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

[Snow Leopard]

I would expect a much more messy result.

Have you done the test yourself? How do you know what to expect?

It is quite possible that participants were no longer encouraged once they had matched their prior days VO2Peak, and I can tell you from experience, you aren't going to want to continue past your VO2max without extremely strong encouragement...

 

[ME/CFS Skeptic]

Have you done the test yourself? How do you know what to expect?

My reservations have little to do with the specifics of the test but with the separation between ME/CFS patients and ICF patients.

My expectation is that, if there is a true effect, ME/CFS diagnostic criteria would not have separated people almost perfectly so that all ME/CFS patients show a reduction in workload at the ventilatory threshold while all those with ICF have an increase.

 

[cassava7]

The only studies I have seen that measure PEM in Fukuda patients find that over 90% of people have that symptom. Also, I'm pretty sure the first two day maximal studies diagnosed on the basis of Fukuda, and had the same findings. Nobody wanted to throw away those findings.

Could this not reflect that the investigators of studies that assessed PEM in patients meeting the Fukuda criteria were more familiar with PEM? If there is such a detection bias, it is likely to be compounded in studies that focus on screening PEM in a Fukuda cohort, compared to studies that only report PEM along with other symptoms of the criteria.

This could be the case with the first 2-day CPET studies. I believe they were conducted by the Workwell Foundation, who are well aware of PEM -- and screen it among their patients before realizing the 2-day CPET --. Further, referral bias is likely, given that the 2-day CPET is exclusive to ME/CFS and that the Workwell Foundation focus on ME/CFS (like Stitching CardioZorg and the CVS/ME Centrum in Amsterdam). Most participants were likely to be symptomatic enough to match stricter ME/CFS criteria (e.g. CCC/ICC).

Conversely, if another research group less familiar with ME/CFS did a 2-day CPET study, they might select patients diagnosed per the Fukuda criteria but they might not verify all have PEM.

 

[cassava7]

I agree with Hutan. This looks too good to be true. All the male ME/CFS patients had a reduction in workload while all the male ICF patients had an increase in workload at the second CPET.

Given how arbitrary ME/CFS diagnostic criteria are, this seems extremely unlikely. Even if there was a true and large effect, one would expect that some patients might have been misdiagnosed in either the ME/CFS or ICF group. No overlap is really strange.

It would help to know, before the 2-day CPET, how (or even whether) PEM was assessed, which symptoms of the ME/CFS criteria the participants suffered from and why they underwent the test. The clear-cut results from the study would be an artefact of selection bias if the test served to clarify the diagnosis of ME/CFS by inducing PEM (or not), whether in some or all patients, but presumably the patients' own accounts would already have helped assess PEM before the test.

ETA: The female paper mentions that "all patients underwent a detailed clinical history to establish the diagnosis of ME/CFS according to the ME criteria [1] and CFS criteria of Fukuda [3]". It seems that the results of the 2-day CPET were not used to make the diagnosis, i.e. only the patients' accounts were relied on. If this is to be believed, the 2-day CPET would likely only have been done for disability testing / administrative reasons. @Hutan

However, this reason is not explicitly mentioned; the only one that the authors provide is "to quantify exercise intolerance" in (female) ICF patients. They do not list other reasons, nor do they explain why some participants only had a single-day CPET or multiple single-day CPETs but not on consecutive days.

Why a single-day CPET, rather than a 2-day one, would not have sufficed to quantify exercise intolerance in ICF patients is unclear to me. If I am not mistaken, this is the main purpose of a CPET. This casts doubt over the claim that the diagnosis of ME/CFS was based on clinical history alone.

Of the 111 male patients undergoing CPET over the study period, 35 were diagnosed with idiopathic chronic fatigue of whom 25 underwent a 2-day CPET protocol. We excluded 33 male ME/CFS male patients who had only completed a single-day CPET and 10 others who had more than one test, but not on 2 consecutive days. Seven severe male ME/CFS patients were excluded, leaving 26 male patients with data from a 2-day CPET protocol available for analysis.

