Post-Exertional Malaise - a discussion including defining and measuring PEM

Measuring fatigue/PEM is something I've been looking into for a while. I found that the amount of time lying down or walking speed is a reasonable proxy for the measure. I know I'm having PEM when the measure goes out of whack from what is predicted by the model. The first pic is the excess fatigue after the flu shot that deviated for 2 weeks. I was mystified by it for a while till I realized that I also got a flu shot while I was getting HEP B. The severity of PEM could be measured by how far it deviates from the model. The second pic is the plot of my walking speed against the subjective fatigue measure. No, it's not scientific; it wasn't a double-blind RCT. But both the speed and time spent lying down showed a good correlation to how I felt.

 

I lost stamina after my second HEP B jab during PVFS. I didn't feel fatigue though.

I also lost stamina after contracting Covid and every subsequent Covid vaccine.

 

That's a great question! I don't think anybody really knows what fatigue is, other than how it makes you feel. At the end of it, I think you can measure it only by its physical effect on you and how it prevents you from doing what you want/need to do.

I measured it daily at a certain time by timing how long it takes for me to walk in a maximal unstrained pace across a certain distance. (Again, not scientific). Since PEM last several days, it'll will show up in the measure regardless of when in the day you measure it. The amount of time spent lying down is measured throughout the day, so the value for your PEM day will be different from your "normal" day.

I didn't use the fatigue survey everyday (It's a chore to go through the questionnaire every day). But I compared my subjective feeling against it, and they did match fairly well. At the end though, the survey is as subjective as the feel. I'm now using the time spent lying down as the sole measure. (I'm hoping to automate it eventually with an activity tracker). It doesn't need to be in a scale. The total number of hours/minutes works just fine as the measure.

Measuring the exertion has been a bigger challenge. I shelved the project in 2016 when I couldn't raise the correlation to more than 0.4. I'm picking it up again now that I got my brain back. Still the model is not working out as well as I'd like it too...

 

I didn't feel anything after the first two, but the last one put me in the penalty box for 2 weeks. I couldn't figure out why till I remembered that I also got a flu shot at the same time. That was my first encounter with flu shot since I got sick with MECFS.

 

BTW, the pace can be measured with an activity tracker. I just found that it was more accurate to measure them manually. My max pace for 7/3/2016, for example, was about 95/min according to Fitbit.

 

The following posts have been moved from another thread

But the 2 day CPET is not an objective measure of PEM. PEM is a symptom that is either there or not. If you have PEM and a normal second day CPET you still have PEM. The second day CPET does not demonstrate PEM. Its value is in possibly providing indirect evidence that might shed light on a mechanism.

 

“The 2 day testing protocol is particularly helpful in documenting post-exertional malaise (PEM) and symptom exacerbation following physical activity”
https://workwellfoundation.org/testing-for-disability/

 

Copied post - greyed content discusses a different topic

It might be semantics. But I think the more relevant aspect is that it plays a potential role when it comes to disability determinations, being specifically referred to as evidence that one might say is qualifying.

Spoiler: More on CPET as objective evidence for disability payments

I say 'might' because I've recently seen someone on Twitter who provided their test results which were apparently what one would expect to see in ME, was turned down anyway. But the sense I got was that this person may have relied too much on the strength of those results as qualifying evidence, while perhaps not providing the detail I imagine they'd want to see as far as the rest of the application package (which is extensive) goes. But that was just the sense I got, don't quote me on that. Nevertheless I don't see it as an untrue statement as far as patient community perspective goes to view results reflecting PEM as providing objective information.

Not that we should have to think this way, but an ME patient is always on the defensive and has to deal with disbelief, rhetoric, insults, and even accusations about something that's widely perceived to rely entirely on self-report and therefore unprovable. It seems to be the one validated item in a decades-long, seemingly neverending battle with skepticism.

