Trial By Error: Dutch Study Links PEM in Long Covid to Biological Abnormalities

By David Tuller, DrPH

A new study in Nature Communications, called “Muscle abnormalities worsen after post-exertional malaise in long COVID,” caused a stir after it was published last week. The investigators identified significant biological differences after an exercise challenge between long Covid (LC) patients with post-exertional malaise (PEM) and matched healthy controls who had recovered from acute bouts of COVID-19.

The study, which was conducted by a team of Dutch investigators, has received lots of media attention as well as buzz among patients, physicians and other researchers. It has also gotten some polite pushback from Professor Alan Carson, a neurologist and a leader of the movement to increase awareness of functional neurological disorder (FND) as well as a long-time associate of Professor Michael Sharpe, a co-author of the discredited and arguably fraudulent PACE trial. Professor Carson weighed in on X—formerly known as Twitter—and raised two issues, both of which seemed to be irrelevant and non-responsive to the actual findings. As a result, his comments seemed like non-sequiturs and left the impression that he hadn’t read or understood the research in question.

It is not surprising that Professor Carson might want to raise concerns about a study documenting biological differences between long Covid patients and healthy controls. He and his colleagues have been pushing the theory that many manifestations of long Covid are “functional”—that is, driven not by underlying physiological dysfunctions but by, among other factors, anxiety, depression, excessive focusing on symptoms, deconditioning, and disrupted brain networks. A necessary corollary of this argument is that biomedical research cannot identify pathways that adequately explain the extent of the reported symptoms.

The prospective, case-control study described in the Nature Communications paper included 25 LC patients and 21 matched healthy controls. All the LC patients suffered from post-exertional malaise. Both groups of participants underwent a cardiopulmonary exercise test on a cycle ergometer. Blood samples and muscle biopsies were taken before and one day after the exercise test. A key question for the researchers was whether they could identify markers that distinguished PEM from normal physical responses to exercise. As they wrote: “The extent to which the underlying physiology of impaired exercise capacity can be separated from factors related to the onset of post-exertional malaise remains unclear.”

The study, noting that it was  “observational in nature, and therefore…cannot establish causality,” reported a number of significant associations. Here’s a key section from the discussion:

“Patients with long COVID displayed a markedly lower exercise capacity, which related to skeletal muscle metabolic alterations and a shift towards more fast-fatigable fibers. The pathophysiology of post-exertional malaise includes an acute exercise-induced reduction in skeletal muscle mitochondrial enzyme activity, an increased accumulation of amyloid-containing deposits in skeletal muscle, signs of severe muscle tissue damage, together with a blunted exercise-induced T-cell response in skeletal muscle. Collectively, these findings help to decipher the underlying physiology of fatigue and a limited exercise capacity from the development of post-exertional malaise in patients with long COVID.”

(For a more in-depth look of the paper and the biological issues involved, check out the discussion on the Science For ME forum.)

The media ran enthusiastically with the news—a bit too enthusiastically, perhaps. Given the study’s small sample and the need to replicate the findings, cautious coverage would be warranted. In the past, stories about supposedly authoritative ME/CFS research—the 2009 Science study that linked the illness to a mouse retrovirus, the 2011 Lancet report on the PACE trial—have not aged well.

Here’s the headline on the National Public Radio’s web story: “A discovery in the muscles of long COVID patients may explain exercise troubles.” The Guardian’s headline declared: “Long Covid causes changes in body that make exercise debilitating – study.” (As noted, the study does not in fact make assertions about “causes” but about associations)

And here’s the top of the Guardian story:

“Many people with long Covid feel tired, unwell and in pain for lengthy periods after exercise, and researchers say they now know why.

“Experts say they have evidence that biological changes are to blame, such as severe muscle damage, mitochondrial problems and the presence of microclots in the body.

“It’s really confirming that there is something inside the body going wrong with the disease,” said Dr Rob Wüst, an author of the study at Vrije Universiteit (Free University) Amsterdam.”


Professor Carson raises silly questions on social media

Dr Wüst tweeted—or X’d–about the study. In a tweet of his own, Professor Carson wrote: “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?” (Professor Carson has blocked me.)

Professor Carson appeared to be suggesting that bed rest could be causing the poor performance of the LC group. This suggestion relates to the key role played by deconditioning in the BPS ideology, which attributes much of the symptomology to the effects of long periods of sedentary behavior. But the study itself already included a rebuttal of this point, noting that “the observed abnormalities are not reflective of physical inactivity” and that the LC patients “were not bed-ridden” and averaged 4,000 steps a day. In other words, they were definitely not deconditioned.

