Cardiopulmonary and metabolic responses during a 2-day CPET in [ME/CFS]: translating reduced oxygen consumption [...], Keller et al, 2024

Nightsong

Nightsong

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Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations

Abstract
Background
Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking.

Methods
Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case–control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed.

Results
Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, V ̇ e, V̇ O2, V ̇ CO2, V ̇ T, HR, O2pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for V ̇e/V ̇CO2, PetCO2, O2pulse, work, V ̇O2 and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1.

Conclusions
Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered.

Keller et al. in Journal of Translational Medicine (open access) | Link | PDF
 
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Well that paper was a game of two halves. I wished they'd stopped at the limitations section instead of wildly speculating on autonomic dysregulation and treatments thereof. Did I miss it or was there no consideration of peripheral oxygen extraction (per Systrom) and only impaired cardiac output?
 
Yann04 said:
@forestglip tested with sedentary controls. Could add to your me-pedia page.
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Nice! Added.

This looks like a pretty good comparison if their claim is true that performance on CPET-1 is a good indicator of activity level. See Figure 5B below for an impressive looking result.

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"Figures 5A–C illustrate the similarity between phenotypes in impairment status at baseline (CPET-1) for all three indices of impairment. Based on VO2peak, 62% of CTL and 52% of ME/CFS had none to mild impairment, suggesting that the CTL in this study were indeed, sedentary and low active, and similar in functional capacity to ME/CFS at baseline. While no participants for either phenotype met the severe impairment category, 14% of ME/CFS met moderate to severe impairment compared to only 4% of CTL. Based on VO2@VAT, phenotype differences were more striking. Most CTL (42%) identified as mild to moderate impairment whereas the majority of ME/CFS (52%) were in the moderate to severe category. Additionally, 14% of ME/CFS classified as severe impairment compared to only 4% of CTL. Lastly, using VE/VCO2@VAT impairment standards, 80% of CTL and 66% of ME/CFS fell into none to mild impairment. The remaining 20% of CTL compared to 29% of ME/CFS showed mild to moderate impairment with 5% of ME/CFS rated as moderate to severe. Overall, baseline data from CPET-1 suggests that ME/CFS and CTL were comparable regarding impairment status based on VO2peak and VE/VCO2@VAT, but less so for VO2@VAT where a greater severity of impairment in ME/CFS was apparent.

Post-exertional data (CPET-2) reveals a shift toward increasingly severe impairment in ME/CFS compared to CTL for all three indices. Using VO2peak, 56% of ME/CFS were impaired ranging in severity from mild to severe (including mild to moderate, moderate to severe, and severe) compared to 48% from CPET-1. In contrast, there was little appreciable shift in impairment status in CTL from CPET-1 to CPET-2. Notably, marked shifts in impairment status of ME/CFS were most evident based on VO2@VAT, with 95% of cases ranging from mild to severe compared to 87% based on CPET-1. Importantly, the percentage of ME/CFS rated as severe from CPET-2 (27%) was doubled compared to severe cases based on CPET-1 (14%), illustrating the deleterious impact on the gas exchange threshold (VAT) due to exertion intolerance in ME/CFS. In contrast, only a slight increase was observed in CTL in moderate to severe plus severe impairment cases from CPET-1 (34%) to CPET-2 (38%). Finally, impairment based on VE/VCO2@VAT revealed a similar trend of worsening impairment status for ME/CFS with an overall increase in mild to severe cases on CPET-2 and only a slight increase in impairment severity for CTL.

Figures 5D–F for the matched-pairs show impairment ratings based on VO2peak, VO2@VAT and VE/VCO2@VAT. Similar trends discussed above for the total sample were evident for ME/CFS compared to CTL from CPET-1 to CPET-2. Because pairs were matched on VO2peak, not surprisingly, impairment status for both phenotypes based on CPET-1 were remarkably similar. Still, however, impairment ratings based on CPET-2 reveal an increase in impairment severity of ME/CFS ranging from mild to severe (including mild to moderate, moderate to severe, and severe) compared to little change in CTL. Shifts in impairment ratings based on VO2@VAT and VE/VCO2@VAT from CPET-2 in the matched-pairs were consistent with those discussed above for the total sample suggesting that matching participants based on VO2peak had little impact on the post-exertional (CPET-2) decline in energy metabolism in ME/CFS."
 