On the issue of research misconduct...there are a few pieces that I wonder about. Todd Davenport has of course been apopleptic and calling for retraction; I imagine his strongest point may be what he's pointed to regarding the role of Anthony Komaroff as both having participated to some extent in the project, and also being a referee. I do think this should be seen as no small issue considering the issues around how patients were selected, and what case definitions were and weren't used. He played a role in the selection process. Remember, first they included Reeves. Then they said CCC/IOM or whatever. Later they changed this again. In the end they said Fukuda + IOM.

Spoiler: More on criteria used - Reeves, Fukuda, IOM, CCC?

But "Fukuda" can mean 1994. Or 2003. Or something else? Can it mean Reeves 2005? It's been years. I know @Dolphin was on top of this & could probably speak to it. Reeves 2005 was 'random digit dialing' and 'are you fatigued' and anyone answering 'yes' was more or less given a CFS diagnosis. Some were people working 48-hour weeks if I recall. And there was that Lenny Jason paper that found that a cohort of people with a dx of MDD would qualify for a CFS dx. And it's easy to spot if they claimed to use CDC 2005 or Empirical or whatever, as in the Emory psych studies. But at some point I seem to recall that there were also instances where they claimed there was something called 'Operationalized Fukuda' which apparently was Reeves 2005. And also went as far as to work with the tired people in Wichita & Bibb County GA & call it just plain Fukuda anyway & there wasn't much of anything anyone could really do about it. Now, I may not be remembering this properly, but that is my recollection.

Lenny Jason just had an article in MedPage today about the issues with Reeves 2005, in relation to a recent CDC paper, mentions something called "Fukuda Empirical Criteria" which I don't think I've ever even heard of before, and asserts that pts fulfilling Reeves 2005 are still being selected for "ME/CFS research." I'm assuming there's a thread on this, but here's the link:

Spoiler: More on criteria used - Reeves, Fukuda, IOM, CCC?

https://www.medpagetoday.com/opinion/second-opinions/109274

Even if I'm getting some or much of that wrong, they still started out naming Reeves as one of the qualifying criteria, which should've generated outrage in the larger scientific community. But it was CFS, so...pfft. The noise made by the pt community forced them to drop it. But there were further shenanigans. I'm sure a lot of this has been hashed over in a thread I haven't been able to fully read, and also that Jeannette covered this in her blog, so apologies. But...that FAQ page they felt compelled to put up after the blowback about the criteria promising all pts would fulfill CCC was edited later in 2016. When presumably people weren't paying as much attention. The question about the criteria had been dropped from #1 to #10 sometime in early autumn, and it was now said that they would "consider" 1994 Fukuda & 2003 CCC 'along with other information.'

https://web.archive.org/web/20161027033201/http://mecfs.ctss.nih.gov/faq.html

The question itself was bizarre--it'd been "Will the ME/CFS patients satisfy the Canadian Consensus criteria?" and all of a sudden was "Are diagnostic criteria going to be used in the adjudication process?"

I do not remember hearing about this change at the time, though of course I could've missed it. Regardless...the IOM criteria are clinical criteria that were not designed to be used in research. They are devoid of exclusions and yes, they require PEM. Unfortunately, that requirement is satisfied by self-report. In the end they all pts fulfilled IOM, 14 "1994 Fukuda," and 9 CCC.

They didn't perform a 2-day CPET.

They started out trying to use a case definition @Dolphin has said, if I recall, is as bad as Oxford, possibly worse, and less than a year after publication of the IOM report. They changed their story. "All patients will be objectively tested for post-exertional malaise (PEM)" in the first FAQ. Then they changed it again. Plus in the first FAQ #6 asked about ME/CFS experts selecting pts & they named Unger, Lipkin, Walitt, Saligan, & Gill. Does anyone reading this trust those names? I mean, Lipkin might get an asterisk, but he's a virologist, not an 'ME/CFS' expert, and the rest to one extent or another are the epitome of who shouldn't have been anywhere near this, let along selecting patients.

