Cardiopulmonary, metabolic, and perceptual responses during exercise in ... (ME/CFS): A Multi-site Clinical Assessment, 2022, Cook et al

Andy

Andy

Retired committee member
Full title: Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-study.

Abstract
Background
Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear.

Purpose
To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness.

Methods
As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent (
file
,
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), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges’ g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20–100% peak
file
). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak
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(~1 ml/kg/min-1).

Results
Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20–100% peak
file
) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for
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,
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and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency,
file
,
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, and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g.,
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) were generally reflective of those seen throughout exercise (i.e., 20–100%).

Conclusion
Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.

Open access, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0265315
 
This is an important study because it shows that healthy people exist that move as little as ME/CFS patients, but that these people do not have the same abnormal results on cardiopulmonary exercise testing.

With "inefficient exercise ventilation" they mean a problem that they interpret as likely being poor oxygen utilization by muscles due to a metabolic problem.
 
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Looks like this is the data presented by Cook during a CDC call last year, discussed here: https://www.s4me.info/threads/dane-cooks-analysis-of-exercise-data-of-the-cdcs-mcam-study.22191/

I think it is rather interesting.

In the past exercise studies of ME/CFS reported lower VO2Max, an inability to reach maximal heart rate etc. Cook et al. also found this in their sample, but when they matched patients and controls for fitness, these differences disappeared. The authors write:
Importantly, when we performed more rigorous matching for fitness (and age), many of the group differences were eliminated including V_ E, HR and indices of oxygen delivery such as the O2 pulse, OUES, V_ O2=WR. These results extend upon Cook et al. [56] and indicate that many of the cardiopulmonary differences that have been reported in previous studies are explained by differences in aerobic fitness, and consequently exercise time, and are not pathophysiologic characteristics of ME/CFS.
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There were however some small to moderate differences that remained after matching for fitness. I'm not expert at what these measures mean but here's how the authors describe and discuss them:
Although oxygen appears able to effectively reach the periphery and be utilized, our results suggest that individuals with ME/CFS do so in an inefficient manner. These gas-exchange inefficiencies are reflected on CPET primarily by increased V_ E=V_ CO2nadir and V_ E=V_ O2 at peak exercise. The elevated V_ E=V_ CO2 nadir reflects mismatch between ventilation and perfusion to active skeletal muscle; the peak V_ E=V_ O2 data suggest a higher ventilatory cost of oxygen uptake perhaps due to poor extraction from skeletal muscle. Inefficient exercise ventilation is, however, non-specific and may reflect pulmonary, cardiac, and/or metabolic mechanisms. We do not believe there is evidence to support a pulmonary or HR mechanism (discussed below) but hypothesize these inefficiencies may be attributable to metabolic features of ME/CFS
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Grigor said:
It's a really interesting study, but my question is what happens on the second day? Pity this was just a single CPET.
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Yes.

The key result of this study is simply the higher tidal volumes were identified for ME/CFS. This combined with the increased effort perception could be explained by ongoing stimulation of type III/IV muscle afferents which sense inefficient metabolism and provide not only the sensations we assoicate with fatigue, but also suppress the excitability of the motor cortex (a supraspinal form of central fatigue) - the purpose of this central fatigue is normally to increase the level of ventilation for a given force output.
 
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A well-done study
In a nutshell: This large, well-done study cleared much of the smoke around what we can learn from a single maximal exercise test. It showed that many previous 'findings' disappeared when researchers only compared patients and controls with similar fitness levels. The effects that remained are rather small and probably do not help explain what is going wrong in ME/CFS.​

This is an unusually large and well-done study. It has a total of 363 participants. Crucially, it has a fitness matched group of 99 patients and 99 controls. Although it's possible to make statistical adjustments for fitness levels, the most reliable way to get data is to match groups (as the authors point out) carefully.

The study also statistically adjusts for the large number of comparisons made. So the results look particularly reliable.

