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

[Sly Saint]

The paper comparing results in female CF And ME/CFS patients is posted later on the thread here and had its own thread that is now closed and the discussions merged

Comparing Idiopathic Chronic Fatigue and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Males: Response to Two-Day Cardiopulmonary Exercise Testing Protocol

Abstract
(1) Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS )patients, using the gold standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfill the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET.

(2) Methods: We compared 25 male patients with ICF who had completed a 2-day CPET protocol to an age-/gender-matched group of 26 male ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities.

(3) Results: Baseline characteristics for both groups were similar for age, body mass index (BMI), body surface area, (BSA), and disease duration. A significant difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs. zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload.

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

https://www.mdpi.com/2227-9032/9/6/683?type=check_update&version=1

 

[Sly Saint]

 

[Snow Leopard]

Figure 4 (not shown by Sly saint in above post at time of posting) is very curious - 100% of the idiopathic cases either reproduced or increased their workload at the ventilatory threshold, whereas most patients had a decline. However absolute difference was not large, so this is not going to be useful as a diagnostic marker, yet it is a vital clue as to what is going on physiologically...

The general improvement on day 2 for patients with idiopathic chronic fatigue, who are without the symptom of post-exertional malaise and who on the second day of CPET-show a pattern similar to sedentary and healthy controls, suggesting that the changes found on day 2 in ME/CFS patients are disease-specific.

(edit- I've updated the ME Pedia page too)

 

[Peter T]

A potentially very important study as it stresses how essential using the right diagnostic criteria in ME/CFS research is and that studies using such as the Oxford criteria that is unable to distinguish between ICF and ME/CFS are totally irrelevant to service planning for people with ME/CFS.

Also this is useful evidence in countering the ideologically driven BPS approach of lumping ever broader patient groupings in their treatment and service recommendations. If lumping ME/CFS with ICF is problematic as this paper indicates, how much more dangerous is their waste bin MUS diagnosis. Given the ongoing debate about harms arising from exercise related interventions now moving on to include Long Covid and the criticism of the BPS research failing to recognise or record such harms in their research, this highlights a failure to distinguish ME/CFS and ICF or the use of over broad patient groupings such as MUS is likely to mask levels of harm in ME/CFS.

 

[Hoopoe]

Nice and simple study, clearly showing the different response patterns. Some people still claim that PEM is a common response to exercise and not unusual.

 

[Trish]

It's studies like that that I hope will transform ME research to ensure the old Oxford and Fukuda definitions that don't require PEM, are no longer used in research, and that old studies that used these broad criteria should be recognised as no longer valid. For example all the GET studies based on these old definitions are scuppered because there's no information on what proportion of patients had PEM.

 

[Peter T]

Also studies like this are so import in developing our understanding and definitions of what PEM is, and to distinguish it from the widespread confusion with increased fatiguability.

The same researchers that struggle to differentiate ME/CFS from ICF, fail to understand that PEM is a physiological change and not just getting tired more easily.

 

[JemPD]

I hope this will feature in the cochrane review?

 

[cassava7]

The same study with females (51 ICF / 50 ME/CFS patients): https://www.mdpi.com/2227-9032/9/6/682

Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol

Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, using the golden standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfil the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET.

Methods: Fifty-one female patients with ICF completed a 2-day CPET protocol and were compared to an age/sex-matched group of 50 female ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities.

Results: Baseline characteristics for both groups were similar for age, BMI, BSA, and disease duration. A significance difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload.

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.

 

[Snow Leopard]

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.

 

[Marky]

Nice. Was it international consensus criteria used here? I assume thats why they referenced it

 

[Andy]

Nice. Was it international consensus criteria used here? I assume thats why they referenced it

To me, it's not clear. The relevant section of the paper seems to be
"We identified males who satisfied the criteria for ME/CFS, comparing them with male patients not fulfilling the criteria and who had been diagnosed with idiopathic chronic fatigue (ICF) [1,3]."

where reference 1 is the ICC, and reference 3 is Fukuda.....

They also talk about not including patients who met the severe category from the ICC because the didn't have fatigued patients who were that disabled to be able to compare the results, but that doesn't, to me, confirm whether one or both selection criteria were used.

 

[Hoopoe]

I think it means patients who met ICC and Fukuda were compared against patients who had been diagnosed with unexplained fatigue and didn't meet the ICC or Fukuda criteria. Otherwise it just doesn't make sense.