The effects of deconditioning are well-known; despite the creative hypotheses advanced by Professor Carson and his colleagues, these effects do not include ME/CFS or long Covid. The psycho-behavioral cabal’s continuing obsession with the purported role of deconditioning reeks of desperation. I mean, you might want to study whether LC patients who are in fact deconditioned respond differently to a bout of exercise than LC patients who are not. And it appears, from Dr Wüst’s response to Professor Carson on X, that a bed-rest study is soon to be published. The point is that, judging from Professor Carson’s comment, he believes this study is somehow incomplete or cannot be interpreted adequately absent such results. If he holds that view, he is wrong.

In a subsequent tweet, Professor Carson wrote: “As you note delayed onset muscle soreness has been recognised for at least 120 years and must ov [sic] course have a mechanism – i think thats where the issues of inference become key- but of course maybe your other data speaks to that.”

Like deconditioning, delayed onset muscle soreness (DOMS), is a well-known phenomenon. But the researchers essentially controlled for DOMS by including the healthy comparison group. A key point of the study was to tease out the standard impacts of exercise—such as DOMS–from the factors implicated in the pathophysiology of post-exertional malaise. The study documented that both the LC patients and the healthy controls experienced some similar physical setbacks from the exercise test. These shared changes would be linked to any experience of DOMS. The factors strongly associated only with the LC group are the ones that seem to help distinguish PEM from other effects of exercise.

People, this is not that complicated! But Professor Carson is apparently unable to grasp that his comments were beside-the-point. He would have done himself a favor and avoided possible embarrassment had he consulted someone with greater scientific acumen before posting his comments.

5 thoughts on “Trial By Error: Dutch Study Links PEM in Long Covid to Biological Abnormalities”

  1. I hope this can now be followed up on a larger scale.
    As for ‘silly questions’ – surely it’s far better in teaching to have silly questions that reveal the gaps than students sit silent not having a clue? ‘Thought-provoking’ may be a kinder description in that context though?

  2. “A necessary corollary of this argument is that biomedical research cannot identify pathways that adequately explain the extent of the reported symptoms.” – David

    ” it’s far better in teaching to have silly questions” – CT

    One professor, while giving a presentation, pointed out that there are no inappropriate (stupid, silly) questions so long as it is in a spirit of seeking a better understanding of an issue.

    So, forgive me for asking “where da psychons at?”

    This was provoked by a study that considered the atomic structure of SARS-Cov-2 compared with E. coli in the context of Eugenics influenced doctors who were enamored of the concept of psychons and “psychic organs” (The Advent Of The Psychons).

    Some of the stuff CT and David have commented on are in situations where today’s doctors are ‘kicking over the traces’ and they both want them to get back on the correct side of the border line.

  3. I’m not even sure if it makes any sense to discuss the comments by Garner and Carson at all. They’ve shown that they’re unwilling to contribute anything meaningful for years and that they’re unable to conduct rigorous research into this matter. When has Carson ever cared about cause or effect in any of his studies, he doesn’t even care about blinding…

    I desperately hope the study can be followed up by a larger study, ideally including some of the following
    – Bed-bound control group and bed-bound LC group (possibly without inducing exertion in the LC group due to severity, but just to quantify muscle abnormalities and to have a bed-bound control group to overall control the methodology).
    – Studying some less local abnormalities since PEM is not a local muscle response (this will be harder to do, possibly it can be accomplished by induced PEM and studying areas not directly involved in the exertion). Thus far these findings indicate something like a local inflammatory response.
    – More lab research trying to understand signs of necrosis without signs of muscle breakdown products in the blood.
    – Some doubts were mentioned about the robustness of the amyloid measurements in the small sample size. I hope those can be resolved via extra methods or larger cohorts. Perhaps they can even study how these deposits are eventually cleared up to some extent?
    – Comparison between this and an acute infection model.

    It would also be interesting to have a very severely affected LC group that has become disabled and inable to work (for instance a very severe neurocognitive phenotype without psychological abnormalities) that doesn’t have PEM, to see how much of a PEM specific reponse this. But this is far less important as it’s far more important too finally study PEM.

    If none of the above are possible due to non-existent funding than it would at least be lovely if the exact same metholodogly could be used but simply in a much larger cohort. I’m looking forward to the same work in ME/CFS. I hope they’ll then be publishing a pre-print which could already be available some time this year.

  4. Carson’s ‘Silly Questions” are the usual undermining of biomed research to try to put seeds of doubt in the minds of anyone reading his tweets.

    The FND and Psych Cabal are terrified for their careers and reputations.

    Every time good news pops up in M.E or Long Covid, I’m waiting on these people to launch some media release or social media attack.

    It’s getting tedious.

    Thank you for picking his silly questions apart.

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