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This feels kind of weird to me:

"ME/CFS participants who met maximum effort criteria during test 1 but did not meet criteria during test 2 due to failure to achieve heart rate and/or RER criteria were not excluded from analysis. ME/CFS who did not meet heart rate or RER criteria during test 2 but did meet RPE criteria (perception of maximum effort) are emblematic of post-exertion symptom exacerbation that contributes to exertion intolerance. For example, chronotropic incompetence and/or other symptoms of dysautonomia that emerge following exertion (CPET-1) may preclude the ability to satisfy the heart rate or RER criteria during test 2."
 
forestglip said:
This feels kind of weird to me:

"ME/CFS participants who met maximum effort criteria during test 1 but did not meet criteria during test 2 due to failure to achieve heart rate and/or RER criteria were not excluded from analysis.
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I agree, if data from such people were used to calculate mean VO2max. If they did that, and didn't also do a calculation excluding those people, we can't know if the reduced VO2max was because some ME/CFS people just gave up too early. It wouldn't affect the VO2 at VAT (anaerobic threshold) though, and that seems to be the point where the biggest differences were seen.
 
Interesting study. Unfortunate that it was not published in a more prominent journal. The results and discussion sections are also quite extensive, making it is hard to find the main data.

What I would like to see is a group comparison between the 55 ME/CFS patients and their matched controls for the difference between CPET1 and CPET2. For example, the mean difference for Workload at the AT (the most consistent finding in previous studies) decreased by 7.9% in the ME/CFS group compared to 4.8% in the control group. I wonder if this difference was significant (my guess it is not).

What is already clear is that, although there is an increase in various measures in the ME/CFS group, the effect size are not that big. I filled in the differences for the total sample of 84 in the MEpedia overview and the percentage decrease are much lower than some of the figures reported previously.
upload_2024-7-7_12-23-2.png

Graphs like these also indicate that the overlap is large and the differences between CPET1 and CPET2 rather small. But it would more interesting to see a graph of the percentage change for all participants.
upload_2024-7-7_12-27-24.png
 
Todd Davenport wrote on Twitter:
Now, this whole “fitness matching” trend seems like a super-good idea but it’s basically nonsense. We know all CPET measurements are highly collinear with sex and VO2peak, so it’s not a surprise that whole group differences reduce when participant pairs are matched based on them.

This paper did a more careful job of matching than the Cook paper of a couple years ago, so the effect of matching was not nearly as extreme. The whole practice is a big statistical no-no. Hope the trend dies with this paper. I won’t do or recommend it.
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I have no idea what he means by this. If many CPET measurements are collinear with sex and VO2peak, than this simply means that these difference in the measurements could be due to sex or deconditioning rather than ME/CFS. So it would mean that it is important to control for these!
 
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ME/CFS Skeptic said:
I have no idea what he means by this. If many CPET measurements are collinear with sex and VO2peak, than this simply means that these difference in these measurements could be due to sex or deconditioning rather than ME/CFS. So it would mean that it is important to control for these!
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I'm not sure I understand either. He quotes a previous tweet of his about the Cook CPET study:

https://twitter.com/user/status/1619606887200325632


...

2. “Fitness matching” based on VO2 compares lowest performing controls and highest performing patients

3. “Fitness matched” ME/CFS group still significantly less active than control group
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...

