Comparing Idiopathic Chronic Fatigue and ME/CFS: Response to 2-day CPET, two papers males & females, 2021, Van Campen & Visser

[Trish]

The suggestion of doing a CPET every day for a fortnight:

If you have someone who loses apparent fitness on the second CPET, ie they haven't recovered from the first CPET and may trigger PEM if they then don't rest for several days to return to their day1 level, why would you suggest doing repeated CPET's over further consecutive days? That would surely be unethical, as, like GET has done for many patients, it would be risking permanent worsening.

 

[Hutan]

I would do it, because if there is a constant decline during that period, it says a lot about how GET is damaging. And I don't want my son and all the other young people now and to come to have to live in a world where the BPS view about ME/CFS has credence.

...Well, maybe I'd do a week. And you could stop if people became ill. I felt fine on the second CPET, but my performance dropped by 20%.

 

[Snow Leopard]

It is highly likely that a negative response to exercise in the CPET has contributed to the label of ME/CFS being applied to some of people, while a positive response to exercise was assumed to indicate the absence of PEM, and so those other people were labelled 'idiopathic chronic fatigue'.

While the analysis was retrospective, I don't think this had anything to do with the actual diagnoses, which was prospective (as referred to the clinic). They certainly didn't change the diagnosis on the basis of the CPET, which would be circular!

We need studies of multiple CPETS in people with ME/CFS - not just two. So, what happens if you do a CPET every day for a fortnight? Some people would volunteer to do that, I am sure.

Yeah, nah!

 

[Hutan]

While the analysis was retrospective, I don't think this had anything to do with the actual diagnoses, which was prospective (as referred to the clinic). They certainly didn't change the diagnosis on the basis of the CPET, which would be circular!

I don't think we can know that from the information in the papers. They say the CPETS were done to assess exercise intolerance. It seems unlikely that the male study did not have a single person diagnosed with ME/CFS who did not show a drop in performance. That's a pretty impressive diagnosis rate if the CPET had no influence at all on the diagnosis. You might be right, I just think we can't know.

 

[Hutan]

Yeah, nah!

Fair enough, it certainly wouldn't be for everybody. But people are still talking about GET trials, and trials of CBT to convince people they need to increase their activity levels - and ethics boards are approving them. People are putting their health at risk every day already.

If you got a handful of people and had them do multiple CPETS, and documented the impact day by day, I think you'd have something very compelling that might cut through all the BPS nonsense and change the situation for people with ME/CFS. I doubt any researcher would be interested of course.

 

[Marky]

We need studies of multiple CPETS in people with ME/CFS - not just two. So, what happens if you do a CPET every day for a fortnight? Some people would volunteer to do that, I am sure.

Agree! I suggested this too when i did a summary of this study

 

[Snow Leopard]

Anyone spot the error? ICF BMI : 224.2 (kg/m2)

Not sure the participants are even human with that number!

Agree! I suggested this too when i did a summary of this study

If you got a handful of people and had them do multiple CPETS, and documented the impact day by day, I think you'd have something very compelling that might cut through all the BPS nonsense and change the situation for people with ME/CFS.

For what purpose though? It will still be unsuitable as a diagnostic marker due to the burden placed on patients.

I'm trying to put this politely, but a the reason why a few patients didn't record a decline is because they didn't work very hard in the first place. I mean for the males, the mean HR peak on the first day was 148 BPM, for women the figure was 156 BPM (the men were about 12% older, partly explaining the difference). Both of these figures are well below the age predicted peak heart rates for people of their age. One point that many people often don't realise is that deconditioning can lead to a higher peak heart rate than a highly conditioned individual - which I think is one of the reasons why my heart rate peaked at 202 BPM on the first CPET.

 

[Hutan]

For what purpose though? It will still be unsuitable as a diagnostic marker due to the burden placed on patients.

It's not about being a diagnostic marker - it's to demonstrate that there is a real consequence from exercise, that it can make people very sick. And exercise every day has a cumulative effect. Still, many people do not believe that. If there are CPETs, there is data to accompany what people are saying about how they feel.

 

[Snow Leopard]

It's not about being a diagnostic marker - it's to demonstrate that there is a real consequence from exercise, that it can make people very sick. And exercise every day has a cumulative effect. Still, many people do not believe that. If there are CPETs, there is data to accompany what people are saying about how they feel.

I'd rather demonstrate the difference with electromyography, MR spectroscopy, doppler flowmetery (and even pharmacological nerve blockade), rather than a nightmarish scenario of daily maximal CPETs! Even if the CPETs are not maximal, it is still a strong ask of patients.

