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The GIST

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THE GIST

  • At least eight studies have told us that when people with ME/CFS engage in a 2-day exercise test that their ability to produce energy drops the second day. While this appears to be one of the most anomalous findings in all of medicine all we know is that it applies to people with ME/CFS, in general.
  • A Korean study asked if the same findings apply to people whose ME/CFS was triggered by a toxic exposure; i.e. would exercise one day produce the same drop in energy the next day?
  • The study found that the toxin-injured ME/CFS patients switched from using the highly efficient and cleaner mode of aerobic energy production to the much more inefficient and dirtier mode of anaerobic energy production more quickly than the norm. It also appeared that their tissues were experiencing a reduced delivery of oxygen – the key component of aerobic energy production.
  • The authors concluded that the results demonstrated “an underlying limitation in the exercise capacity to meet daily energy demands via aerobic energy production“. They also proposed that one of the chemicals in question that had damaged the mitochondria in smooth muscle cells, nerve tissues, and peripheral blood mononuclear cells was responsible for their reduced ability to exercise.
  • That seemed to set the stage for a similar finding in a 2-day exercise study of people with another toxin triggered illness – Gulf War illness (GWI) but it was not to be. The 2-day exercise test found no drops in energy production or early entry into anaerobic energy production on the second day of the exercise test.
  • Indeed, some earlier studies suggested that when it came to postexertional malaise, GWI might be very different from ME/CFS. One study found that about half GWI patients didn’t experience it. A more recent and comprehensive study found that while some people with GWI did experience increased symptoms after exercise, the group as a whole did not.  Despite the other similarities between ME/CFS and GWI, PEM does not appear to play a significant role in GWI.
  • Cooke has levied several critiques of the exercise studies in ME/CFS and has found that when he uses peak aerobic capacity as a starting point the findings indicating that energy production is disrupted in ME/CFS disappear. Instead, he believes that the problem in ME/CFS is reduced “aerobic fitness”.
  • He proposes several hypotheses how this has happened the most prominent of which is that metabolic problems at the cellular level are impairing oxygen flows to the muscles – causing strange breathing patterns during exercise – and impairing ME/CFS patients fitness.
  • While it may seem strange that two diseases, ME/CFS and GWI, that look so similar on the surface might be very different it should be noted that the ME/CFS community birthed the term postexertional malaise (PEM) because it was such a problem. PEM, however, has never figured in any of criteria for GWI.
  • It’s possible then that because the Korean study studies toxin triggered people with ME/CFS that it naturally included participants who had both PEM and an inability to exercise. Since GWI does not produce significant amounts of PEM it stands to reason that people with GWI might not get as slammed by exercise.
  • Small brain imaging GWI studies do suggest that exercise does have negative effects on the brains of GWI patients. The few joint GWI/ME/CFS studies done also indicate that while similarities exist differences do as well.
  • These recent studies suggest that something other than problems with metabolism or energy production is producing GWI.
Chronic fatigue syndrome (ME/CFS) exercise studies have generally disregarded the disease trigger. While some people can’t identify a trigger, infections, pregnancy, overwork, exposure to chemicals, serious illnesses, time spent in the ICU, etc., have all triggered ME/CFS-like conditions, but when it comes to exercise, we don’t know how important the initial trigger is. We know of cases, for instance, where exposures to toxins produced an ME/CFS-like condition, but we don’t know how similar or different they are to other kinds of ME/CFS.

A recent Korean study, “A 2-day cardiopulmonary exercise test in chronic fatigue syndrome patients who were exposed to humidifier disinfectants“, asked how people with toxin-induced ME/CFS fared when subjected to the most intense test of all: the 2-day cardiopulmonary exercise test (CPET).

tired woman on treadmill

A Korean 2-day exercise test of toxin-induced ME/CFS essentially replicated past ME/CFS 2-day exercise study results.

The 2-day CPET test has been around for a long time but was little used until Staci Stevens and the crew at Workwell found it showed that exercise one day somehow inhibited the ability of ME/CFS patients to produce the same amount of energy during exercise the following day. This was a seriously anomalous finding, as past studies had shown that even people with serious illnesses were able to replicate their energy production over two days.

Since then, at least 8 ME/CFS studies have found that intense exercise one day damages the ability of people with ME/CFS to produce the same amount of energy the next day.

The Korean Study

The Koreans with ME/CFS had been exposed to chemicals put into humidifiers to prevent microbial overgrowth. While some people came down with lung damage, others without lung damage came down with an ME/CFS-like condition.

Instead of the bicycle usually used, a treadmill was used in 29 Korean patients who met the Fukuda criteria for ME/CFS. (While the Fukuda criteria are not the best criteria, the ME/CFS field did successfully use it for decades.) There was no healthy control group. Instead, the results of the first day’s test were simply compared to the second day’s test. If the results dropped more than expected (a 7% variation in results is allowed), an abnormal result was found.

low battery

The Korean 2-day exercise study found that intense exercise one day reduced the capacity to produce energy the next day.

