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

Muscle Abnormalities Contribute to Post-Exertional Malaise in Long COVID

A poster presentation of the very soon to be published work by Rob Wüsts team has been uploaded to Twitter.

Paper now published, see post #8

https://twitter.com/user/status/1696272269641764949

 

Looks interesting, will be good to follow what Wuest and his team do. I don't know much about how to interpret muscle histological data like this, but - like with the WASF3 paper - I'm concerned about what the effect of deconditioning will have on muscles and therefore these results. Would be good to have disease controls who are deconditioned as a part of their illness. Maybe major depressive disorder you might expect to be less mobile? Or paralysis? Not sure.

Looks like the PEM associated differences are of amyloid deposition, and of 'necrosis' pictured here from the first poster:

Again I don't know what I'm looking at in that histology figure, is there someone who knows more who's able to comment? Is necrosis a normal part of muscle damage after exercise? maybe @Snow Leopard knows? I think I've seen them comment on this kind of thing before.

They say oxygen consumption rate is lower in muscle from long covid patients, which would be consistent with what Hwang et al say in their WASF3 paper (although for ME not long covid). Looks like they're arguing (in the second poster) that long covid patients have more glycolytic fibres, so maybe that links up with the reduction in citric acid cycle metabolites seen in the first poster (if these cells have reduced oxidative phosphorylation). We can't see their methods obviously so can't scrutinise that yet.

 

Agreed. I wanted to mention that all these patients seem to still be fit enough to partially work (at least that was the case for IDO2 study), were at least fit enough for hospital appointments 3 days in a row along with a bicycle test and have had Long-Covid for less than 1.5 years, so deconditioning might be slightly less of a big factor than in other studies, but of course has to be considered.

 

I find the histology here very difficult to interpret. The single picture of 'necrosis' shows an area of tissue without normal muscle fibre structure and what looks like white cell infiltration, but the picture is not good enough to be certain. Areas of inflammation and fibre damage occur after exercise normally but this looks quite marked - on the other hand it is probably the most extreme case they saw, so the one they show. It is hard to know what to make of it. I find it extremely hard to fit it in with what we know of Long Covid clinically. If this was significant I would expect the simple Creatine Kinase blood test to be through the roof. I did not see any mention of that.

The fluorescence pictures are weird. There seem to be little green fluorescent line structures in connective tissue including an arteriole. They cross the tissue planes, which is weird for amyloid. They also seem to be present between muscle fibres as dots or very short lines. The only thing I have ever seen that looks a bit like this is nerve fibres. I wonder whether they are picking up a non-specific carbohydrate component on nerve endings - I have made that mistake myself in the past.

If something serious was going on in muscle I think we would expect a simple CK to show it. I don't think anyone has even shown abnormal CK rises in ME after exercise. But I may have missed that.

 

They say the amyloid deposits do not block capillaries, and further increased with exercise.

The authors propose that amyloid depots might have something to do with PEM. I think I can understand why. Presumably if they are deposits, they don't form or degrade instantly, but take time to do so. And they will accumulate more with repeated activity if there is insufficient rest between the activity. That sounds very similar to the behavior of PEM I observe in myself. That would make these amyloid deposits candidates for being somehow involved in PEM.

 

An idle thought: might some of the advanced thermal imaging techniques available now tell us anything about differences in muscle function between ill people and sedentary controls? From what I've read on the board, it seems to be quite difficult to work with and compare muscle tissue samples, not to speak of the level of soreness for the participants. There must be other ways to approach it, surely?

 

At quick glance I can only find Publications on Amyloid deposition in skeletal muscle in relation to Amyloidosis

https://www.sciencedirect.com/science/article/abs/pii/S0046817798900612
https://jnnp.bmj.com/content/jnnp/60/6/655.full.pdf

and many more

 

The paper has now been published in Nature Communications.

Muscle abnormalities worsen after post-exertional malaise in long COVID

Abstract
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear.

With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise.

This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

https://www.nature.com/articles/s41467-023-44432-3

 

Merged thread

Guardian article:

People with long Covid should avoid intense exercise, say researchers

Study finds biological changes may explain why those with lasting symptoms feel muscle pain and fatigue for weeks after working out

https://www.theguardian.com/world/2...should-avoid-intense-exercise-say-researchers

 

Nice to see good articles from the guardian for a change. Wish ME was included in it somewhere too, but can't have everything(yet).

 

Fantastic to see it finally published. Still have to read it later.

Note that they're researching the same in people with ME as we speak.

 

The exercise results for 25 Long Covid patients showed poorer ventilation function, which some similarities to what Cook et al. found in 99 ME/CFS patients compared to fitness-matched controls. Cook for example also found higher VE/VCO2.


