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

Of relevance to the amyloid question, the peer review file contained —

Authors replied —

We are aware of the work that other scientists have done on endothelial dysfunction in patients with long COVID. There is however not a single marker for endothelial abnormalities and endotheliitis, and as such, drawing conclusions from the results of one particular marker is, in our opinion, inappropriate. Such a study requires a more elaborative approach from different angles, and as such, we reason that studying endothelial dysfunction in long COVID and its potential link with exercise intolerance and the development of PEM requires multiple new experiments. This would, in our view, slow down the current publication specifically targeting skeletal muscle aberrations and post-exertional malaise. We have added this avenue for future research to the discussion, as the reviewer suggests.

Discussion, page 9, line 323-326: “We only evaluated the presence of amyloid, but not the function of the endothelium, or local blood flow. As such, the possible contribution of chronic endotheliitis or reduced blood flow to the development of post-exertional malaise and/or exercise intolerance in long COVID remains open (Charfeddine et al, 2021, Turner et al, 2023)”​

Authors replied —

In this article, we tested the notion that accumulation of amyloid-containing deposits inside capillaries causes local hypoxia by local stoppage of blood flow. This has been hypothesized to be the cause of the diverse symptoms of long COVID (Kell et al. 2022, Aschman et al, 2023), and this was what we intended to address here.

We agree with the reviewer that a halted RBC flux is a possible reason for a potentially reduced blood flow. Unfortunately, we cannot directly measure microvascular blood flow, and do not know if local blood flow is reduced. The measurements suggested by the reviewer are presently intractable in humans and unfortunately, thus not possible for us to verify in this cohort. No animal model of Long COVID currently exists, to verify this hypothesis.

As opposed to the hypothesis, our NIRS-derived muscle deoxygenation data does not support the theory that a reduced microvascular blood flow and lower local O2 delivery causes hypo-circulation in skeletal muscle during exercise, although we realize these data are not conclusive.

There are various other potential mechanisms that can explain a potentially reduced O2 transport in patients. Since we do not find proof of an impaired (or unimpaired) blood flow, we prefer not to speculate about possible ways by which (local) blood flow can (or cannot) be impaired in long COVID.

In light of the reviewer suggestions, we have now revised the results section to include the following revised text:

Results, page 6, line 205-210: “Neither did we observe any signs of skeletal muscle tissue hypoxia, as the skeletal muscle capillary-to-fiber ratio, capillary density (Fig.2B) and intracellular and circulating lactate concentrations (ED Fig.3G+6A) were not different between long COVID patients and controls. Therefore, we conclude that post-exertional malaise cannot be explained by the hypothesis that these deposits block vessel perfusion, causing local tissue hypoxia (Kell et al. 2022, Aschman et al, 2023).”

And also within the limitations section of the discussion, to highlight that functional impairments may still persist:

Discussion, page 9, line 323-326: “We only evaluated the presence of amyloid, but not the function of the endothelium, or local blood flow. As such, the possible contribution of chronic endotheliitis or reduced blood flow to the development of post-exertional malaise and/or exercise intolerance in long COVID remains open (Charfeddine et al, 2021, Turner et al, 2023)”​

 

Had a quick look at the R file they used for the statistical analysis and I think that the errorbars in figure D and E are just a standard deviation from the mean. For the healthy group they show it going upward, and for the Long Covid group going downward. The statement 'the whiskers show the 1.5× interquartile range' probably only applies to figure 1 A, B, and C.

 

On a lighter note, I did chuckle at the Dutch sense of humour —

Response: There is no mention of “sex” in line 410, and we assume a typo of the reviewer. We remain open to suggestions.​

 

Didn't Hanson do a metabolite study post-exercise?

 

The Times has an article on this study today, which includes mention of ME.

Long Covid changes your muscles, scientists find (thetimes.co.uk)

"People with myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome, also report suffering from PEM."

If someone with more scientific expertise than me has time/interest, I wonder if it might be useful to collate the feedback and questions in this thread into a concise email to be sent on behalf of the S4ME Committee to the corresponding author? If the same team is in the process of doing the same study in ME, it might be feasible to incorporate and address some of the feedback in their on-going work.

 

van Vugt on National TV yesterday, unfortunately no translation in English:

https://twitter.com/user/status/1743019924140794356


PS
Shocked by all the comments under this tweet, about 90% by people blaming vaccins

 

I feel there's a fair bit of gatekeeping going on with regards to LC with people pointing each other to posts they can "attack".