 

[cassava7]

Nice. Was it international consensus criteria used here? I assume thats why they referenced it

To me, it's not clear. The relevant section of the paper seems to be
"We identified males who satisfied the criteria for ME/CFS, comparing them with male patients not fulfilling the criteria and who had been diagnosed with idiopathic chronic fatigue (ICF) [1,3]."

where reference 1 is the ICC, and reference 3 is Fukuda.....

They also talk about not including patients who met the severe category from the ICC because the didn't have fatigued patients who were that disabled to be able to compare the results, but that doesn't, to me, confirm whether one or both selection criteria were used.

The accompanying paper on the female cohort mentions: "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]."

 

[Ravn]

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.

Could those ICF patients be undiagnosed ME/CFS patients? Either very mild cases, or early cases, or cases starting to recover? It's not like our diagnostic criteria, let alone their application, are perfect.

Given it was a retrospective analysis I wonder if the authors had access to current diagnostic status?

 

[Hutan]

I've just caught up with this paper and have still only skim read it. But to me, it has a serious methodological problem. The sample is of males who have done CPETs as part of a diagnostic process. To be clear - no new CPETs were done as part of this study, the authors just looked at existing clinical data.

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'.

Then, the authors have taken the CPET results for the two different groups (defined at least partly by the CPET results) and graphed them.

I don't think such a circular process tells us anything much.

 

[Medfeb]

To me, it's not clear. The relevant section of the paper seems to be
"We identified males who satisfied the criteria for ME/CFS, comparing them with male patients not fulfilling the criteria and who had been diagnosed with idiopathic chronic fatigue (ICF) [1,3]."

where reference 1 is the ICC, and reference 3 is Fukuda.....

Fukuda explicitly defines idiopathic chronic fatigue (ICF) as:

"A case of idiopathic chronic fatigue is defined as clinically evaluated, unexplained chronic fatigue that fails to meet [Fukuda] criteria for the chronic fatigue syndrome" ​

So I had assumed they used ICC for ME/CFS and Fukuda for the ICF criteria. But on a reread, you are right, it's not clear.

 

[Ravn]

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.

This is from the study on females. I'm not sure I understand what they did.

It sounds as if everyone who met ICC was excluded? If so the ME/CFS cohort was a Fukuda one which means we don't know how many did not report PEM (not necessarily the same as 'did not experience' - whether someone reports or not depends on how questions are asked).

It's not clear to me to what degree the CPET results were used in the diagnostic process. Later in the paper it looks as though some with mildly abnormal CPETs were not diagnosed as ME/CFS but as ICF. All very confusing.

But whichever way you look at it, the two studies show that not everyone presenting with chronic fatigue has abnormal CPET results.

 

[Hutan]

235 patients undergoing CPETS for clinical reasons
170 met ICC and Fukuda criteria = ME/CFS + 65 did not meet the criteria = ICF

Of the 170 ME/CFS, 57 only had 1 CPET, and 38 had CPETs spaced too far apart, leaving 75 ME/CFS with two CPET spaced appropriately
Of the 75 ME/CFS with two CPET spaced appropriately, 24 were categorised as severe, and weren't included (as not a good match for the ICF)
leaving 51 ME/CFS

Of the 65 ICF, only 50 were used (15 had data for only 1 CPET)

( the abstract says 50 ME/CFS and 51 ICF, but this is the wrong way around, according to the text and diagrams)

It's not clear to me to what degree the CPET results were used in the diagnostic process.

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. Although the fact that there are some ME/CFS female patients who didn't show the ME/CFS typical drop in performance means that it's not so clear what role the CPET played, versus the situation with the men where all ME/CFS men did what was expected of ME/CFS patients.

 

[Hutan]

This is useful I think. 22% of the ME/CFS females did not qualify as being 'deconditioned' as defined here (i.e. their VO2 peak was at least 85% of that predicted for their age). Note how only 16% were not deconditioned one day later. So over a fifth of the ME/CFS sample would not meet the criteria for being deconditioned on the first day, that is, they are at least fairly fit. And yet they still have ME/CFS. So, what exactly would GET be aiming to achieve with that 22% who appeared fit on the first day? Do they need to become super athletes in order to experience some benefit from GET?

And it seems, doing the brief cycling made nearly a third of the women who were fit become unfit. So, doing exercise made them less fit - all in the space of a day.



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.