2. “Fitness matching” introduces more problems than it solves through biasing the analysis

3. Comparing patients with ME/CFS with sedentary people is practical and relevant
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All the “fitness matched” analysis showed was their cherry-picked highest performing patients looked similar to their cherry-picked lowest performing control subjects on a single test. This finding isn’t new to me. What happened on the next day? We won’t know from this dataset.
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But to say, in essence, “there’s nothing to see here after fitness matching,” is understating the shortcomings of this new style of analysis, overstating what can be said based on the available data, and disregards function, which at the end of the day, should be what it’s about.
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One concern I have, is maybe some of these people have undiagnosed or very mild ME/CFS, being the cause of their deconditioning/sedentary-ness, which would make the comparison less useful. A problem with using strict criteria for ME (CCC in this study) is you might get some people with ME in the control group, I think. Maybe they should make sure the control group doesn't fulfill less strict definitions either, like IOM.

ME/CFS Skeptic said:
Unfortunately, I can't seem to find the data at the mapMECFS repository: has anyone else found it?
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Me either, doesn't seem to be uploaded yet.
 
forestglip said:
One concern I have, is maybe some of these people have undiagnosed or very mild ME/CFS, being the cause of their deconditioning/sedentary-ness, which would make the comparison less useful. A problem with using strict criteria for ME (CCC in this study) is you might get some people with ME in the control group, I think. Maybe they should make sure the control group doesn't fulfill less strict definitions either, like IOM.
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That doesn't sound very reasonable to me. It's a sedentary control group that has passed different screening phases (see also https://clinicaltrials.gov/study/NCT04026425). I'd be a pretty sure none of those people have ME unless we want to degrade ME to some bengin syndrome. If anything the intramural study has shown that it's relatively hard to actually recruit pwME, rather than the opposite.

I also haven't found it in the mapMECFS data nor do I understand Todd tweets. Maybe someone should ask him again? I'm getting the feeling that the main problem he sees is that it's a single test not telling us what happens after that.
 
EndME said:
Maybe someone should ask him again? I'm getting the feeling that the main problem he sees is that it's a single test not telling us what happens after that.
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I've asked him the following:

https://twitter.com/user/status/1809927601172992229


Could you explain why you think fitness matching is not a good idea? If many CPET measurements are collinear with VO2peak, doesn't this suggest that differences could be due to deconditioning rather than ME/CFS?

I would think that fitness matching makes comparisons more interesting because it is less likely that the differences found are due to deconditioning and more likely that they reflect ME/CFS pathology.

Conversely, abnormalities in ME/CFS patients that are also seen (same size and effect) in healthy but deconditioned controls might be less interesting because they are less likely to represent ME/CFS pathology.

So it seems really important to control for fitness level. Matching patients and controls might not be the best approach for this because it might lead to discarding the most interesting (and abnormal) ME/CFS cases for which there was no match. (Perhaps this is what you meant?)

Perhaps a better approach would be to use all data and simply control for VO2, sex and age using a regression model? Would be interested in hearing your views on this.
 
EndME said:
That doesn't sound very reasonable to me. It's a sedentary control group that has passed different screening phases (see also https://clinicaltrials.gov/study/NCT04026425). I'd be a pretty sure none of those people have ME unless we want to degrade ME to some bengin syndrome. If anything the intramural study has shown that it's relatively hard to actually recruit pwME, rather than the opposite.
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Where does that page talk about the screening phases?

In the study itself, concerning ME status in recruitment, I just see this: "endorsement of ME/CFS symptoms and compliance with Canadian Consensus Criteria"

As I understand it, CCC is strict so that false positives are minimized in research active groups, at the expense of false negatives (who theoretically might end up in the control group).

We all know how hard the delayed effects of PEM can be to notice in oneself for someone when they're mild or very delayed, and don't have a lot of experience with the condition. Would you be okay with people in the control group having PEM and no other symptoms of ME?

degrade ME to some bengin syndrome.
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Some people have severe ME, some have mild, some have very mild, probably all the way to barely noticeable. Doesn't mean they don't have the same underlying mechanisms (to a lesser degree).
 