The Koreans with chemically induced ME/CFS showed classic signs that other ME/CFS groups had shown on this protocol. The study found a reduction of 16.4% in energy production at anaerobic threshold (VO2@VT) – similar to that found in other ME/CFS studies (~26%,~16%,~22%). Plus the researchers found that the time to reach the anaerobic threshold was significantly reduced in the second test.

That suggests that the ME/CFS patients switched from using the highly efficient and cleaner mode of aerobic energy production to the much more inefficient and dirtier mode of anaerobic energy production more quickly than the norm. Using anaerobic energy production to power our bodies quickly results in fatigue. Plus, a decrease in the peak O2 pulse of 4.9% suggested that reduced delivery of oxygen – the key component of aerobic energy production – to the tissues in ME/CFS also occurred.

The authors reported that the results demonstrated “an underlying limitation in the exercise capacity to meet daily energy demands via aerobic energy production“. When it comes to producing energy, toxins, it appears, can trigger the same breakdown in energy production in ME/CFS as can infections. The authors proposed that one of the chemicals in question (polyhexamethylene guanidine phosphate (PHMG-p) had damaged the mitochondria in smooth muscle cells, nerve tissues, and peripheral blood mononuclear cells.

So far so good…

The Gulf War Illness Studies

Because nobody was probably exposed to more toxins in a shorter period of time than people with Gulf War Illness, one might expect the same results to show up in that group.

No such luck, according to Dane Cook and comrades. Cook has been digging into exercise and Gulf War Illness for about five years and during that time, some unexpected findings have shown up. His 2020 study, “Post-Exertional Malaise in Veterans with Gulf War Illness“, found that about half the GWI patients experienced post-exertional malaise (PEM) after an exercise trial while the other half didn’t.

man running

Not only did Cook’s GWI studies find no reduction in energy production after exercise but no evidence of symptoms exacerbation in the group as a whole. (Image by Gerd Altman – Pixabay)

His 2021 study found an acute (one-time) exercise challenge did result in more muscle, fatigue and other symptoms and lower energy production in the GWI group, but those findings did not help explain who was to go on to experience post-exertional malaise. (One finding – which Cook did not use in that analysis – energy production at anaerobic threshold – did.)

Cook was a co-author of a third study led by Lindheimer, “An analysis of 2-day cardiopulmonary exercise testing to assess unexplained fatigue“, which did not find any significant drops in energy production or other CPET measures in the GWI patients from the first exercise test to the second (!).

Cook’s latest, more comprehensive post-exercise PEM GWI study also found no evidence that exercise impacted symptoms, pain sensitivity or cognitive performance; i.e. it did not produce PEM (!). The study reported that while some GWI patients did report increased symptoms (PEM) after exercise, the group as a whole (n=40) did not.

“Undesirable effects such as symptom exacerbation were observed for some participants, but the group-level risk of PEM following light-, moderate-, or vigorous-intensity exercise was no greater than seated rest. These findings challenge several prior views about PEM and lend support to a broader body of literature showing that the benefits of exercise outweigh the risks.”

The finding of that no PEM after exercise in GWI will surely trigger calls for graded exercise therapy, but a large cognitive behavioral therapy (CBT)/ exercise GWI clinical trial found that it produced only “modest” – and it was quite modest – help. Exercise is not going to return GWI patients to health.

My experience suggests that the Cook team could be right: exposure to toxins may produce chemical sensitivities and other problems, but they do not necessarily trigger PEM. In an effort to get rid of my chemical sensitivities, I participated in a sauna/exercise program at Dr. Rea’s Environmental Health Center in Dallas. I tried to engage fully in the exercise part of the program but had to quickly pull back. I was astonished to watch other chemically sensitive participants – many of them farmers and painters who had been injured by toxins – vigorously pedal away. They had no problems with exercise.

Kyle McNease’s story, on the other hand, demonstrates how exposure to toxins can produce an ME/CFS condition characterized by post-exertional malaise.

The Suffering of One – Relieved: Kyle McNease’s ME/CFS Recovery Story Detailed

Cook’s Critiques

Cook has been trying to insert what he believes is more statistical rigor in ME/CFS exercise studies – rather unsuccessfully – since 2006, when he asserted that the findings needed to be matched for aerobic fitness (peak VO2 levels). Once that is done, he’s found that many of the problems with energy production disappear. People with ME/CFS fail on these tests, he believes, because they are less aerobically fit -not because they have problems with energy production, per se.

Far be it for me, a layman, to get into the middle of this but while peak VO2 is considered a valid measure of both aerobic capacity and endurance in healthy people one wonders if it’s necessarily so for ME/CFS? I have been told that peak VO2 – which assesses the highest level of energy produced during an exercise test – is among the least important measures of the CPET test for people with ME/CFS and that a more significant measure is how quickly they enter into anaerobic energy production. I know of a person with severe ME/CFS who has a very high peak VO2, who is still severely disabled, but can apparently at least temporarily generate high amounts of energy but who also enters almost immediately into anaerobic energy production.

