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Unravelling the nature of postexertional malaise in ME/CFS: the role of elastase, complement C4a and interleukin-1β 2010, Nijs et al

Discussion in 'ME/CFS research' started by Sly Saint, Oct 23, 2022.

  1. Sly Saint

    Sly Saint Senior Member (Voting Rights)

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    Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β

    Abstract
    Abstract. Nijs J, Van Oosterwijck J, Meeus M, Lambrecht L, Metzger K, Frémont M, Paul L (Vrije Universiteit Brussel, Brussels; University College Antwerp, Antwerp; University Hospital Brussels, Brussels; Private Practice for Internal Medicine, Gent/Aalst; and RED Laboratories N.V., Zellik; Belgium, and University of Glasgow, Glasgow, UK). Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β. J Intern Med 2010; 267: 418–435.

    Objectives. Too vigorous exercise or activity increase frequently triggers postexertional malaise in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a primary characteristic evident in up to 95% of people with ME/CFS. The present study aimed at examining whether two different types of exercise results in changes in health status, circulating elastase activity, interleukin (IL)-1β and complement C4a levels.

    Design. Comparative experimental design.

    Setting. University.

    Subjects. Twenty-two women with ME/CFS and 22 healthy sedentary controls Interventions: participants were subjected to a submaximal exercise (day 8) and a self-paced, physiologically limited exercise (day 16). Each bout of exercise was preceded and followed by blood sampling, actigraphy and assessment of their health status.

    Results. Both submaximal exercise and self-paced, physiologically limited exercise resulted in postexertional malaise in people with ME/CFS. However, neither exercise bout altered elastase activity, IL-1β or complement C4a split product levels in people with ME/CFS or healthy sedentary control subjects (P > 0.05). Postexercise complement C4a level was identified as a clinically important biomarker for postexertional malaise in people with ME/CFS.

    Conclusions. Submaximal exercise as well as self-paced, physiologically limited exercise triggers postexertional malaise in people with ME/CFS, but neither types of exercise alter acute circulating levels of IL-1β, complement C4a split product or elastase activity. Further studying of immune alterations in relation to postexertional malaise in people with ME/CFS using multiple measurement points postexercise is required.

    https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2796.2009.02178.x
     
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  2. rvallee

    rvallee Senior Member (Voting Rights)

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    Oh, that's useful with the current nonsense over "loss of fitness" or losing the edge in exercise, how it completely misunderstands that it's about exertion and that it can be as low as simply sitting up once. Because in the mind of most physicians, "too vigorous activity" is what's at, some common limit that shouldn't be crossed but is similar between people, when there is no such thing, it's not at all about exercise, it has nothing to do with exercise, it's exertion, of any kind, of any intensity, good or bad, fun or awful.

    The fact that it's somehow impossible to reconcile how post-exertional symptom exacerbation relates to exertion, of which exercise is the highest intensity kind, is maddening. Both are discussed as if completely unrelated and with zero overlap. But it's understood as post-exercise fatigue thanks to our patient-hating charlatan overlords, so all of this is missed.

    There is no level of safe exertion, it depends entirely on the individual and as much as on a minute-by-minute basis. This shouldn't be hard to people who clearly can deal with the reality of the same initial issue, COVID, can kill so many, badly injure some, while many others barely have any symptoms. One cause, many outcomes. This is not hard at all.

    All of this is holding off the cognitive side, too. Everything is made about stress or emotions, when it's all about exertion, the brain uses energy, too.

    Of course since this is about ME and it's still taboo, it will be a while until this can be applied onto LC and understood correctly. Because we are still on the black list.
     
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  3. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    Many times over the years I have felt physically and cognitively exhausted after a 10 to 15 munute phone call. Laying on the couch talking on the phone to anyone.

    No vigorous exercise there.

    After mild physical exertion, my body and brain both feel taxed. This manifests as tired painful muscles, fatigue, unusual headaches, and an inability to continue with physical and more cognitive tasks. Rest in the form of laying down is required
     
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  4. Hutan

    Hutan Moderator Staff Member

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    First sentence of the paper.

    The researchers don't see PEM as a mandatory diagnostic criteria for ME/CFS. Also the framing of "bad" exercise or activity is that it is "too vigorous". Actually, we don't know if a short burst of vigorous activity is worse or better than a longer period of moderate activity. The researchers have not conveyed, and perhaps themselves don't understand, how simply sitting up chatting can be too much. Or the cumulative effect of activity for triggering PEM.

    In the researchers' minds, the debate is not about whether people with ME/CFS benefit from exercise therapy, but rather what sort of exercise therapy.

    So, that's where these researchers are coming from - they think exercise is causing a reaction, but that by undertaking increasing amounts exercise that doesn't cause symptom exacerbation, people with ME/CFS can exercise themselves out of the disease.

    Reference 10 by the way is
    10 Sorensen B, Streib JE, Strand M et al.Complement activation in a model of chronic fatigue syndrome. J Allergy Clin Immunol 2003; 12: 397–403.
    That study reports finding that
    "Exercise challenge induced significant increases of the complement split product C4a, but not C3a or C5a, at 6 hours after exercise only in the CFS group (P < .01), regardless of allergy status."
    So this 2010 study aimed to investigate that finding. And that's interesting.
     
