The overviews of the 2021 IACFS/ME Conference continue with a focus on exercise studies.

The Big Test: Is Long COVID Really Like ME/CFS?

Cardiopulmonary Exercise Test Findings in Post-acute Sequelae of COVID-19

An exercise study suggests that long COVID causes similar energy production problems as ME/CFS

Donna Mancini’s presentation may have been the most consequential of the conference. If long COVID impacts one’s ability to produce energy and exercise, we have a direct tie-in to the defining feature of ME/CFS. If it doesn’t, then long COVID may, despite its many similarities to ME/CFS, be, at its heart, something very different.

Given how drastically COVID-19 can affect lung and heart functioning, it was important to determine how they were doing. The long-COVID patients’ normal chest x-rays, pulmonary and cardiac functioning indicated that nothing structural was impeding their ability to exercise. Something else was causing their exercise problems.

Her use of a 1-day vs a 2-day cardiopulmonary exercise test (CPET) handicapped her a bit, as we know that some people with ME/CFS with normal readings on a 1-day CPET can see their readings fall dramatically on the second exercise day of a 2-day CPET.

As the CPET maximal exercise test slowly ramps up over the 8-10 or so minutes of the test, it’s able to determine how much energy a person can put out, at what point they blow through their aerobic energy production capacity and enter into anaerobic function, if their heart rate is able to keep up the pace, and what’s going on with their breathing, etc.

CPET studies have shown that people with ME/CFS tend to rely on their less productive (and more symptom-producing) anaerobic energy production systems more quickly, aren’t able to produce as much energy, have trouble increasing their heart rates to the levels expected, can display hyperventilation and others. As noted above, these problems are usually much more obvious on the 2nd day of a 2-day exercise test than on the 1st day.

Despite doing only one exercise test, Dr. Mancini found evidence that people with long COVID, like people with ME/CFS, are having trouble with exercise. Peak VO2 dropped about 25%, and 50% of long-COVID patients entered into their anaerobic threshold – the point at which anaerobic energy production becomes dominant – early.

Ninety-two percent had a reduced O2 pulse and 96% had an excessive ventilatory response. That appeared to go hand in hand with the hypocapnia (low CO2 levels) found – which suggested that the long-COVID patients were having trouble removing that toxic compound.

Those long-COVID patients with more normal peak energy production levels tended to have odd patterns of ventilation; i.e. they had problems in other areas.

In short, once they were put on the bike, most of the long-COVID patients looked very much like people with ME/CFS – which, given the extraordinary amount of funding going into long COVID, is good news for the ME/CFS community. It suggests that long-COVID researchers would do well to take deep dives into energy production, and trying to understand what’s going on during exercise in their studies.

This is a field that ME/CFS researchers, in particular, have, despite much pushback, led in. Exercise stressors are often used in ME/CFS provocation studies because they’re so revealing, and that fact alone tells us much. Instead of beneficial boosts that exercise usually brings, exercise has been used time and again to reveal and uncover derangements in ME/CFS patients’ (and probably long-COVID patients) systems.

This study surely wouldn’t have happened without a large amount of work put into assessing energy production and exercise from ME/CFS researchers. It’s very good to see a long-COVID exercise study popping up so quickly. Hopefully, it’s the first of many to come.

low blood volume

The Natelson and Mancini study underway tests out the idea that low blood volume play a major role in the exertion problems found in ME/CFS

Interlude: Opportunity Knocks! The Natelson – Mancini ME/CFS Exercise Study Is Open

A fascinating exercise study led by longtime ME/CFS researcher Ben Natelson and long-COVID researcher Donna Mancini recently got underway. An NIH-funded 2-day exercise study – called “A Cardiovascular Analysis of Post-exertional Malaise” – aims to dig deeper into the exercise problems found in ME/CFS than has been done before.


The question they’re trying to answer is a central one: why do people with ME/CFS tend to blow through their aerobic energy production systems so quickly during exercise – leaving them trying to squeeze little bits of energy out of their anaerobic energy production system?


They believe reduced blood volume – which leads to reduced blood being pumped by the heart (stroke volume) – may have something to do with it. The deep, rapid breathing occurring in people with ME/CFS during exercise results in even greater losses of blood volume – and causes further drops in energy production during the second day.


It’s an intriguing idea given that Visser-Van Campen-Rowe found reduced blood flows to the brain in virtually every person with ME/CFS tested.


Low Brain Blood Flows and Orthostatic Intolerance Ubiquitous in Chronic Fatigue Syndrome (ME/CFS)

They’re going to determine blood volume levels before each exercise test and assess cardiac output, and then they’re going to replenish blood volume in a group of patients and see if their ability to exercise improves. That too is intriguing given that oral rehydration saline was recently found to be pretty darn effective at relieving orthostatic intolerance.

Oral Rehydration Solution More Effective than Saline IV at Improving Orthostatic Intolerance

This several million-dollar, 120-person study is going to have severe and non-severe ME/CFS patients, and healthy controls. It’s taking place at the Icahn School of Medicine at Mount Sinai University In New York City. They have funds to help participants with travel expenses and time spent (but not airfare). To find out more, call the Pain & Fatigue Study Center research staff at 212-844-6665.


