Cardiopulmonary Exercise Test Results Do Not Change Over Two Sequential Days in Patients with Chronic Fatigue Syndrome, 2026, Mancini, Natelson et al

[richie]

I did a VO2 max test recently, and to my suprise my VO2/kg was 'excellent', and my heart rate was 'normal'. So, I was congratulated for being very 'fit'.

It is very confusing to me, because I feel far from 'fit'. When I go for a walk and start too fast, I get out of breath and feel unwell (faint, and I need to stop until I have enough oxygen again to continue walking). When I cycle uphill, the same story applies. I can walk and cycle if I go slowly, but start to feel unwell if I have to 'push' myself.

How is this possible given the good VO2 max results? The healthcare provider seemed at a loss...

Any ideas?

Maybe cytokines

 

[richie]

I wonder how that Dutch work on muscles in long covid fits in and also what was Workwell finding? Subgroups? PEM as heterogenous phenomenon? My old GP used to say "The latest thinking is" He was of course routinely disproved which was exactly his point....

 

[ME/CFS Science Blog]

Waiting to see the paper before I make any judgements as two of the authors (Natelson and Mancini) were co-authors on this CPET paper that used Fukuda to identify ME participants.

Older 2-day CPET studies such as the one by Davenport also used the Fukuda criteria so that alone likely wouldn't explain the results.

what level of severity of ME patients,

Severe ME/CFS patients can't do these test so highly likely that these were mild-moderate patients just like in previous 2-day CPET studies.

what did they use for controls

The idea was that only ME/CFS patients are unique in failing to replicate their CPET results, in contrast to healthy or deconditioned or patients with other medical conditions such as MS, lung- or heart disease. So not sure how the selection of controls would explain these results.

how did they determine sufficient effort,

If there was a methodological error that caused the lack of difference and contrasts with previous studies, think it would be something like this (patients not going deep enough on the test), or something like a high drop-out rate.

Also note that even if there is a true effect, if you do multiple underpowered studies to test it, some will have non-significant results so this isn't necessarily a big problem. Would be interesting to see what direction the effect was, regardless of the evaluation of statistical significance.

 

[Medfeb]

@ME/CFS Science Blog - My point was just that there can be any number of things that could explain differential results. I'm waiting to see the paper.

 

[duncan]

Differences in VO2Peak or VO2 at VT has not replicated in previous studies so I don't know why they're wasting their time claiming they found no results when they didn't bother to measure the one thing that was different across previous studies.

Natelson?

 

[BrokenBeaktheBrave]

Natelson?

Natelson.

 

[Turtle]

Natelson.

Would there be more researchers that don't want to find anything wrong with ME/CFS or LC?

 

[richie]

Non specific symptoms, subjective reporting of PEM, no set definition, some divergence in description, other conditions esp sarcoidosis reporting "colloquial" PEM and no evidence in Sarkies ever of 2 day CPET, worsening, few people raising questions such as "does it start when ME starts" or "does it fade in those who subsequently recover?", "does it vary over time?" etc. No surprise in conflicting findings. More work to be done.

 

[Mij]

I got mixed up. thanks for the correction. I will delete it.

 

[BrokenBeaktheBrave]

 

[forestglip]

Now published. Only minor syntax and formatting changes in abstract since first posted.

Cardiopulmonary exercise test results do not change over two sequential days in patients with chronic fatigue syndrome

Spoiler: Authors

Mancini, Donna M.; Cook, Dane B.; Brunjes, Danielle L.; Soto, Tiffany; Blate, Michelle; Quan, Patrick; Yamazaki, Tadahiro; Norweg, Anna; Natelson, Benjamin H.

Background
Two consecutive cardiopulmonary exercise tests (CPETs) performed 24 hours apart are increasingly used to determine post-exertional malaise (PEM) and disability in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Declines in functional capacity on Day 2 reflect impaired recovery and PEM. However, reports have variably described a reduction in peak oxygen consumption (VO2 ) and/or VO2 at the anaerobic ventilatory threshold (VT).

Given the inconsistent findings, we sought to replicate the studies by performing sequential 2-day CPETs in ME/CFS and age- and sex-matched sedentary controls.

Methods
Accordingly, maximal bicycle ergometer CPETs were performed on two consecutive days in 58 patients with ME/CFS (mean age 38.6 ± 9.6 years, Body Mass Index (BMI) 24.1 ± 3.3 kg/m 2 , 11 men and 47 women) and 25 age-matched sedentary control (CON) subjects (age 38.2 ± 9.9 years, BMI 24.2 ± 3.4 kg/m 2 , 5 men and 20 women). Peak VO2 was reported as the highest 30-sec average; VT was selected as the nadir of the VE/VO2 and PETCO2 curves, and VE/VCO2 as the slope throughout exercise.

Findings
For ME/CFS and CON subjects, there were no significant changes in Peak VO 2 between Day 1 and Day 2 studies (ME/CFS Day 1, 22.3 ± 5.4; Day 2, 22.5 ± 5.4 mL·kg −1 ·min −1 ; CON Day 1, 23.4 ± 3.5; Day 2, 22.8 ± 3.6 mL·kg −1 ·min −1 ; NS).

Similarly, VO2VT and VE/VCO2 slopes were not significantly different between the ME/CFS patients and CON, and on Day 2, they did not show any differences within or between groups.

Peak heart rate was significantly higher in CON versus ME/CFS. The level of perceived exertion was significantly greater at all levels of exercise on the Day 1 and Day 2 tests for ME/CFS patients versus CON.