    Last edited: Oct 23, 2022
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  5. Hutan

    Hutan Moderator Staff Member

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    That's quite a big and consequential statement, but it's oddly downplayed in the conclusions where the researchers just call for more study of immune alterations.

    So, what did they actually find?

    Well, I haven't got to what they found yet, but I just have to divert briefly to note this:
    That's nearly half of the women with ME/CFS (there were 22 people with ME/CFS, all women) taking anti-depressants! (and half taking analgesics). And, what's worse, they were asked to abruptly stop taking the anti-depressants just before the trial. Goodness knows what that would have done for subjective reports of wellness, let alone physiology. I guess this was in the time before there was an understanding of the problems caused by rapid changes in anti-depressant dosage.

    To me, that high rate of anti-depressant use indicates something very wrong in the approach to care of people with ME/CFS in Belgium back in 2010.

    Another aside, the selection criteria is Fukuda and they don't actually say that PEM is a requirement. The women were also required to have chronic widespread pain.

    It took me a while to note that this paper is from 2010. @Sly Saint, it's an interesting paper, but what prompted you to make a thread for it now?
     
    Last edited: Oct 23, 2022
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  6. Hutan

    Hutan Moderator Staff Member

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    Screen Shot 2022-10-24 at 8.01.15 am.png

    Screen Shot 2022-10-24 at 8.01.36 am.png

    First I note the very short duration of the exercise. 4 minutes or so of cycling. I think that the impact of this exercise challenge could get lost in the noise of the other activity of the person's day including the effort of getting to the test facility.

    Check out the differences in RER

    The RERs for people with ME/CFS are very high for 4 minutes of cycling. Even the RERs for the controls look abnormally high - over 1 for sub maximal exercise and even higher when the person is doing even less intense exercise.
     
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  7. Creekside

    Creekside Senior Member (Voting Rights)

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    Some of us, myself included, can do fairly strenuous exertion without triggering PEM. I've had periods where I've done strenuous daily exercise (long hikes, digging soil) for weeks or even months. None of that reduced my ME symptoms. The reduction in ME symptoms was the cause of doing more exercise.
     
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  8. Hutan

    Hutan Moderator Staff Member

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    IL-1β
    They didn't find any detectable IL-1B before or after either bouts of exercise in the ME/CFS group of the controls. This was in line with the study that was Reference 10 - and that study made measurements at more time points than just 1 hour after exercise.

    This is quite funny, as the Introduction presented a story of HPA axis problems and bouts of ''too vigorous exercise" among other stressors driving the release of pro-inflammatory cytokines including IL-1B:
    So, their hypothesis doesn't seem to be well supported by IL-1B levels.
     
    Last edited: Oct 23, 2022
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  9. Hutan

    Hutan Moderator Staff Member

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    Getting to the molecule that was proclaimed as a biomarker in the abstract:
    Complement C4a level

    First activity challenge
    Baseline: ME/CFS 1790.4 ± 424.3 Controls 1901.8 ± 398.4
    1 hour Post-exercise: ME/CFS 1645.9 ± 503.6 Controls 1654.5 ± 399.9
    Because the drop in C4a coincided with an increase in reported PEM symptoms, the authors concluded in the discussion:
    I'm sorry, but that's just crazy talk. The controls had a bigger drop in C4a and they managed to continue going about their lives without PEM. There was no statistical difference in C4a levels between the two groups at baseline.

    For what it is worth, here are the figures for the second activity challenge
    Baseline: ME/CFS 1786.5 ± 371.1 Controls 2019.5 ± 335.1
    1 hour Post-exercise: ME/CFS 1564.7 ± 514.8 Controls 1778.4 ± 512.7

    There does not look to be much there.
    What I can't understand is why they only measured C4a one hour after exercise when they already knew that a previous study had found that the change only became apparent 6 hours after exercise. It seems like a study designed to produce a null result.



    That conclusion is a mass of contradictions. Maybe the most important finding is that even the type of exercise intervention where they bent over backwards to make it as non-PEM causing as possible still apparently caused PEM.

    A typo:
    (I also don't understand how they can in the one breath be saying that although C4a levels didn't drop at the one hour mark, C4a levels might drop abnormally 6 hours after exercise, and in the next breath be suggesting that the fact that elastase didn't drop at the 1 hour mark tells us anything much about exercise having effects, delirious, deleterious or otherwise on ribonuclease L enzyme. Perhaps they just didn't measure the right things at the right time.)
     
    Last edited: Oct 24, 2022
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  10. rvallee

    rvallee Senior Member (Voting Rights)

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    Ugh. Not exactly stellar, then. And the complement thing is nonsense, a single result from a single study.
    But they clearly misunderstanding pacing. In fact the exact opposite meaning. As usually happens. The Orwellian use of pacing to mean the opposite of what it means is endlessly revolting.

    So, seriously, is most medical research just plain bad? Even when a few things are done right, so many details aren't. And science is really all about details. Not here. Definitely not here. We are in such awful hands.
     
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