”. The authors
Exercise studies can be dangerous things. Exercise tests that delve more deeply into exercise physiology will reliably pick up abnormalities in ME/CFS patients. Exercise studies that skirt the surface may not.
It’s no surprise that the idea that deconditioning (lack of activity) is causing exercise problems has shown up in long COVID. The deconditioning idea led large parts of the ME/CFS field astray for decades.
Thus far two long-COVID studies have concluded deconditioning is causing the impaired energy production found. One study which found a keystone ME/CFS result – early entry into anaerobic functioning – concluded that absent problems with the lungs, deconditioning must be the cause. Another study that found reduced peak oxygen consumption – another common finding in ME/CFS – also concluded that absent any evidence of problems moving oxygen into the blood, deconditioning must be the cause as well.
Inderjit et. al also asserted that the authors’ assumptions were faulty because two hallmarks of deconditioning (reduced peak CO, increased heart-filling pressures) were missing, and one of them (heart-filling pressures) actually moved in the opposite direction expected.
More complete exercise tests – the 2-day exercise tests and the invasive exercise tests – as well as other studies have incontrovertibly shown that while deconditioning is, of course, present, it is not responsible for the energy production problems in ME/CFS.
Enter Chronic Fatigue Syndrome (ME/CFS)
The authors then went on to propose that a similar process to that found in ME/CFS may be occurring in long COVID. A small fiber neuropathy that’s shunting the blood away from the muscles (and presumably other tissues) is preventing oxygen from getting to the mitochondria.
Systrom’s team has come up with other possibilities including mitochondrial problems, “leaky veins” which reduce blood flows, and low blood volume, but the small fiber neuropathy/microcirculatory shunt appears to be the best fit for this small group of long-COVID patients.
A Heart Failure Connection?
The authors highlighted the “exaggerated hyperventilation” found during exercise. (Hyperventilation occurs when you breathe more quickly and deeply than normal.) They concluded that the abnormally high “ventilatory efficiency” was likely due to an enhanced peripheral mechanoergoreflex and metaboergoreflex sensitivity.
Twelve years ago, Alan Light appears to have found something similar when he found dramatically increased levels of metabolites produced by the muscles.
The authors then dropped a bombshell when they suggested that the skeletal muscles in people with long COVID may be undergoing a process akin to that seen in heart failure (!). They suggested that along with alterations in the makeup of the long-COVID patients’ muscle fiber types, the enzymes responsible for activating aerobic activity may also be depleted.
That depletion would block the ability to produce energy aerobically, thus causing an early dependence on the less productive and ultimately toxic (when overused) anaerobic energy pathways. That would then cause the small (group III-IV) nerves associated with the muscles to send out signals calling for more rapid, faster breathing; i.e. hyperventilation. Since Systrom has also found hyperventilation during exercise in ME/CFS, the same should apply to ME/CFS as well.
- This small study – led by a Yale pulmonologist- and involving David Systrom, did the first invasive exercise testing of people with long-COVID.
- The study’s results – reduced energy production, reduced uptake of oxygen, and hyperventilation, jived with Systrom’s findings in ME/CFS.
- Two long-COVID exercise studies have concluded that deconditioning is causing the energy production problems in long-COVID. This more comprehensive invasive exercise study showed that it wasn’t.
- The authors proposed that something similar to what’s happening in ME/CFS may be happening in long-COVID as well. A small fiber neuropathy that is shunting the blood away from the muscles (and presumably other tissues) is preventing oxygen from getting to the mitochondria in the muscles – thus reducing long-COVID patients’ ability to produce energy.
- Attempting to explain the hyperventilation, the authors hypothesized that something akin to what occurs in heart failure may be occurring in the skeletal muscles in long-COVID patients. Studies indicate that the exercise intolerance found in heart failure is partly due to alterations in muscle fiber types and reductions in aerobic enzyme production. Those changes appear to trigger the nerves in the muscles to produce hyperventilation during exercise.
- This DOES NOT suggest that heart failure is a possibility in long COVID. (Decades of ME/CFS have not produced heart failure in ME/CFS.) The heart failure hypothesis appears to apply to the skeletal muscles – not the heart – which is not a skeletal muscle.
- It’s clear that as time goes on exercise physiologists are delving deeper and deeper into the core issues found in ME/CFS and now long COVID.
- Since the pioneering work of Workwell and Dane Cook in the 2000s, the exercise physiology field in ME/CFS has steadily grown in significance and breadth. Long COVID is bringing more exercise physiologists to the ME/CFS field and more are sure to come – taking us hopefully closer and closer to the heart of what’s happening in both diseases.
The skeletal muscle finding, interestingly, came about when researchers tried to understand why people with heart failure experienced such dramatic exercise intolerance. It turned out that the exercise intolerance was in part due to reduced aerobic energy production and an early entry into anaerobic energy production – precisely what is happening in ME/CFS. Establishing a link between long-COVID and ME/CFS, and a disease like heart failure would, of course, be a huge step forward for both diseases.
It should be noted that Ron Tompkins of the Open Medicine Foundation-funded Harvard Collaborative Center for ME/CFS is studying the muscles in ME/CFS.
The study was small but David Systrom has assessed hundreds of people with mysterious fatigue and exercise intolerance over time and knows his subjects well. I would be shocked if this small sample wasn’t representative. With regard to the small sample size, the authors noted how striking their findings were.
“Data for this study were drawn from a small number of patients who had recovered from COVID-19. However, the peripheral limitation to exercise intolerance exhibited by the patients who recovered from COVID-19 were striking compared with those of control participants.”
All study to date suggests that energy production problems in long COVID match up well with those in ME/CFS.
Slow Moving Revolution
It doesn’t appear that anyone seriously considered the possibility that exercise was damaging the ability to exercise, or even more importantly, was able to document it until the exercise physiologists at Workwell group (Staci Stevens, Christopher Snell, and Mark Van Ness) began doing 2-day exercise tests in ME/CFS over ten years ago. When I first came across Workwell’s work in 2009, I assumed it would revolutionize our understanding of ME/CFS – and it has over time – but much more slowly than I would have thought.
For one thing, those 2-day test results so messed with exercise physiologists’ heads that rather than believe those results they assumed something MUST be wrong with Workwell’s testing equipment. With few exercise physiologists interested in ME/CFS, the “revolution” has been a slow one. Slowly but surely, though, the exercise physiology field in ME/CFS has grown.
Exercise studies are now routinely used to provide insights into ME/CFS pathophysiology and multiple studies have confirmed Workwell’s early findings. Since Workwell and Dane Cook at the University of Wisconsin began digging into exercise and ME/CFS in the 2000s, other exercise physiologists such as Betsy Keller, Ruud Vermeulen, Franz Visser, and David Systrom have joined the field. Their work inspired Avindra Nath to make an exercise stressor a key part of his study and to employ a 2-day exercise protocol.
The pre-COVID-19 ME/CFS exercise physiologists prepared the way well for long-COVID exercise physiologists who are being greeted with some startling findings from the ME/CFS field. Thus far the new long-COVID exercise physiologists appear to be embracing ME/CFS results. Donna Mancini is studying both long- COVID and ME/CFS (she and Dr. Natelson snagged a huge NIH study), and Inderjit Singh noted the ME/CFS results in his long-COVID study.
These two will hopefully be just the tip of the iceberg as more exercise physiologists and energy production specialists join the field and take us closer to the heart of what’s happening in ME/CFS.