Of the initially 235 female patients undergoing CPET for clinical reasons for determining exercise intolerance, between June 2010 and October 2019, 65 patients did not fulfill the ME/CFS criteria and were therefore diagnosed with idiopathic chronic fatigue. Fifty-seven ME/CFS female patients only had a single CPET and 38 patients had more than one test, but not on 2 consecutive days. Female ME/CFS patients clinically graded as having severe ME/CFS according to ICC were excluded from this analysis [1]. This was done in order to have the patient and control group of similar clinical severity, as none of the ICF patients of the control group had a clinically severe disease. Twenty-four clinically severe female ME/CFS patients were excluded, leaving 51 female patients with data from a 2-day CPET protocol available for analysis. In this period, 50 female patients with idiopathic chronic fatigue underwent a 2-day CPET protocol to quantify exercise intolerance. They were considered the control group for this analysis.

 

[Kalliope]

The Norwegian news site about research, forskning.no, has an article today about the study with comments from professor Karl Johan Tronstad from the University in Bergen.

Forskning.no: Trening virket ulikt på pasienter med ME og pasienter med annen utmattelse
google translation: Exercise worked differently in patients with ME than patients with other fatigue

quote:
Perhaps the difference between ME and other fatigue may be one of the reasons for the disagreement about the effect of physical activity on people with ME?

- Yes, I think that is correct, writes Tronstad from UiB.

- Activity intolerance is associated with exertion-triggered symptom exacerbation (PEM), which is an important point in the diagnostic criteria for ME.

- This means that ME patients can become ill from physical activity, sometimes for a longer period. Care must therefore be taken to find the individual ME patient's tolerance limit.

- People who have fatigue, but not activity intolerance, on the other hand, will not be as vulnerable to aggravation due to physical activity.

 

[Midnattsol]

The Norwegian news site about research, forskning.no, has an article today about the study with comments from professor Karl Johan Tronstad from the University in Bergen.

Forskning.no: Trening virket ulikt på pasienter med ME og pasienter med annen utmattelse
google translation: Exercise worked differently in patients with ME than patients with other fatigue

quote:
Perhaps the difference between ME and other fatigue may be one of the reasons for the disagreement about the effect of physical activity on people with ME?

- Yes, I think that is correct, writes Tronstad from UiB.

- Activity intolerance is associated with exertion-triggered symptom exacerbation (PEM), which is an important point in the diagnostic criteria for ME.

- This means that ME patients can become ill from physical activity, sometimes for a longer period. Care must therefore be taken to find the individual ME patient's tolerance limit.

- People who have fatigue, but not activity intolerance, on the other hand, will not be as vulnerable to aggravation due to physical activity.

I liked this one, except for calling PEM increased fatigue.

 

[cassava7]

The Norwegian news site about research, forskning.no, has an article today about the study with comments from professor Karl Johan Tronstad from the University in Bergen.

Forskning.no: Trening virket ulikt på pasienter med ME og pasienter med annen utmattelse
google translation: Exercise worked differently in patients with ME than patients with other fatigue

Thank you for linking the article. The translation adds to the confusion as to why patients underwent 2-day CPETs:

Gold standard

There are some weaknesses in the study, write van Campen and Visser.

For example, patients were not recruited specifically for this study. The results were obtained from tests performed during the evaluation of patients.
​

Does the original Norwegian term "utredning" translate to "evaluation" as in follow-up care, or to something closer to "diagnosis" (suggesting that the 2-day CPET was used to establish the diagnosis of ME/CFS)?

 

[Kalliope]

Thank you for linking the article. The translation adds to the confusion as to why patients underwent 2-day CPETs:

Gold standard

There are some weaknesses in the study, write van Campen and Visser.

For example, patients were not recruited specifically for this study. The results were obtained from tests performed during the evaluation of patients.
​

Does the original Norwegian term "utredning" translate to "evaluation" as in follow-up care, or to something closer to "diagnosis" (suggesting that the 2-day CPET was used to establish the diagnosis of ME/CFS)?

Well spotted. "Assessment" would have been a better translation.

 

[borko2100]

Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546966/

This study that @Hutan posted is so relatable. Namely, it showed that controls got reduced lactate on the second CPET, while people with ME/CFS had their lactate levels the same or increased. This describes my efforts to increase my fitness perfectly. I used to try jogging for 500-800m to see if my rapid fatiguability / reduced stamina was due to deconditioning and needless to say I made zero progress, just like the study predicted. Every run I did felt just as difficult as the previous one, despite being the same distance / duration -> zero improvement after several weeks of trying.