Metabolism

Cook proposed that metabolic problems involved with oxygen extraction may be present in ME/CFS.

The question also remains, even if Cook is right, why people with ME/CFS would be “less fit”. Is it because they’re not getting much exercise – and if that’s the case – why is that? What is preventing them from getting more exercise?

While Cook’s approach discards several of the most significant findings from other CPET studies, Cook isn’t going psychological on us. In his big, multisite CDC exercise study, Cook proposed that the “unique” breathing issues he detected (which he also found in GWI) may reflect difficulty extracting oxygen from the muscles. He proposes that metabolic issues at the cellular level, and/or problems with red blood cell deformability, and/or a learned strategy to reduce symptom exacerbation or PEM could be in play. (Regarding the last hypothesis, one would have to ask why exercise is causing symptom exacerbation.)

Interestingly, the most anomalous finding in Cook’s study was a large increase in the “rate of perceived exertion” (RPE) in the people with ME/CFS. RPE tracks how effortful exercise seems to be. Cook believed the increase in effort in the ME/CFS patients might be caused by more effortful breathing patterns that attempt to wrench more oxygen out of the muscles. It also, interestingly, appears to fit with the Intramural Study findings suggesting that the brain attempts to slam the brakes on exertion by making it more effortful.

The NIH on the ME/CFS Intramural Study -“Effort Preference”, Exhausted Immune Systems and the Crucial Male/Female Divide

In Lindheimer et Al., Cook and colleagues also questioned whether the drops seen in the 2-day exercise studies are “clinically significant” because they lack “established reference values for absolute or percent changes”. They used a statistical method called smallest real difference (SRD) that adjusts for “standard error of the measure”, or measurement error, which can arise from a multitude of factors. (If I have it right – I’m poor at statistics – that assesses the variability of the sample results?)

Using that approach, they reported that a peak VO2 drop from 17.4% from day 1 to 2 for one veteran would not be considered to be “clinically significant”, and the person would not be considered to have PEM. (The person would have had to have a drop of over 22% for the drop of over a fifth in energy production to be considered “clinically significant”). I may very well be missing something, but I don’t get it.

Disability metrics have been developed specifically for CPET results, and two-day CPET results are used to demonstrate clinically meaningful reductions in the ability to work in disability cases. That doesn’t seem to be in question.

Conclusion

Subsets

Not all fatigue, pain, sleep and cognition impairing diseases are the same.

The Korean and GWI study results seem contradictory. The Korean study seemed to extend the 2-day CPET findings to toxin-induced ME/CFS, while Cook’s study found no evidence of exercise-induced damage to energy production in people with an obvious toxin injury in Gulf War Illness.

This is despite the fact that, symptomatically, GWI looks exactly like ME/CFS. Note, though, that the criteria for ME/CFS and Gulf War Illness are different. The most accepted ME/CFS criteria require post-exertional malaise while the Kansas criteria for GWI – which was based on a survey of veterans – doesn’t mention it. (The Kansas Criteria mentions fatigue/ sleep problems, pain symptoms, neurologic/cognitive/mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.) While the two groups are symptomatically quite similar, GWI appears to lack the signature symptom found in ME/CFS – post-exertional malaise.

That suggests the Korean study may have found reductions in energy production in its toxin-triggered ME/CFS patients because it used an ME/CFS criteria (albeit not a great one :)).

While the research focused on both diseases is limited, it does bear out the differences between the two. When Nancy Klimas looked under the hood of GWI and ME/CFS patients, she found both differences and similarities. Baraniuk has consistently found different brain signatures in the two diseases. Comparing the effect of exercise on ME/CFS and GWI patients, Baraniuk found opposite patterns of midbrain activation in them.

Exercise has been much less studied in GWI than in ME/CFS, where studies abound showing the negative effects of exercise. Small studies have, however, consistently found exercise is having an impact on people with GWI.

Baraniuk found that exercise triggered two different reactions – an autonomic reaction that was associated with brainstem atrophy in one group – and one associated with increased pain sensitivity and basal ganglia changes in another. Similarly, exercise improved working memory in one GWI group but impaired it in another. He also found altered cortical activity after exercise and deactivation of the default mode network after exercise in GWI, and exercise-induced postural orthostatic tachycardia syndrome (POTS) in a subset of people with GWI.

Cook’s study suggests that the post-exertional malaise symptom is crucial part of ME/CFS but not of GWI. In a way, that’s a not a surprise – the post-exertional malaise term was, was after all, birthed by the ME/CFS community because it was an obvious manifestation of the disease that was not being taken into account. Problems with “fitness”, metabolism, aerobic energy production – whatever term you want to use – all follow on from that.

Cook’s findings suggest that problems with metabolism or energy production are not present in GWI which lacks PEM; in other words, there’s more than one way to produce a disease with symptoms like fatigue, pain, gut, sleep and cognitive issues.

 

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