The importance of fitness matching

Many differences in the main group comparison were not seen in the fitness match group, which shows how important it is to match patients and controls on fitness levels. I don’t know if the 2-day CPET studies do

Only modest differences and these may not be specific to ME/CFS

The study found physiological differences: lower breathing frequency, higher ventilatory equivalent (VE/VO2 & VCO2), and higher tidal volumes (volume of air breathed per minute). These differences were modest: the effect size was typically 0.3-0.4. A standard threshold for a "clinically meaningful difference" is an effect size of 0.5, and only tidal volume per minute (0.48) gets close.

The authors were unable to recruit a sufficiently large disease control group, so they are unable to say if these differences are specific to ME/CFS. They could be an effect of chronic illness.

Hard to see this explaining what causes ME/CFS

Aside from not being shown to be specific for ME/CFS, the effect size is relatively small. The disease has a massive impact on our lives — how can such small differences explain what's going wrong at a fundamental level?
Also, almost everybody has huge problems with mental fatigue as well as physical fatigue.

Surely it’s more likely that there is a single mechanism that accounts for both. I don’t think maximal exercise testing says anything about mental energy problems
strategist said:
This is an important study because it shows that healthy people exist that move as little as ME/CFS patients, but that these people do not have the same abnormal results on cardiopulmonary exercise testing.
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You would think so, but it's not the case.

Subjects are matched on fitness, defined as peak oxygen consumption per kilogram of body mass per minute. The study also measured self-reported physical activity, and here there is an enormous difference between patients and controls in the matched fitness group. Effect sizes = 2.58 (which is hardly surprising). Weirdly, matched on fitness does not mean matched on daily activity.

Based on the information presented here, someone in the control group could manage multiple flights of steps, walk extensively and run a modest amount. By contrast, the average patient would have limited ability to climb stairs and walk and couldn't even run to catch a bus (though this puts them well ahead of typical ME/CFS patients).

When researchers finally identify a cause of ME/CFS, I suspect it will have a large effect size, albeit only for a subgroup. The authors present no information here about a subgroup with a large effect.

ADDED Ruling out lactate changes and "chronotropic incompetence".

A few years ago, several studies claimed PwME had chronotropic incompetence - the heart wasn't able to pump blood fast enough to keep up with demands. While the overall study found the same thing, the effect disappeared in the fitness-matched group. So the effect was driven by lower levels of fitness, not ME/CFS itself.

Earlier small single CPET studies had given a mixed picture about whether or not PwME had higher level of lactate in a single CPET. This would be a sign that the body was falling back on anaerobic respiration, which could have been due to mitochondria not working properly (amongst other things). This large study found patients did not have higher lactate levels.

Finally, it was a bit worrying to see the researchers commenting that there should be work to see if maximal exercise tests can guide exercise prescription to help people manage ME/CFS (not treat it). I don't think it's responsible to suggest a maximal exercise test as a tool for routine patients. It risks causing immense harm. (Note: I’m not aware that any CPET studies have monitored any long-term harms caused by their protocol.)
 
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Reviewer 1 said:
Lines 453-468: Again, this is just mere speculation. Similar to my previous comment, would not you expect a difference in ventilation in the groups matched by fitness level if muscle fatigue in the ME/CFS group was an issue?
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I'd like to reply to this, though anonymous Reviewer #1 is unlikely to read this.

Ongoing fatigue due to metabolic inefficiencies would feed back into increased ventilation (tidal volume, driven by increased afferent feedback leading to central fatigue as described in my previous comment) versus workrate at below-peak values but not at VO2Max. Since the limiting factor of VO2Max is always delivery of oxygen, rather than uptake as there is still excess unused motor units and hence unused mitochondrial capacity. This is consistent with the data observed.
 
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Simon M said:
Only modest differences and these may not be specific to ME/CFS

The study found physiological differences: lower breathing frequency, higher ventilatory equivalent (VE/VO2 & VCO2), and higher tidal volumes (volume of air breathed per minute). These differences were modest: the effect size was typically 0.3-0.4. A standard threshold for a "clinically meaningful difference" is an effect size of 0.5, and only tidal volume per minute (0.48) gets close.

The authors were unable to recruit a sufficiently large disease control group, so they are unable to say if these differences are specific to ME/CFS. They could be an effect of chronic illness.