Does anyone know if this study has been replicated or if there are other similar studies measuring lactate differences from CPET 1 to 2?

EIDT: answering my own question, it seems like there arent other such studies according to the researchers

To our knowledge, repeated exercise testing with lactate profiles on two consecutive days has not been studied in ME/CFS patients fulfilling case definitions where PEM is a mandatory symptom.

 

[Mij]

My blood lactate levels were 'normal' the next day (and second day) when I was in PEM after exercise (running).

 

[cassava7]

I contacted the corresponding author by mail to clarify the role of 2-day CPETs in the study.

They were not used to make (or rule out) the diagnosis of ME/CFS -- it was established on the basis of the diagnostic criteria alone, which, according to Dr van Campen, is "no problem at all if you are experienced with [them]".

The patients who had multiple CPETs but not on consecutive days chose to plan them so, as they estimated that their PEM took longer than 24h to set in or that it was more severe after 24h. In order to standardize their protocol, the authors later restricted testing to (consecutive) 2-day CPETs only.

 

[Hutan]

Thanks for doing that @cassava7. That sounds encouraging, but to me, the very clear separation and the nature of the data continues to leave room for doubt. There is a conflict of interest in the clinic demonstrating that they provide a test that is essentially perfect in identifying people with ME/CFS, and in demonstrating that their ability to diagnose ME/CFS without CPETs is essentially perfect too.

The clinic's data is a tremendous source of information going forward. I wonder if there is a way they could doubt-proof their data - have the data kept in a system that timestamps all entries and have an independent party scrutinise it before a new analysis is done?

Of course, some more large trials of paired CPETs done by researchers who are not involved in providing clinical services would help a lot.

 

[cassava7]

Thanks for doing that @cassava7. That sounds encouraging, but to me, the very clear separation and the nature of the data continues to leave room for doubt. There is a conflict of interest in the clinic demonstrating that they provide a test that is essentially perfect in identifying people with ME/CFS, and in demonstrating that their ability to diagnose ME/CFS without CPETs is essentially perfect too.

Indeed. Dr van Campen’s point that clinical experience with the diagnostic criteria suffices to pose an accurate diagnosis of ME/CFS was her response to both of my queries on the clear-cut results and possible misdiagnoses.

I would only argue that Stichting CardioZorg is not likely to need much advertisement as it is already is one of the two prominent clinics specialized in ME/CFS in the Netherlands (the other one being Ruud Vermeulen’s CVS/ME Centrum in Amsterdam). Still, you are right that they have a conflict of interest — in any case, positive advertisement is good for the taking.

Of course, some more large trials of paired CPETs done by researchers who are not involved in providing clinical services would help a lot.

Prof Betsy Keller at Ithaca College is currently running a 2-day CPET trial funded by a NIH grant, in collaboration with Dr Hanson’s NIH-funded ME/CFS center at Cornell (registration link). She does, however, offer 2-day CPET testing for a fee of $2200.*

At least until this larger trial is completed, I believe that independent research teams will be unlikely to want to study 2-day CPET. From an ethical standpoint alone, the risk of harm is enough to turn them away. Positive results may bring more momentum, and in particular validating them outside the US could help in turning the local (medical) views on ME/CFS in some countries towards a more biomedical approach.

* ETA: removed “privately” before “offer” as I do not know which party out of Ithaca College and Prof Keller charges patients for the 2-day CPET.

 

[Hutan]

From an ethical standpoint alone, the risk of harm is enough to turn them away.

Am I right in thinking that a test that involves going just a bit beyond ventilatory threshold on consecutive days would be enough though? I don't know what amount of exertion required to get to that point is for people at different levels of ME/CFS severities, but I suspect many of us have to get to ventilatory threshold frequently, just to do the daily living tasks we have to do. (For a mostly bed-bound person, maybe just walking to the bathroom gets them to that point? Has anyone tried determining the CO2/O2 ratios of someone with severe ME/CFS?)

If just getting a bit beyond ventilatory threshold is enough to provide a good comparison with healthy controls, I don't see that there's such an ethical problem, with informed consent of course.