 

[Amw66]

The female data shows a similar pattern, however there was some overlap between patients and controls - several ICF patients had a small (smaller than CFS patients) drop in peak workrate and workrate at the ventilatory threshold.

this may make no sense at all as I am woefully ignorant of exercise chemisty and physiology- but could this be linked to proteomics studies which show that females are more likely to utilise protein as fuel when glycolysis is dodgy and not not fat as males do?
Would this be a more common mechanisim in females which could impact outcomes

 

[Snow Leopard]

this may make no sense at all as I am woefully ignorant of exercise chemisty and physiology- but could this be linked to proteomics studies which show that females are more likely to utilise protein as fuel when glycolysis is dodgy and not not fat as males do?
Would this be a more common mechanism in females which could impact outcomes

No. I think it is due having double the number of participants and is more reflective of real-world variability during the test (also given that I don't believe all participants worked hard enough to achieve a true VO2 Max).

 

[Marky]

I'd rather demonstrate the difference with electromyography, MR spectroscopy, doppler flowmetery (and even pharmacological nerve blockade), rather than a nightmarish scenario of daily maximal CPETs! Even if the CPETs are not maximal, it is still a strong ask of patients.

Its a strong ask, but I think it would have proved a lot with PEM and could even be THE study to refer to when someone propose graded exercise.
Im sure someone would agree to do this to forward the field. I probably would honestly

 

[Medfeb]

235 patients undergoing CPETS for clinical reasons....
It's hard to believe people would have been put through two CPETs over this whole period between 2010 and 2019, without the test being used to help with diagnosis.

In the US at least, CPET is used to support disability evaluation and I know of patients that had it done as far back as 2011 for that purpose and not for diagnosis -
Edited to fix an error
at least not recommended for diagnosis by most of the ME clinicians

I took "undergoing CPETS for clinical reasons" to be referring to its usage in disability evals but maybe other reasons as well.

 

[Hutan]

Yes, but look at the change in Vo2 at the ventilatory threshold in both males and females:

Male

Female


The split looks suspiciously too perfect for the paired CPET to not be playing some part in the diagnosis decision. I mean, assuming the diagnosis was made before the CPET, what if an ICF diagnosed person did the paired CPET and had a significant drop in performance on the second CPET? Wouldn't the clinician be likely to look hard at the diagnosis, and change it to ME/CFS?

And if someone was definitively diagnosed with ICF, why would they then do the paired CPET for insurance purposes? Surely they would only do that if there was some chance that the diagnosis would be changed?

The difficulty is in knowing whether the authors consistently used an initial diagnosis, or the most recent one, or a mix of both. I don't think they tell us in the papers. I hope I'm wrong and the diagnoses used come from the first diagnosis the patient is given, prior to doing a paired CPET. But the data is from clinical notes - it's almost certainly not as clean as data from a specific trial would be, and therefore less credible, even if the clinicians said now that a pre-CPET diagnosis was used in every case.

Also, if insurance is a big reason for doing the test, the patients have a big incentive to show the performance drop. I haven't read the paper for information on the effort made. But @Snow Leopard has already mentioned it, and I'm sure can tell us more.

 

[Snow Leopard]

The split looks suspiciously too perfect for the paired CPET to not be playing some part in the diagnosis decision. I mean, assuming the diagnosis was made before the CPET, what if an ICF diagnosed person did the paired CPET and had a significant drop in performance on the second CPET? Wouldn't the clinician be likely to look hard at the diagnosis, and change it to ME/CFS?

Or there is a true effect.

Another study by this clinic provides more detail on the diagnostic process:

https://translational-medicine.biomedcentral.com/track/pdf/10.1186/s12967-020-02397-7.pdf

This was a retrospective study of patients referred between 2012 and 2019 to the Stichting CardioZorg, a cardiology clinic that specializes in the assessment and treatment of those with CFS and ME. All eligible participants had been referred by their general practitioners for the diagnosis of ME/CFS. Patients underwent a detailed clinical history, physical examination, laboratory analysis, ECG and echocardiography. Based on their symptoms the diagnosis of chronic fatigue syndrome (CFS) according to the Fukuda Criteria [1] and myalgic encephalomyelitis (ME) according to the international ME criteria [2] was established. In all patients alternative diagnoses which could explain the fatigue and other symptoms were ruled out. We excluded patients with a body mass index of ≥50 because the normal reference values for the CPET [37] were based on female healthy volunteers with a BMI up to 50. The diagnosis of fibromyalgia was based on either the previous diagnosis of a rheumatologist or based on the American College of Rheumatology questionnaire 2010 [38]. Those with fibromyalgia did not have arthritic or secondary forms of the disorder. A subset of patients completed the SF-36 questionnaire, wore a Sensewear™ armband for 5 days and underwent cardiopulmonary exercise testing. These tests were primarily performed to demonstrate the degree of disability because of conflicts with the social security administration. From among those who had undergone all three tests, to minimize between-measures variability in functional status, we selected for study those in whom the interval between the SF-36 questionnaire, the Sensewear™ measurements, and the cardiopulmonary stress test was less than 3 months. In addition, patients who were re-evaluated because of worsening of symptoms were analyzed separately.