In the second FAQ #9 names members of the ajudication committee: Bateman, Kogelnik, Natelson, Peterson, and...Komaroff, whose name is clearly visible on the peer review report.

Nothing against this list in particular, but, I'm sorry, I find it hard to trust that they could definitively determine that the selected pts were chosen properly. The test protocol that demonstrates the hallmark/cardinal/whatever feature wasn't employed. So how can anyone possibly know that 9 pts fuifilled CCC? Look, I don't want to get into this rude act of second-guessing diagnoses. It never goes well with arguments over people who 'recovered,' typically with NLP or exercise or LP or diet who don't know anything about the differences in criteria & insist "But I DID have CFS!" However...in research? Sorry. Why would a reasonable person trust that, in spite of every attempt they made to *not* apply criteria that would've been far more effective at selecting the pts they claimed to be studying, which they said straight up they were, until they didn't.

I don't know if this amounts to anything that could be credibly argued represents scientific misconduct. And I'm not sure how it can be linked to Walitt's garbage end product. But there is a history of researchers classifying pts as "CFS" pts when they weren't. Mary Schweitzer wrote a blog about this many years ago, how the CDC would respond to a given pilot study that produced a potentially novel finding by coming out with their own, on their own chosen cohort, which would find nothing. Dutch researchers published a study on CBT in CDC-defined CFS but dropped the 4-symptom requirement, called it CDC CFS anyway, and got it published in the Lancet. Hans Knoop recently published a glowing CBT study in CFS where they used Fukuda. Nobody cared. They still don't. NIH doesn't care & are obviously happy with this result. I can't imagine they'll take complaints seriously.

But they pulled some real crap here that I would like to think should mean something.

 

In other words you are the exercise physiologist and they are not?

“To document and assess PEM in CFS, a 2-day CPET was conducted to measure baseline functional capacity (CPET1) and provoke PEM. Twenty-four hours later, a second CPET assessed changes in related variables, focusing on PEM effects on functional capacity. This CPET also measured changes in energy production and physiological function, objectively documenting PEM effects.”

objectively documenting PEM effects.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10014750/

 

Edit: This may just repeat Hutan's immediately prior post but I wrote it anyway!

I am not sure what your rhetorical statement is intended to imply, @Mark Vink.
I agree with Hutan that the 2 day CPET is not actually a measure of PEM and I am not sure it helps that much to say it documents 'PEM effects'.

My understanding of PEM is that it is a symptom pattern - something that patients and physicians can agree on as in their sphere of expertise. Exercise physiologists may be very good at physiology, but that doesn't necessarily mean they have a good grasp of what PEM is.

My reading of the 2 day CPET data is that they seem to show a change in physiology that might be relevant to the fact that PWME often feel terrible and have even more difficulty doing things at a delayed time point after exertion. The change in physiology picked up cannot possibly be the cause of the PEM directly because the PEM, if felt, is felt before trying to do a CPET. Certainly my own post-exertional symptoms post Covid tell me just to go to bed and not bother even to do a little light pruning in the garden.

It would be reasonable to say that the 2 day CPET may be a way to objectively measure a component of the impact of exertion on physiology in ME. But it doesn't objectively measure malaise.

This may be pretty important because well-intentioned therapists will only too readily confuse the symptomatic pattern with some physiological shift they think they can monitor or even treat. And we are in the middle of such a confusion right now it would seem.

 

This is such a fascinating discussion and semantics are really important. The second CPET shows reduced physiological performance as a cardinal marker of exercise intolerance. In itself it is a post-exertional effect and yet as Hutan describes you can be "asymptomatic" approaching CPET #2 but still show this objective effect of post-exertion pathophysiology. PEM/PESE is so much more than reduced physiological performance at CPET #2, it's all the other symptoms that worsen. But are they biologically distinct? Is whatever is happening to muscles, mitochondria and cardiovascular system directly related to the other symptoms or separable? PEM can last a long time - can it be ongoing while the physiological performance would have returned to baseline at a CPET #3 (not that I'm suggesting that would be a wise idea).