Plus……Natelson’s Rocking Bed Study Reopens 

After a pandemic initiated break Natelson’s unique study to see if a rocking bed can improve sleep is back open. If you live in New York City and want to see if this unique kind of nap can improve your symptoms check out this study.


Gender Matters and Metabolomic Weirdness in ME/CFS

Progression of Post-exertional Malaise in ME/CFS Patients from a Plasma Metabolomics Perspective – Arnaud Germain, PhD

Maureen Hanson’s Big Data metabolomic study uncovered the kind of intriguing findings that only large, complex studies can.

Arnaud Germain from Maureen Hanson’s team at Cornell University presented on what is almost certainly the biggest exercise/metabolomic ME/CFS study ever done. With over 1,000 metabolites being picked up, the study produced what Gernain called an unprecedented dataset containing almost 500K data points. The 105-person two-day CPET study compared the metabolites showing up before and after each exercise bout in people with ME/CFS and healthy controls.

Since metabolomic studies assess what’s going on right now in the body, they’re a particularly good match for uncovering what happens when something like an exercise stressor is included in an ME/CFS study.

We’ll surely learn much more when the study is published, but the initial findings are intriguing. The gender difference that Nancy Klimas’s modeling study has suggested is present showed up in spades. The study suggested that exercise affects many more metabolites in women than men – about 3x’s more. Plus, as the second exercise test was done, the levels of even more metabolites were altered in the ME/CFS women.

The second exercise test in the men, on the other hand, didn’t appear to affect the levels of the men’s metabolites much. Only during the recovery period did the number of altered metabolites jump up in the ME/CFS men.

This doesn’t necessarily mean that exercise affects men less but does appear to suggest that the metabolic hit from exercise is broader in women with ME/CFS than men.

Past metabolomic research has suggested that some form of hypometabolism exists in ME/CFS and this study bore that out.  Most of the metabolites that popped up in ME/CFS were found in lower concentrations. While the cause of this is unclear, it would seem to jive with the energy production problems found thus far in ME/CFS: since it takes energy to metabolize or break down substances, less energy production could – at least to this layman – very well result in lower levels of metabolites.

The Core Problem in Chronic Fatigue Syndrome Identified? Naviaux’s Metabolomics Study Breaks Fresh Ground

The Gist

  • The first cardiopulmonary exercise test done in long COVID produced results much like those found in ME/CFS. That was very good news given the extraordinary funding given long COVID and the potential it provides for a REALLY deep dive into energy production in long COVID (and ME/CFS).
  • The biggest exercise/metabolomic study ever done in ME/CFS found that a 2-day exercise study altered the levels of many more metabolites in women than in men, that new and different kinds of metabolites were altered during the recovery periods, that many of the metabolites that appeared to play a significant role in ME/CFS had unknown functions, that some metabolites that increased or decreased in the healthy controls did the opposite in some ME/CFS patients, and that the metabolites that popped up the ME/CFS patients were associated with energy production, metabolic processes, and the immune system.
  • Benjamin Natelson’s NIH-funded New York study is seeking to determine whether low blood volume plays a major role in the exercise problems in ME/CFS. It will also attempt to repair some of the exercise problems in ME/CFS by increasing blood volume. His “rocking bed” study which seeks to determine if a rocking bed could improve sleep is now open again after a pandemic associated shutdown as well. See the blog for enrollment information.
  • Two symptoms were all a Workwell study needed to differentiate ME/CFS patients from healthy controls after exercise. The two symptoms (reduced functioning/lack of positive affect or mood) demonstrated how different ME/CFS is from most diseases as exercise usually produces the opposite result. More work is needed but ultimately Workwell hopes that these two symptoms will help doctors quickly determine when they’re treating a person with ME/CFS.
  • Another Workwell study did not find that ventilation (lung functioning) problems were affecting energy production. Instead, the study validated past findings of energy production issues and pointed a finger at the autonomic nervous system.
It’s been said many times that ME/CFS has a tendency to fall between the cracks, and so they did here. The function of about 20% of metabolites that had significantly altered levels in the ME/CFS cohort was unknown. With that figure rising to over 40% in the female cohort, it appears that some really significant discoveries are being hidden right now.

It wasn’t just that the metabolite levels were often low in the ME/CFS patients and increased in the healthy controls (HCs) – they were often altered in weird ways. Arnaud showed graphs of one unknown metabolite which increased during exercise in the healthy controls but decreased in about 30% of the ME/CFS patients. Another which decreased in the healthy controls, as one would expect, during the recovery period, actually increased in about half the ME/CFS patients. (So much for recovery).

As the participants went into the recovery period, the clusters of metabolites that popped up in the study shifted as well. The fact that many new clusters of altered metabolites showed up during the recovery phase in the ME/CFS patients suggested that both the exertion part of exercise and the all-important recovery phase were damaged – and in different ways. While the metabolite levels tended to be lower before and during the exercise period in ME/CFS patients, they were higher than normal in the recovery period.

