Muscle abnormalities worsen after post-exertional malaise in long COVID, 2023/4, Wüst, van Vugt, Appelman et al

Ravn said:
I agree that PEM remains poorly characterised - and even more poorly operationalised. Even the peculiar delayed start/peak of symptoms - which is well documented - is, in practice, being confused with DOMS by some. As for the more non-specific symptoms, we all know what a confused mess that is.

I also agree that a sharper characterisation of PEM could help focus minds on areas of research more likely to be revealing. Sure, PEM symptoms are most likely a downstream effect, but trying to work your way up from something at least somewhat specific, like the PEM delay, is more likely to bear fruit than doing so from something completely non-specific like fatigue. And knowing whether we should view symptoms after cognitive or physical exertion as same or different is relevant to assessing the value of different proposed mechanistic explanations

But I think achieving a better characterisation of PEM is going to be much harder than asking a few short questions. That's because we've all seen and internalised the memo that all types of exertion can cause all types of PEM symptoms. This may well be correct. Or not. I don't know. And I suggest nobody truly knows. We interpret our experiences in the light of the language and the stories we have at our disposal. We also tend to seize on the most memorable events when trying to establish causality and forget about all the other minor but cumulative exertions we do throughout the day. In the process we can mislead ourselves or others or both. Using my own fallible reasoning as an example (from another thread)

I actually once tested my reaction to purely cognitive exertion with a little experiment which I'm sure I wrote about somewhere in detail but I can't find it now. Briefly, I lay down and listened to some audio in one language and mentally simultaneous-translated until my brain shut down and I didn't even know what language I was hearing anymore. So no physical movement and no orthostatic challenge involved. Just hardcore thinking. I felt wiped out for I can't remember how long but a matter of hours. Next day: fine. No PEM.

This doesn't prove PEM (beyond the immediate and severe fatiguability) from cognitive exertion isn't possible, only that I can't push myself hard enough cognitively to get delayed PEM from cognitive exertion alone. But it illustrates the point that we can attach an incorrect story to our own experiences. Before my experiment I would have answered Simon's questions with 1. both 2. broadly similar and 3. broadly the same. After my experiment, my answers would be quite different
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I did a kind of experiment on myself while I had about 5 weeks of post-COVID symptoms (mostly cognitive issues + light sensitivity + fatigue, feeling like I needed to turn it in for the day by 1 pm). I had regular exposure to cognitive exertion by trying to work intensively as normal - I always recovered from it come the next morning. I tried vigorous cardio on an exercise bike for about 30 minutes, one time early in the day before I was wiped out and once late in the day after I was wiped out. Both times, I got very dizzy and cognitively useless and woke up still feeling the same for all of the following day, but much more strongly in the latter case where I was already cognitively exhausted before exercising. Felt like it transported me a fortnight backwards. I had no muscle pain or weakness in any of these scenarios.

So yes, my experience with a kind of PEM was definitely exercise-induced and not cognitively-induced. Just another anecdote and I am sure others may have different experiences and I do not wish to minimise those.

Sidenote (speaking of anecdotes) at another time I was disabled for nearly a year with effectively no physical activity and very minimised manual activity around the house. I had objective deconditioning evident from hand-grip strength tests recorded over time and undertaken by an unbiased professional. I had zero ME/CFS / LC -esque symptoms associated with my deconditioning ;).

So in my experience, empirical muscle deconditioning had no relationship to ME etc as I understand it (as we would expect, not being BPS people), while exercise, specifically, strongly induced something like PEM during a nasty post-COVID period.
 
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I did a power walk 5 week post Covid infection after I felt recovered and woke up the next morning unable to stand or walk for 3.5 weeks. No negative effect on my cognitive functions. It was not delayed PEM as I experience with M.E.

Same thing happened in 1992 post-infectious viral infection after 9 months. Exercised a bit and couldn't walk for 5-6 months after. It was my first "PEM" experience with no cognitive issues or other symptoms except for my legs muscles that I exercised.
 
Watch! Solve Ramsay Research Grant winner Rob Wüst, PhD presents "Skeletal Muscle Fatigue & Post-Exertional Malaise (PEM) in People with Long Covid & Implications for ME/CFS."

Dr. Wüst received a Solve M.E. Ramsay Research Grant in 2022 to study muscle pain, PEM, and treatments for pain and malaise in patients with diseases like Long Covid and ME/CFS. He found that, at the physiological and molecular levels, PEM differs from general fatigue. These differences have big implications for how physical exercise affects patients with Long Covid or ME/CFS.

In this webinar, Dr. Wüst updates us on his studies of these two central symptoms of Long Covid and ME/CFS (PEM and general fatigue), and answers questions from attendees.