 

All of this, & indeed other recently published research, reminds me of why we need GWAS studies (like DecodeME) i.e. to focus research on the most promising areas. I think I recall Simon M posting that we've had decades of hypothesis drive research and it's got nowhere.

 

For that it is crucially important that someone actually tries to replicate already existing research, which requires the research to be methodologically strong since the replication crisis is to a very large extent a methodological crisis. It's equally important that if findings can't be replicated that negative results are published as well, since negative findings are just as valuable as positive findings. Unfortunately, some research groups seem to be just jumping from hypothesis to hypothesis, without ever providing much evidence of the hypothesis being true or why they abandoned it.

A couple of weeks ago there was comment that alluded to the fact that muscle cells appear to look normal in patients with ME/CFS. Not knowing nearly enough about past research I was of the impression that Rob Wüst was one of the first people to have looked at this. @Andy was quickly able to change my mind as he posted an abundance of studies that had looked at similar things in the past. Unfortunately, after having a looked at these studies I'm none the wiser. They all varied extremely heavily in the methodology as well as in the recruitment criteria they used (unfortunately very often Fukuda).

In my eyes the work by Wüst et al carries many properties, most prominently w.r.t. to cohort selection in LC patients, that are needed for others to see if they can replicate these findings and if not what phenomena could explain these anomalies. Apart from Wüst conducting the same research in ME/CFS, I hope someone picks this up in a larger cohort (including bed-bound patients as well as bed-bound healthy controls) and possibly even examines connections to the work of other groups (for example the muscle findings by Hwang or PEM w.r.t. cognitive exertion).

 

Twitter/X exchange between Alan Carson and Wüst:

Carson: “Interesting and longitudinal design helpful - but small so needs replication but also needs a bed rest or similar comparison - are we seeing the cause or the effect?”

Wüst: “Dear Alan, please bear with me for 2 weeks, when we publish our results of a bed rest study in Cell Reports Medicine. I am also excited to see this work replicated elsewhere, but this work is in line with previous studies on similar topics (even one dating back from 1980s)”

Wüst: “Also, it’s important to remember that people undergoing bed rest get better when they start exercising again, but this is not the case in long COVID patients. They get worse…”

Carson: “Look forward to reading it. As you note delayed onset muscle soreness has been recognised for at least 120 years and must ov course have a mechanism - i think thats where the issues of inference become key- but of course maybe your other data speaks to that

 

Good luck to Carson if his last hope for him not to be absolutely wrong is DOMS… I would love the sweet feeling of DOMS instead of PEM, not least being able to exercise in a way that would provoke DOMS.

 

More clutching at straws I'd imagine. Trying to sow a little discord etc. It isn't taking roots anymore, it seems.

 

Only the affected muscles causes DOMS. Delayed PEM and loss of muscle power affects ALL muscles.

 

They should also test the smaller percentage of pwME who don't experience pain during delayed PEM. I've never experienced pain.

 

Most of the framing, and in fact many headlines, has been around "intense exercise", so I don't think this will change anything to their belief system, they will simply insist that they were always right about the need for a slow, gradual build-up in activity, and how their own writings advising to ignore the symptoms was taken out of context, or whatever. I suspect they will simply pivot to making it fun, motivational, instead. The LP is perfect for that, it doesn't really feature exercise per se. It won't change anything for them until the institutions turn away from their ideology, and that is a long way down.

I saw that Alan Carson referred to this as delayed onset muscle soreness, which is nonsense. But these people have thrived for decades on nonsense, so they will never change. The only question is whether the rest of the profession can act professionally about it, recognize the harm that they did, and are still doing. It may change the minds of, at least, a few dozens, but I won't be holding my breath.

 

A screenshot of this or most of it is here:

 

Yeah this is just normal these days. Medicine rejecting the reality of chronic health problems following COVID has allowed for the antivaccine crowds to completely fill the space. This will have huge consequences, but to be fair it was always obvious that it would. This is why public health textbooks advise to tell the truth, because being caught in a lie means that people simply stop listening to you. And they have.

 

More nonsense from Carson. Either that or he is ignorant that most pwME or LC don't extensively bed rest all the time. It's not like it's hard to find data about what % are severe enough to be house- or bed-bound. There is no need for that except for a cohort of severe ME/LC patients, and even then it doesn't make much sense as it's very hard to do well. Controls would have to be monitored 24/7 in a facility for a solid control, and no one's budget allows for that.

Unless of course we can simply take their budget for it. Then that would make sense. But only if it takes from their psych budget, without more being added to compensate. If they cared about anything, if they wanted to know the truth rather than simply being known as the truth, they would be willing to do that. But they don't, so this won't be happening.