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

True. But neither do CPET studies or any studies that rely on provoking PEM based on a physical challenge.

 

Maybe, but the poetinsf's point remains I think.

Also, the CPET studies suggest some general metabolic shift after exercise, which might tie to feeling generally unwell. The present study indicates local muscle changes that might be more likely to tie to delayed muscle soreness than general symptoms.

In my experience of being limited post Covid, there is no problem with local muscle symptoms. I am just drained out.

I am not sure that either tell us what we want to know but I have some sympathy with Carsons's scepticism - but for different reasons.

 

Does the paper claim to account for PEM caused by mental exertion?

 

Maybe not but the title says that muscle abnormalities 'worsen after PEM' (unspecified).
I think researchers should be more careful about the way they present things. In the old days you presented your findings and let readers interpret, as far as possible. These days abstracts, discussions and summary statements and even results sections are full of interpretation for the benefit of the reader.

The study actually shows muscle changes after muscle exercise, but most people are likely to assume that there is a link to PEM. I am not sure it even explains PEM after physical exertion.

 

No it doesn't, but we need to. The study presents muscular changes and putatively link it to PEM. It's possible that the observed physiological change is real, and I 'll have to assume it is till it fails to replicate, but it's hard to imagine PEM having separate mechanisms for physical and mental exertion. As far as I know, PEM is singularly defined as "worsening of symptoms after a physical or mental exertion"

 

During the period of 8 years early M.E w/o cognitive issues, I did experience severe cognitive impairment during delayed PEM after exercise for 3+ days. They are related.

I'm not sure if immediate mental exertion is the same though since I recover from this within an hour. I'm guessing in my case it's mostly OI related since it's quickly relieved after lying down.

 

By definition there'd have to be some difference in the mechanism, wouldn't there? Or at least in the initial phases of how a mental or physical exertion would be translated into PEM? In any event, it would be a good question to ask Dr Wust, if I get a chance to talk with him.

 

From the paper,
"The most reported symptoms of long COVID include limited exercise tolerance and post-exertional malaise, representing the worsening of symptoms after mental or physical exertion"

and

"In this study, we systematically induced post-exertional malaise in a cohort of 25 well-defined patients with long COVID and controls. We obtained blood and skeletal muscle biopsies before and after a maximal exercise test (Supplemental Fig. 1) with the aim to study the biological factors contributing to the limited exercise capacity and post-exertional malaise in long COVID."

So their claim is that they are studying PEM after physical exertion. As is noted, PEM is defined as "the worsening of symptoms after mental or physical exertion", so it is clear they are claiming to be studying PEM after physical exertion, not mental.

Also from the paper,

"This study is observational in nature, and therefore we cannot establish causality. We only included individuals with severe long COVID, but the observed abnormalities are not reflective of physical inactivity."

"As the sample size of this study is relatively small, our results require replication in other cohorts."

"While these explain the symptomatology of post-exertional malaise in long COVID, the molecular pathways underlying these alterations in patients suffering from post-exertional malaise remain to be determined."

Do we need more clarity around PEM, sure, and this paper is obviously not going to be the complete explanation of PEM, but I think criticising the authors for it not being so is being unfair on them, especially when they highlight replication is needed.

 

Yeah, that "initial phase" will have to lead to a common mechanism, something like physical, mental -> inflammation -> PEM, for example. But physical->muscle change->PEM does not leave much room for a common pathway. I think it is best to leave it as muscle change after exercise without any link, putative or otherwise, to PEM and wait till someone to replicate.

 

It seems to me that putting PEM in the title begs an awful lot of questions.

I have clearly had some form of 'Long Covid' and I got exhausted after minimal exertion. But I am not at all sure that I would want to call that PEM - which I regard a response with at least some of the time an anomalous delayed time relation of a 'snakes and ladders' type that puts people back to being ill for an extended period.

I sounds to me as if they are studying worsening of symptoms such as exhaustion after exertion, and I don't think that is enough to use the word PEM as in ME.

The requirement of six months for the diagnosis of ME makes no sense in one way - in that people are needing a diagnosis and help from the start - but it makes sense in another way in that it indicates that an anomalous long term time response has kicked in. The people in this study may have the PEM of ME but the study is looking at muscle changes after exercise. I think any relation to 'PEM' should be limited to the discussion.

 

Neither the ICC, CCC or IOM criteria for ME/CFS require PEM to be delayed. While I am fully in agreement that PEM should be defined as something that occurs after an unusually long delay, currently it isn't, so it seems to me that the authors are justified in calling what they are studying PEM.

 

Interesting, I'd forgotten that. It needs clarifying, then, if it isn't to cause confusion.

 

The Conversation
Long COVID: damaged mitochondria in muscles might be linked to some of the symptoms
by Caroline Dalton, Associate Professor of Neuroscience and genetics, Sheffield Hallam University

Quotes:

PEM remains one of the most debilitating yet least understood features of both ME and long COVID. But new research may point to a probable explanation for why physical activity in particular worsens long COVID symptoms. The study found that people with long COVID exhibit alterations in their muscle structure.

...

This is not the first time that mitochondrial dysfunction has been implicated in an illness featuring PEM. In fact, this was first proposed as the underlying mechanism in ME more than 40 years ago.

...

Traditional programmes work on the basis that gradual increases in effort and difficulty build resilience and exercise capacity. But for people with long COVID, the opposite is true.

This recent paper has now found why this may be the case, showing that for those with long COVID, pushing beyond their capabilities will provoke mitochondrial damage, reducing resilience and provoking a relapse of their condition. These findings are key when considering recommendations for rehabilitation or return to work strategies for long COVID sufferers.

(ETA: Added an extra quote)

 

Which just shows what garbage diagnostic criteria by committee are!

 

That is not the interpretation an eminent mitochondrial expert gave me by email!

 

Maybe I missed you doing so earlier, but could you say more about this expert interpretation?

 

Not a lot other than it was suggested that there is way of knowing what is cause and what is effect when it comes to the mitochondrial side of things.

 

I broadly agree with your very broad and important point, and Occam's Razor is with you.

Though I wouldn't completely rule out there being independent types of mental and physical PEM (because a small but significant proportion of pwme have no mental-triggered PEM and some here report mental and physically triggered PEM feels quite different; think this needs further investigation).

 

I'm not sure how much to worry about this. My experience of physical, cognitive, digestive, sleep, and sensory symptoms in the first two days of PEM is a near-perfect match for the onset of a respiratory virus, which suggests they have something in common.

That brings @Sean's point back in. Downstream effects don't necessarily reveal the cause, specially if they can be prompted by anything from influenza to mild alcoholic poisoning.

I'm not against studying PEM, of course. I just wonder whether some of the differences in our symptoms are more down to individual makeup and/or level of severity than the phenomenon itself. There are differences in the way people experience acute illness too.