Watch here:
https://ow.ly/fXYf50TCPwQ

https://twitter.com/user/status/1842264749020479863
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We are of the view that this interpretation is both scientifically unfounded and harmful to patients. Indeed, although we agree that intense exercise, such as the type tested, is not to be recommended, several studies have reported benefit from more gradual increases exercise both in patients with ME/CFS10 and patients with post-COVID-19 conditions11. It is particularly notable that no patient in these studies of the benefits of collaboratively graduated exercise had to stop because of worsening of symptoms1,11–15. An interpretation of the data that exercise is always harmful must therefore be robustly corrected.
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Nightsong said:
A letter from many of the usual suspects critiquing this study (think this is open access):

Link | PDF
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And of course the make the most of citing the Walitt 'effort preference' term
A recent study on chronic fatigue conditions, including ME/CFS, shows an alteration of effort preference, rather than physical fatigue, due to dysfunction of integrative brain regions, with consequences on autonomic functioning and physical conditioning9 . Therefore, an alternative explanation of post-exercise symptoms is that they result from the interaction between altered interoception (conscious and unconscious selfawareness of internal bodily state), allostatic load (failure of stress adaptation with perceived burden that influences how current and future energy needs are maintained) and peripheral influences (muscle fatigue).
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9. Walitt, B. et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nat. Commun. 15, 907 (2024).


And they reference the Cochrane review, though strangely citing the 2017 version even though they accessed it in 2023. Note that the 2017 version concluded:
"Patients with CFS may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes." [Larun et al, 2017]
The 2019/24 version is less definite about lack of harm.

Also quotes the dreadful living review of exercise for Long Covid that Garner also co-authored.
Indeed, although we agree that intense exercise, such as the type tested, is not to be recommended, several studies have reported benefit from more gradual increases exercise both in patients with ME/CFS10 and patients with post-COVID-19 conditions11. It is particularly notable that no patient in these studies of the benefits of collaboratively graduated exercise had to stop because of worsening of symptoms1,11–15. An interpretation of the data that exercise is always harmful must therefore be robustly corrected.
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10. Larun L., Brurberg K. G., Odgaard-Jensen J., Price J. R. Exercise therapy for chronic fatigue syndrome. Cochrane Common Mental Disorders Group, editor. Cochrane Database of Systematic Reviews. 2017 Apr 25 [cited 2023 Nov 16]; Available from: https:// doi.wiley.com/10.1002/14651858.CD003200.pub7
11. Zeraatkar D., et al. Interventions for the management of post COVID-19 condition (long COVID): Protocol for a living systematic review & network meta-analysis. Infectious Diseases (except HIV/ AIDS); 2024 [cited 2024 Nov 17]. Available from: http://medrxiv. org/lookup/doi/10.1101/2024.03.15.24304168

Garner and 2 people I don't know are listed as the main authors.
This has Garner's fingerprints all over it. I don't understand his zeal to make our lives worse.
 
Their response seems to largely be built around the intramural ME/CFS study with some references to the usual stuff.

I do think Garner et al actually raise one good point, one that had been discussed on S4ME a year ago, that “PEM symptoms and their duration described in long COVID or myalgic encephalomyelitis/chronic fatigue syndrome (ME/ CFS, in which PEM is commonly reported6) do not correspond to the post-exercise symptoms of known inflammatory myopathies, meta- bolic, or mitochondrial disorders7,8.” Perhaps some of the authors are avid readers of S4ME?

It is notable that they are citing the intramural study and that effort preference is being quoted here as “A recent study on chronic fatigue conditions, including ME/CFS, shows an alteration of effort preference, rather than physical fatigue, due to dysfunction of integrative brain regions, with consequences on autonomic functioning and physical conditioning9”.

I find it rather inventive to say that the intramural study is a study on “chronic fatigue conditions including ME/CFS”, when it is only a study on ME/CFS and nothing else. Perhaps they want these ideas to apply in a broader context?

Garner et al point out that “It is particularly notable that no patient in these studies of the benefits of collaboratively graduated exercise had to stop because of worsening of symptoms1,11–15.”. I think this is something worthwhile examining. What about the Magenta data?

“Nevertheless, the fear of developing PEM has the potential to contribute to a vicious circle of an attentional focus on symptoms, leading to exercise avoidance which itself worsens the symptom experience and leads to further physical deconditioning and associated disability.” Is a rather nice way illustrate the problem at hand. There are no improvements in their studies worth mentioning. If people aren’t dropping out because of a symptom increase it suggests they are dropping out because there are no improvements. This together with a lack of improvement to me suggests that their therapies are unable to address “fear-avoidance”, independent of whether this hypothesis bares any connection to reality. If fear and exercise avoidance lead to associated disability surely GET and CBT should improve disability status?
 
Nice response.