I guess with a test that just went to ventilatory threshold, it would be really important to manage activity levels immediately prior and during the test.

At least until this larger trial is completed, I believe that independent research teams will be unlikely to want to study 2-day CPET.

I would have thought that this is a really interesting thing for exercise physiologists to study. I'm biased, of course.

 

[Snow Leopard]

The citation of the Ithaca College study brings up another potential confounding factor.

The CPET begins with 3 minutes of seated rest followed by cycling during incremental workloads which increases 15 watts throughout each minute of exercise. The participant will cycle until volitional exhaustion and/or the participant and/or test administrator determines to stop the test. Actual exercise time usually varies between 8-10 minutes.

The ramping of the workload can differ between different CPET studies.

Notably, for the Stichting Cardiozorg studies:

A RAMP workload protocol was used varying between 10–30 Watt/min increases, depending on sex, age, and expected exercise intolerance.

So while this was held constant between the days, it was not constant between patients. But the authors do not report whether there was a difference in workload ramping rate between the different groups.

There is no clear-cut answer to which protocol is better. Holding the rate constant at 15 watt increase per minute means that individuals that have a higher level of fitness can end up doing the test for twice as long as other participants. This also means exercising for quite a long time past the ventilatory threshold. This is not hypothetical In my case (in one of the published studies), I was on the bike for around 19 minutes (40w warm up, 15 watt/minute ramp) and was exercising beyond the ventilatory threshold for over 8.5 minutes! Which in itself could be a confounding factor. (This may also be why I keep insisting that the 2 day maximal CPET is very demanding on participants...)

Am I right in thinking that a test that involves going just a bit beyond ventilatory threshold on consecutive days would be enough though? I don't know what amount of exertion required to get to that point is for people at different levels of ME/CFS severities, but I suspect many of us have to get to ventilatory threshold frequently, just to do the daily living tasks we have to do. (For a mostly bed-bound person, maybe just walking to the bathroom gets them to that point? Has anyone tried determining the CO2/O2 ratios of someone with severe ME/CFS?)

The ventilatory threshold is an artefact of the ramped exercise protocol (gradual increase in workrate), so it does not make sense to say that individuals will exceed this during day to day tasks as the motor unit recruitment patterns are different.

It is uncertain how demanding the exercise needs to be on the first day to provoke a significant change. But I do agree there is no need for a maximal CPET on both days, especially the second day. But I'd also like to see a move beyond CPET testing and towards utilising other measures, such as EMG, blood flow measures etc. (and even TMS).

 

[Sean]

Posts moved from separate thread on the female research that is now closed.

Conclusion: This study confirms that female ME/CFS patients have a reduction in exercise capacity in response to a second day CPET. These results are similar to published results in female ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.

If this result holds up then it is important.

 

[Amw66]

If this result holds up then it is important.

Proof that exercise may be beneficial.for those with no PEM and detrimental for those with ME.

This would be useful indeed given the push from Royal Colleges against new guidelines.

 

[Sean]

This would be useful indeed given the push from Royal Colleges against new guidelines.

Yeah, they might want to be a bit careful about demanding new evidence be admitted to the NICE debate. Cuts both ways.

 

[Peter T]

As well as contradicting those that believe exercise is always the answer, if confirmed this is important in relation to the belief of biopsychosocial brigade that all forms of fatigue are the same and that the best way forward is to give identical interventions to ever broader patient groupings.

It is also relevant to those that wish to divide ME/CFS into ‘real’ ME and CFS, as this research suggests there is a degree of continuity across the ME/CFS spectrum. (Sometimes I suspect these advocates are using CFS when they actually mean chronic idiopathic fatigue.)

Though we may find in the future other variables that sub divide ME/CFS this research seems to confirm there is a definite disorder or group of related disorders that can be defined on the basis of the two day CPET.

 

[Sean]

It is also relevant to those that wish to divide ME/CFS into ‘real’ ME and CFS, as this research suggests there is a degree of continuity across the ME/CFS spectrum. (Sometimes I suspect these advocates are using CFS when they actually mean chronic idiopathic fatigue.)

Which is why we need some means of distinguishing between the two. Like PEM 2-day testing.