(This is from figure 3 in the supplementary material).

 

Cohort selection:

n=21 healthy controls (all with previous Covid exposure) vs n=25 Long COVID patients with PEM.
Controls are excellently matched according to the data presented (age, sex, BMI, no hospitalisations for acute Covid, vaccination, last known infection etc.). Perhaps males are somewhat overrepresented (47.6% respectively 48% in both groups).

The type of people studied in the LC cohort appear to be those that you want to study if you want to study PEM as part of LC (rather than possible noise like PICS, a continuing cough, pre-existing conditions etc.). The majority of them used to work full-time and now all work very reduced hours. This means that this is a cohort that isn't bed-bound and is still active enough with an average step count of 4000 daily steps to not be deconditioned and at the same time they are ill enough to expect a larger signal. They've also been sick long enough (minimum duration of 6 months, average duration of almost two years) and PEM was assessed via DSQ-PEM (some believe this not to be accurate enough, but it's certainly more accurate than asking "do you have PEM and/or fatigue" which is essentially what most studies are doing).

Would be interesting to see what a similar study would yield in severe and very severe patients with a control group of sedentary people.

An excellent cohort to study PEM in LC from what I can tell. I don't know enough about the Charlson Comorbidity Index, but it seems like it skews more towards severe comorbidities (I haven't looked at all the data, perhaps it might neglect some comorbidities of metabolic nature to some smaller degree). If I recall correctly the majority of these LC patients are healthcare workers that got ill during the first wave, but I don't see how that homogeneity would change much about the results (some things are overrepresented in this cohort, for instance anosmia at 12.0%, but I would think that those things shouldn't influence these results).

The largest caviat of this cohort is of course the small sample size for such a lab study. Using the same recruitment criteria it should however be easily possible for other groups (ideally this requires a team in a larger city like New York, London, Berlin or similar to conduct such a study, so that travelling doesn't skew results too much and that enough patients of these characteristics exist) to see if they can replicate the findings in larger cohorts.

 

https://twitter.com/user/status/1742875925358748131

 

Other thread about another publication by (some of) these researchers:
https://www.s4me.info/threads/prolo...of-sars-cov-2-infection-2023-guo-et-al.34402/

 

Lots of results in this paper.

They annotated 116 metabolites in skeletal muscle and 83 metabolites in venous blood. Many amino acids were not different between groups at rest, but tended to be lower in patients upon the induction of post-exertional malaise. TCA cycle metabolites were lower in skeletal muscle and blood in long COVID patients, but did not change during postexertional malaise.

They also found increased amyloidcontaining deposits in the skeletal muscle of long COVID patients at baseline. These were, however, not located in capillaries or lymphatic vessels, but in the extracellular matrix between muscle fibers. The authors write:

"We conclude that amyloid-containing deposits are not present within capillaries. 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 (Supplemental Figs. 3G, 6A) were not different." ​

Then they found more small atrophic fibers and focal necrosis in patients which increased significantly after exercise. And more Long COVID patients had CD68+ macrophage infiltration in skeletal muscle compared to healthy controls. They thought this might be due to mitochondrial DNA (mtDNA) fragments circulating in the systemic circulation, but this was not the case. They also did not find an increase in
muscle breakdown products, such as creatinine and creatine kinase.

They also looked SARS-CoV-2 nucleocapsid presence in skeletal muscle. They found it in almost all participants but the there was no difference between patients and healthy controls and therefore think this does not explain the limited exercise capacity.

 

I’ve not managed to read the paper yet. Does this tie in with other metabolites studies – eg The Glass, Hanson urine metabolite study?

 

Merged thread

Long Covid patients risk serious long-term injury from running or cycling

Long Covid patients risk serious long-term injury from running or cycling (msn.com)

 

https://nos.nl/artikel/2503701-long...n-zit-niet-tussen-de-oren-toont-onderzoek-aan

If it's on nos.nl I reckon it's getting circulation in the newspapers too. I'll try to get it onto some large forums in the Netherlands as well. The more people read it and the more often they read it, the better. I don't know if some people here have reddit accounts and would be able to get it onto the relevant subs there? Like r/news etc. I've thrown my away.

*edit* I know Ed Yong has a good article explaining PEM, but I can't remember which one it is. Could someone help me to that as the NOS description doesn't do it justice.

 

"Professor Steve Griffin, of Leeds University, said the study suggests “the approach to treating conditions such as long Covid, ME and CFS [myalgic encephalomyelitis and chronic fatigue syndrome] using graded exercise regimens is entirely flawed. Moreover, it appears that over-exercising under these circumstances is actually directly damaging”."

https://inews.co.uk/news/long-covid-patients-serious-injury-running-cycling-2837180