Hard to see this explaining what causes ME/CFS

Aside from not being shown to be specific for ME/CFS, the effect size is relatively small. The disease has a massive impact on our lives — how can such small differences explain what's going wrong at a fundamental level?
Also, almost everybody has huge problems with mental fatigue as well as physical fatigue.

Surely it’s more likely that there is a single mechanism that accounts for both. I don’t think maximal exercise testing says anything about mental energy problems
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Thanks for the summary, Simon. Always good to see well designed studies even if they don’t give us the answers we are seeking.

I’ve not followed the CPET research very closely, but are these results not pretty much what me might have expected from previous studies? My limited understanding is that single CPETs haven’t usually found anything very unusual in ME/CFS patients and that the more significant results have come from 2 day CPET studies and iCPETs.
 
I have found I can do something strenuous (for me!) for a minute or so without payback but small things repeated without rest cause damage. I worked myself to immobility by 10 minutes of fiddling with the control on a pair of headphones, not able to talk or respond in any way for a good while.

A single exercise test where we have to work hard may not get any result but it would be interesting to have the result of walking on a treadmill at a rate just a bit higher than the patient's manageable speed for a longer time.

Sadly, anything that showed a bad effect in someone with ME risks causing lasting harm. Many patients took months to recover from CPET testing, some even longer, if at all.
 
I haven't read the study yet, but I'm not so sure that it was well designed.

When I did two CPETS, 48 hours apart for a trial, I appeared fairly fit on the first day and definitely not fit on the second. I think fitness was probably defined as it is here - peak oxygen consumption per kilogram of body mass per minute.

Therefore, if I had been in this study and you were choosing a control to match me in this trial, how would you know what level of fitness of the control was appropriate?

It looks like the study has produced some useful findings, but, from reading the abstract, it looks as though the researchers believe that aerobic fitness, using the measure they used, does not change from day to day in ME/CFS.

Rather than referring to 'aerobic fitness', I think they should have said what it was - peak oxygen consumption per kg of body mass per minute.

Sorry if I have misunderstood. Hopefully I can get to reading the paper a bit later.
 
Hutan said:
It looks like the study has produced some useful findings, but, from reading the abstract, it looks as though the researchers believe that aerobic fitness, using the measure they used, does not change from day to day in ME/CFS.

Rather than referring to 'aerobic fitness', I think they should have said what it was - peak oxygen consumption per kg of body mass per minute.
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This is a problem, I speculate that those conducting single rather than two day CPET studies don't actually understand what the 2 day CPETs actually indicate.

I too went from above average (VO2Peak) to below average between the two days (~24 hours). I don't think many of these researchers really understand what the limiting factors are- how hard it is for people with ME to reach a true VO2Max due to fatigue (and in turn extremely high effort during the test compared to a healthy individual.
 
Milo said:
But that is just me.
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You're wrong on that one. It's not just you. :)

I rarely read Cort's blogs either but I like to keep track of what topics he's writing about because he has a dedicated following here and it's good to have some sense of what pwME outside S4ME are thinking about the science (which, for many, is more or less what Cort thinks).

Back on topic, in this particular case I can't comment on the blog, having only skimmed it, but the link to the video by Dane Cook proved useful. It's a good introduction to the study and makes it easier to understand the paper.
 
Coming back to this study it seems to have two main findings when looking at the fitness-matched comparison.

1) ME/CFS patients had the same ventilation (VE) as controls but there was a difference in how they achieved this: patients had a lower breathing frequency (fewer breaths per minute) but took in more air with each breath (higher tidal volume).

2) The ventilation per volume O2 (VE/VO2) and CO2 (VE/VCO2) transported was higher in patients than controls meaning that a greater amount of breathing was required to consume a certain amount of oxygen or to expel a certain amount of carbon dioxide. This could be due to lung or heart problems but because these are absent in ME/CFS, the authors suspected it points to poor extraction from skeletal muscle.

Unfortunately both results were not replicated in the more recent study by Keller et al. that also matched controls for fitness.
Cardiopulmonary and metabolic responses during a 2-day CPET in [ME/CFS]: translating reduced oxygen consumption [...], Keller et al, 2024 | Science for ME (s4me.info)
 
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