It was encouraging to see that the kinds of metabolites that popped up in the big exercise/metabolomic study were as expected: many were involved in the regulation of metabolism, the immune system, and energy production.

This study is going to unpack much and should, one would hope, lead to even larger, more comprehensive studies that allow researchers to start teasing out which metabolites are being altered in which patients – thus providing a personalized approach to the metabolic problems found in ME/CFS.

This is the kind of big, complex study that the NIH typically funds and was part of Maureen Hanson’s NIH-funded ME/CFS Research Center grant. Hanson’s decision to use exercise stressors to dig into ME/CFS pathophysiology appears to have been a good one.

Two Symptoms to Rule Them All?

Two Symptoms Accurately Identify Post-Exertional Malaise in Myalgic Encephalomyelitis/ Chronic Fatigue – Todd Davenport, DPT, MPH – Workwell

ME/CFS breaks a lot of rules… It’s not just that physicians don’t know about ME/CFS – they don’t even know the right questions to ask. The questions they would need to ask to uncover ME/CFS’s signature symptom – PEM – didn’t come with their training.

Reduced functioning ME/CFS

Reduced functioning after exercise was one of the two symptoms that differentiated people with ME/CFS from healthy controls

Hence the need to develop something that our overworked doctors can easily “grok”. (Grok – to understand profoundly and intuitively.“)  Something that will stick in their minds. Something like a single question that could identify if someone was in a PEM-like state after exercise. Workwell knew that symptoms tend to increase dramatically after exercise in people with ME/CFS. The big question was which symptoms were able to accurately differentiate people with ME/CFS from healthy controls.

They used open-ended symptom questionnaires to assess symptoms up to a week after two-day CPET exercise tests, and then they used binary logistic regression to identify symptoms that best identified people with ME/CFS compared to sedentary controls.

Fatigue, not surprisingly, was first; then came cognitive dysfunction and brain fog, and others. They found that even a single report of one symptom a week after exercise was enough to identify someone with ME/CFS.

What they wanted, though, was simplicity. They wanted to find a few symptoms that differentiated people with ME/CFS from people without ME/CFS. In order to pull that feat off, the symptoms had to be overwhelmingly present in ME/CFS and mostly absent from the healthy controls. That restriction would clearly knock off a really common symptom like fatigue.

The findings were simplicity themselves – and very telling. Just two symptoms – reduced functioning and the lack of positive feelings/mood – correctly classified almost 90% of people with ME/CFS and 72% of the sedentary healthy controls.

Not only did they fit ME/CFS like a glove, but they demonstrated how very different exercise experience and its aftermath is for ME/CFS compared to the vast majority of diseases. Exercise almost always leaves people more functional and feeling better, but it did neither in ME/CFS and actually left them less functional. This finding should produce quite a “tell” for doctors used to prescribing exercise for their anxiety/depressed patients. If exercise has the opposite effect, they have an ME/CFS patient before them – not someone who’s depressed.

The next steps are validating the findings in a larger study; integrate step counts, assess ability to do activities of daily living, and integrate CPET findings.

Do the Lungs Have It?

Todd Davenport: Ventilatory Functioning During Serial Cardiopulmonary Exercise Testing in People With and Without Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

We know a bunch of things go wrong during exercise in ME/CFS. The anaerobic energy production system kicks in too early, lactic acid builds up, reduced glycolysis, problems, and problems with redox. We’re seeing evidence of impaired energy production at both the systemic and cellular levels, but we don’t know much about a crucial part of the energy production system – lung functioning.

Four belt-driven ventilation fans

Ventilation did not appear to be a problem in ME/CFS. Instead, Davenport pointed to the autonomic nervous system. (Image from Wikimedia Commons).

The lungs don’t just deliver oxygen to the tissues; they also play a crucial role in getting rid of the CO2 gases produced during exercise. CO2 certainly has its place in a well-functioning body, but if you can’t get rid of it when its levels are too high, then the body acidifies.

In this study, Davenport and the Workwell Foundation used their two-day maximal CPET test to assess both the energy production and ventilatory function on 75 ME/CFS patients and sedentary healthy controls.

The study validated once again the abnormal (and thus far) unique energy production findings in ME/CFS. Particularly during the second exercise test, VO2, workload, heart rate, respiratory rate, and amount of air moved were blunted enough compared to the healthy controls to be functionally disabling.

The one abnormal pulmonary finding – hypoventilation – could, by its inability to “breathe off” CO2 – exacerbate acidosis. Measures of lung functioning (tidal volume, end-tidal oxygen, end-tidal CO2), on the other hand, were normal. After finding no problems in lung functioning that could be causing problems with oxygen delivery, Davenport turned to a common theme. He proposed that a dysfunctional autonomic nervous system (ANS) that is simply not up to the demands that exercise places on it was the cause.

More overviews from the IACFS/ME 2021 Conference



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