Wüst et al very elegantly picked up the following contradiction:
Ranque et al. state that our “findings have been widely interpreted in the media as indicating that exercise in people with Long COVID causes muscle damage and implying that people with Long COVID should not exercise”, but simultaneously agree “that intense exercise, such as the one tested in the study, is not recommended”, albeit without providing argumentation.
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and quite importantly
we disagree with the standard of evidence surrounding graded exercise therapy.
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Since Garner's critique also focused on possible problems occuring when trying to match activity levels of patients with healthy controls, but then goes on to cite the intramural study I do wander whether that wouldn't have provided additional room for debate. Wasn't the activity matching worse in the intramural study than in Wüst et al's analysis?

I do think there may be a few statements by Wüst et al that are maybe not particularly helpful:

"Long COVID is reported to be a heterogeneous disease, which is why we chose to focus on PEM, as ~90% of patients present with this symptom14." (is a reference to Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection, 2023, Thaweethai et al. which makes these claims look rather dubious, especially since the authors mention that PEM occurs only in post-infectious illnesses whilst PEM here is recorded in healthy controls as well).
 
EndME said:
"Long COVID is reported to be a heterogeneous disease, which is why we chose to focus on PEM, as ~90% of patients present with this symptom14." (is a reference to Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection, 2023, Thaweethai et al. which makes these claims look rather dubious, especially since the authors mention that PEM occurs only in post-infectious illnesses whilst PEM here is recorded in healthy controls as well).
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Where does the 90% figure come from?
 
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Utsikt said:
=The Oslo Chronic Fatigue Consortium
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They cited themselves citing themselves about their own work, which is based entirely on their opinions. There are corrupt monarchies that try a little harder than this at not being too obviously inbredly corrupt.

CCEirZAFRjNqmGFcTL6SagjByqh5FtjZqoYJPiOzNRg.jpg
 
InitialConditions said:
Where does the 90% figure come from? I can't access the paper cited. Does anyone have a PDF they could kindly send?
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Presumably from "Among participants with PASC, the most common symptoms were PEM (87%), fatigue (85%), brain fog (64%), dizziness (62%), GI (59%), and palpitations (57%) (Figure 2B; eTable 8 in Supplement 3)."

So in short 28% of infected people reported having PEM vs 7% of uninfected people. Subsequently roughly 90% of people that met the PASC definition had PEM (10% of infected people met the PASC definition). The PASC definition here is that there are 12 symptoms and each of these symptoms have a score attached to them (1 to 8), and then a certain score (12 or above) has to be reached to met the PASC definition. So it's "counting the number of certain symptoms" (they do note that "Higher PASC scores were associated with worse PROMIS Global 10 scores"). For example if you have "PEM+Brain Fog+Thirst" according to this LASSO model you would have PASC, alternatively you could have "Smell/Taste+Cough" and also have PASC whilst "Fatigue+Dizziness+PEM" alone wouldn't suffice in this model.

Of course that creates a bit of a circular argument when talking about rate of PEM because the PASC definition here is sort of built upon the fact that people have to have a certain point score, which is a lot easier to reach if they indeed have PEM (PEM is the most common symptom with the highest score at 7 points). A bit like saying 100% of people that meet the CCC suffer from both ME/CFS and PEM.

From what I can recall the point of using such a model was to offer a large as possible differentiation between people that reported problems after Covid vs a control group. That is why something such as "change in smell/taste" scores so highly, precisely because it is so Covid specific.

Given the high numbers of reported PEM in infected and uninfected people this is likely an overestimate.
 
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Trish said:
Also quotes the dreadful living review of exercise for Long Covid that Garner also co-authored.
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Oddly, it referenced the protocol (in preprint, though now published) rather than the actual review. I guess this simply reflects the BPS approach of make conclusions first then develop the evidence for them.

Indeed, although we agree that intense exercise, such as the type tested, is not to be recommended, several studies have reported benefit from more gradual increases exercise both in patients with ME/CFS [10] and patients with post-COVID-19 conditions [11].
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[11] Zeraatkar D., et al. Interventions for the management of post COVID-19 condition (long COVID): Protocol for a living systematic review & network meta-analysis. Infectious Diseases (except HIV/AIDS); 2024 [cited 2024 Nov 17]. Available from: http://medrxiv.org/lookup/doi/10.1101/2024.03.15.24304168
 
https://twitter.com/user/status/1889336899107696644



Minor addendum: part of picking VO2max is using respiratory exchange ratio or blood lactate concentration. Meeting these criteria has nothing to do with your perception of your body’s internal environment. You either have too much lactate or breathe off more CO2 than O2 or not.


Psychiatrists have never been able to figure out what to do with VO2max as an objective marker. It’s like their kryptonite and it can end the discussion rather instantly. The rest of it just becomes silly bullshit masquerading as a serious scholarly discussion after that.

Of course, this group also has added the wrinkle of seeming to fundamentally misunderstand deconditioning, but aside from that and not getting exercise testing, they seem to have the requisite grasp of the material necessary to participate in an exchange in a prestige journal.
 
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