I think we've commented before on evaluating with a 2xCPET equivalent for neurocognitive performance, to try and capture cognitive-induced PEM effects. But will that be the same: with the PEM symptoms uncertainly related to any demonstrated reduced brain performance?

Sorry to have diverted the thread and we may wish to move this part of the discussion to a PEM thread. Upthread I probably should have said: "And if one were to start a deep phenotyping study today, I think a 2 day CPET or some other objective demonstration of PEM exertion intolerance, and cerebrovascular OI objective data would be satisfactory study inclusion criteria or subgroup differentiators."

But I do wonder when mechanisms are clarified whether the two things will be inextricably linked yet mechanistically separable. Eg challenging impaired mitochondria puts them under further duress: the result is even more impaired ATP production (rapid onset, poor next-day performance, short term); and increased ROS generation (delayed but systemic effects, longer lasting).

 

So, the point is that meaning shouldn't be assigned to the term 'malaise' in the medical sense that doesn't necessarily apply.

Here's the problem. PEM has become a colloquial term & would seem to be a preferred term, as far as communications, to PENE or PESE or any other more specific alternatives. I wouldn't expect to see those used, for example, in the press, when the somewhat simpler, more basic PEM has been widely employed for some time now.

Two wrongs don't make a right, but considering how 'chronic fatigue' has only become even more weaponized as a way to avoid bothering with "ME," I wonder if there aren't better uses of energy to discourage the use of "PEM" which will likely only be taken as an attempt to play down the effect anyway. Even if we take the point that it may not necessarily be accurate. I'd see more urgency to address that if the whole world would stop already with the 'chronic fatigue' stuff. I wish I could be more focused on being on the correct side of every aspect of this, but we just saw "Science proves 'Long Covid' doesn't exist." I can't imagine any credibility is being risked on this point, as it's fairly consistent with how the revised consensus view on ME/CFS has been disseminated over the past decade or so.

 

Does it really? Wouldn't a BPS fanatic just argue, "these people are scared to exert themselves too often so they don't exert themselves as much the second time". What exactly is the physiological/biological finding that couldn't be misinterpreted as psychological?

Even if you run a study with similarly conditioned controls (for example via step-count or by taking sedentary controls) these will likely not be spending most of their time pacing and as such could have a different muscle structure, glycolytic fibers etc (i.e. pwME will mostly spend their life time in exercise "zone 1" and sometimes "zone 2", whilst sedentary controls have no problem being in "zone 4" occasionally) which could all explain differences in a second CPET, rather then these differences being PEM driven (@Jonathan Edwards mentioned this about Wüst et al's muscle biopsy study, which is where I have this idea from, but I'm not sure if it applies here as well).

It only seems sensible to me that any (repetitive) CPET study should always ask the participants whether they experience PEM before and after doing the CPET and I would think that in most study set-ups including travelling etc some people might already be in PEM at the first CPET and on the other hand as in @Hutan's case sometimes one might not even be experiencing PEM the second time around.

 

But what is a 'cardinal marker'?
Does cardinal mean the best available, or definitive, or always the case, or what?
Does marker mean correlate or something in a causal relation? Generally marker means correlate, and that is the issue.

As @EndME implies, the second day COET result might reflect some downstream shift in muscle structure as a result of a history of OEM episodes over months that tells us nothing other than that activity patterns have changed with symptoms.

 

True, that refutes "effort preference" things, but that possibly might not be enough to convince BPS fans as they might still claim the findings to be psychological if things like "anxiety" impact VO2max, which it could according to some studies?

I think the problem at hand is that unless the 2-day CPET procedure (with add-ons like muscle biopsy's, blood samples etc) can actually find something really biologically meaningful, the psychologists could always try to claim that is proves their beliefs about ME/CFS.