Interpretation
Our data indicate that 2-day CPET provides exercise-related results that are the same in ME/CFS patients and CON subjects. ME/CFS patients have a greater perception of exertion throughout exercise and a lower maximum heart rate than CON. The data do not support using the 2-day CPET protocol to define PEM or disability.

Web | DOI | PDF | Frontiers in Physiology | Open Access

 

[richie]

Now published. Only minor syntax and formatting changes in abstract since first posted.

Cardiopulmonary exercise test results do not change over two sequential days in patients with chronic fatigue syndrome

Spoiler: Authors

Mancini, Donna M.; Cook, Dane B.; Brunjes, Danielle L.; Soto, Tiffany; Blate, Michelle; Quan, Patrick; Yamazaki, Tadahiro; Norweg, Anna; Natelson, Benjamin H.

Background
Two consecutive cardiopulmonary exercise tests (CPETs) performed 24 hours apart are increasingly used to determine post-exertional malaise (PEM) and disability in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Declines in functional capacity on Day 2 reflect impaired recovery and PEM. However, reports have variably described a reduction in peak oxygen consumption (VO2 ) and/or VO2 at the anaerobic ventilatory threshold (VT).

Given the inconsistent findings, we sought to replicate the studies by performing sequential 2-day CPETs in ME/CFS and age- and sex-matched sedentary controls.

Methods
Accordingly, maximal bicycle ergometer CPETs were performed on two consecutive days in 58 patients with ME/CFS (mean age 38.6 ± 9.6 years, Body Mass Index (BMI) 24.1 ± 3.3 kg/m 2 , 11 men and 47 women) and 25 age-matched sedentary control (CON) subjects (age 38.2 ± 9.9 years, BMI 24.2 ± 3.4 kg/m 2 , 5 men and 20 women). Peak VO2 was reported as the highest 30-sec average; VT was selected as the nadir of the VE/VO2 and PETCO2 curves, and VE/VCO2 as the slope throughout exercise.

Findings
For ME/CFS and CON subjects, there were no significant changes in Peak VO 2 between Day 1 and Day 2 studies (ME/CFS Day 1, 22.3 ± 5.4; Day 2, 22.5 ± 5.4 mL·kg −1 ·min −1 ; CON Day 1, 23.4 ± 3.5; Day 2, 22.8 ± 3.6 mL·kg −1 ·min −1 ; NS).

Similarly, VO2VT and VE/VCO2 slopes were not significantly different between the ME/CFS patients and CON, and on Day 2, they did not show any differences within or between groups.

Peak heart rate was significantly higher in CON versus ME/CFS. The level of perceived exertion was significantly greater at all levels of exercise on the Day 1 and Day 2 tests for ME/CFS patients versus CON.

Interpretation
Our data indicate that 2-day CPET provides exercise-related results that are the same in ME/CFS patients and CON subjects. ME/CFS patients have a greater perception of exertion throughout exercise and a lower maximum heart rate than CON. The data do not support using the 2-day CPET protocol to define PEM or disability.

Web | DOI | PDF | Frontiers in Physiology | Open Access

Consistent with the assertion that those with normal CPET are nevertheless heavily impeded/disabled. I wonder what interpretation they may have wanted to put on this? I might guess....

 

[ME/CFS Science Blog]

The inclusion criteria were Fukuda, but with PEM required.

They all met both the 1994 case definition of ME/CFS, modified to require endorsement of post-exertional malaise [...] They were also required to report at least a substantial burden with post-exertional malaise with a VAS of at least 3.

Here are the main results, showing almost no decline at all in the ME/CFS patients.


The text also mentions workload at VT, which was the most replicated finding thus far.

There were no statistical differences in the workload at the VT threshold on Day 1 or Day 2 for the CFS patients (Day 1, 58 ± 23; Day 2, 62 ± 26 W; p = 0.07).

The authors argue that the previous study by Keller et al. did find declines in VO2max and other parameters because they didn't require Me/CFS patients to meet full criteria for maximum effort. But I remember that we checked for this and that only a handful of patients didn't meet the criteria, so this didn't explain the results. Here's what I wrote in my blog about it:

Keller and colleagues argued that they did not apply these criteria for ME/CFS patients on the second exercise test because failure to reach them may be part of the illness. Our analysis, however, showed that only 10 participants (8 ME/CFS patients and 2 controls) did not reach these criteria and that excluding them did not make much of a difference. Our analyses and graphs above were calculated with those 10 participants excluded.

The biggest 2-day exercise study - ME/CFS Science

So a bit strange that Natelson's team didn't check this using Keller's data.

Despite there being no decline in CPET parameters, it looks like ME/CFS patients experienced PEM but that they will report on this data in a future publication.

The lack of decline in exercise performance does not preclude subjective symptoms post-exercise consistent with PEM. Therefore,we monitored symptoms (via ecological momentary assessment ona wrist-mounted computer) across each day for the week prior to CPET and the week following it. These results will be reported in a separate publication, but preliminarily, we can report that ME/CFSpatients could be differentiated from HCs across most symptoms and for most post-CPET days

So they do not recommend 2-day CPET to measure PEM but instead symptom assessment

Our findings are important, as the absence of significant changes in CPET does not support the use of two sequential CPETs to infer either PEM or disability. [...] symptom assessment postexercise testing may be the most useful method to identify PEM.