Unfortunately this level of detail was not stated for the current CPET studies. Though it's quite possible that some of the patients did not have the heart testing (ECG/echocardiography), there is no reason to believe that the diagnosis itself was not prospective (before the CPET).
This is also stated by the flow diagram in the appendix of the CPET studies.

 

[Medfeb]

Also, if insurance is a big reason for doing the test, the patients have a big incentive to show the performance drop. I haven't read the paper for information on the effort made. But @Snow Leopard has already mentioned it, and I'm sure can tell us more.

Per the Workwell CPET methods paper, CPET testing reports out a measure, respiratory exchange ratio (RER) which shows level of effort. RER is the ratio of VCO2 /VO2 so I'd imagine it would be hard to cheat on that one. An RER of greater than or equal to 1.1 is considered maximal effort and is considered the best non-invasive indicator of exercise effort

This measure is reported in CPET disability evaluations that go to insurance companies.

 

[Hutan]

RER is the ratio of VCO2 /VO2 so I'd imagine it would be hard to cheat on that one. An RER of greater than or equal to 1.1 is considered maximal effort and is considered the best non-invasive indicator of exercise effort

Sure, I'm just not sure what RERs were reported in the studies- I haven't looked. @Snow Leopard mentioned about effort perhaps being less than full based on heart rates.

Edit - the RERs look fine >=1.1 in both males and females, ME/CFS and ICF.

 

[Hutan]

For the female study, there were 24 people diagnosed with ME/CFS and classed as severe who somehow managed to do two CPETs, appropriately spaced. They were left out of the analysis due to them not being appropriately matched with the ICF, which is fair enough.

Van Campen did a study comparing severe patients with mild and moderate ones, discussed here:
Two-Day CPET in Females with a Severe Grade of ME/CFS: Comparison with Patients with Mild and Moderate Disease. van Campen et al. 2020

 

[Hutan]

On that thread, @wdb mentions a study that had people with ME/CFS and controls do paired CPETS (Lien et al, 2019)
Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome
The chart below is comparable to the ones from the Van Campen and Visser study in terms of what is being measured. But look at the spread of change in Peak VO2 in the ME/CFS and controls. And then look at the charts my post #34 above, the green sides. The Van Campen and Visser ones have the two cohorts well separated; in the Lien one, even the controls are mostly decreasing from CPET 1 to CPET 2, and the spread of values is quite different, even though the units are the same.



That Lien paper is discussed on S4ME.
Snow Leopard suggests that the problems with the Vo2peak result is that patients have not been exercising to their true peakVo2 across all the studies.

This study did reproduce the major consistent finding so far: reduced performance at the ventilatory threshold. The 8th study so far if we include the study based on a single pair of twins.

The VO2Peak findings have been inconsistent because patients have not been consistently exercising to their true VO2Max across studies.

When I did a paired CPET, I did not feel as though I had got near my limit when I was stopped, but my RER was 1.1.

But, if it's a matter of not exercising to the true VO2max, it makes things pretty complicated, with the controls in that study also doing worse on the second CPET.

Perhaps we have to look only at Ventilatory Threshold data - as that isn't confounded by peak effort issues.

 

[Snow Leopard]

Per the Workwell CPET methods paper, CPET testing reports out a measure, respiratory exchange ratio (RER) which shows level of effort. RER is the ratio of VCO2 /VO2 so I'd imagine it would be hard to cheat on that one. An RER of greater than or equal to 1.1 is considered maximal effort and is considered the best non-invasive indicator of exercise effort

VO2Peak can still increase while RER plateaus by increasing ventilation and delivery of that oxygen to the muscle (eg by achieving a higher heart rate or higher blood pressure).

But more to the point, how many participants didn't achieve an RER of 1.1? We don't know.

Note that the ICF cases (both males and females) had a mean RER of 1.2 compared to 1.1 for the ME/CFS cases.

Having said all that, in my experience, my peak RER was 1.11 and plateaued above 1.1 for almost 3 minutes before I achieved my peak VO2 on the first CPET.

I'd suggest that many participants achieved close to a true VO2Max, but a minority did not.

On that thread, @wdb mentions a study that had people with ME/CFS and controls do paired CPETS (Lien et al, 2019)
Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome
The chart below is comparable to the ones from the Van Campen and Visser study in terms of what is being measured. But look at the spread of change in Peak VO2 in the ME/CFS and controls. And then look at the charts my post #34 above, the green sides. The Van Campen and Visser onesare really tight; in the Lien one, even the controls are mostly decreasing from CPET 1 to CPET 2, and the spread of values is quite different, even though the units are the same.

One of the points that Max Nelson made was that there is inconsistent application of 'encouragement' of participants during the tests and it is possible this inconsistency could apply to patients vs. controls in the van campen studies.