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forestglip said:
Where does that page talk about the screening phases?
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Screening phases are talked about in the actual study. For instance
Screening of potential participants who responded to our advertisements involved two phases beginning with a screening phone call, and if deemed eligible, an invita- tion to schedule for the second phase medical screen- ing by either John Chia, MD (LA), Susan Levine, MD (NYC), or Geoff Moore, MD (upstate NY).
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forestglip said:
In the study itself, concerning ME status in recruitment, I just see this: "endorsement of ME/CFS symptoms and compliance with Canadian Consensus Criteria"

As I understand it, CCC is strict so that false positives are minimized in research active groups, at the expense of false negatives (who theoretically might end up in the control group).

We all know how hard the delayed effects of PEM can be to notice in oneself for someone when they're mild or very delayed, and don't have a lot of experience with the condition. Would you be okay with people in the control group having PEM and no other symptoms of ME?

Some people have severe ME, some have mild, some have very mild, probably all the way to barely noticeable. Doesn't mean they don't have the same underlying mechanisms (to a lesser degree).
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I'm not sure I understand your point on false positives and the use of the CCC in the ME group. Application of different criteria for the ME group should have no influence on your controls as false negatives don't end up in your control group afaik, the controls are not recruited by not fulfilling certain ME criteria since they are healthy and there is absolutely no evidence to suggest they have ME/CFS.

It simply doesn't seem reasonable to me, there's thousands of far more likely reasons why someone would be sedentary rather than being perfectly healthy but yet still somehow having ME/CFS. If a cancer or rheumatic arthritis study is conducted and there is little difference between healthy controls and the illness group, I don't think anybody thinks that would be an effect of everyone in the control group having cancer or rheumatic arthritis rather than the lack of differences being that one didn't observe a key pathology. The incidence of ME/CFS is simply not that high in the general population, especially not in the general population that considers itself to be healthy.

I'd probably be far more worried about false positives even with the CCC, similar to what was seen in the intramural study, but the authors seem to have taken as much care as they can within the study setting.

Maybe it could indeed still be very sensible to have an additional screening round of healthy controls where those that fulfill the weakest criteria, such as Fukuda, are automatically excluded, but I don't think theres much evidence to suggest that something like that would be driving the results, or lack thereof, in this study. But maybe this is indeed a valuable idea, but I wouldn't be surprised if clinicans are already automatically ruling out such participants in the screening phase.

forestglip said:
Would you be okay with people in the control group having PEM and no other symptoms of ME?
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Certainly not. However, I don't think there is any evidence to suggest that they would have PEM. In my opinion someone that is a healthy control but experiences PEM is unlikely to participate in a study that purposefully puts them into PEM, especially if they are anyways sedentary, i.e. prefer to be less physically active. The reason why pwME participate in such studies is because they want to help advance ME/CFS research and as such endure the PEM, I don't think a healthy control would have a similar motivation.
 
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Hutan said:
I agree, if data from such people were used to calculate mean VO2max. If they did that, and didn't also do a calculation excluding those people, we can't know if the reduced VO2max was because some ME/CFS people just gave up too early. It wouldn't affect the VO2 at VAT (anaerobic threshold) though, and that seems to be the point where the biggest differences were seen.
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This seems like an important point. I think they should have done a sensitivity analysis and report in the discussion how the data looks like if they maintained the same requirements (might have overlooked this but couldn't find it in the paper). Hopefully we will get access to the data so that we can try to do the analysis ourselves.

Focusing on the matched ME/CFS patients and controls, it does seem like the biggest differences between CPET1 and CPET 2 were found at VO2 peak rather than VAT (I tried to make an overview below).
upload_2024-7-7_15-6-23.png
 
I have to agree with ME/CFS Skeptic here that I think the risk of having false positives with a looser ME criteria is far higher (and likelier to mess with results), than having people with PEM in the control group.

And for the control group, I doubt any would fit the IOM, as it requires a 50% reduction in functioning. I don’t think people would be recruited as “healthy” controls if they had 50% reduction.
 
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