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

[Sly Saint]

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

 

[rvallee]

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.

 

[DokaGirl]

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

 

[Hutan]

There is evidence to support specific exercise therapies as a cornerstone in the comprehensive management of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [1-4].

First sentence of the paper.

However, too vigorous exercise or activity [5-8] frequently triggers postexertional malaise in people with ME/CFS, a primary characteristic evident in up to 95% of people with ME/CFS [9].

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 addition, debate regarding the appropriate method of pacing exercise for people with ME/CFS remains.

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.

Previous work revealed increased expression of the lectin pathway (C4 and mannan-binding lectin serine protease 2) in PBMCs of ME/CFS patients in response to submaximal exercise, resulting in significant increase of C4a spilt product [10, 16]. It was hypothesized that people with ME/CFS are able to perform a self-paced, physiologically limited exercise without symptom exacerbations and without triggering complement C4a split product increase.

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.

 

[Hutan]

Postexercise complement C4a level was identified as a clinically important biomarker for postexertional malaise in people with ME/CFS.

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:

In the ME/CFS group, 12 patients used analgesics and 10 patients used anti-depressants. In the control group, 1 patient used anti-depressants. All participants were asked to refrain from taking their medication for at least 1 week before the start of the study and were instructed to stop medication use throughout the study period.

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?

 

[Hutan]

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

Respiratory Exchange Ratio (RER) is the ratio between the volume of CO2being produced by the body and the amount of O2 being consumed. This value of this ratio gives us an indication as to whether the body is operating aerobically or anaerobically.

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.

 

[Creekside]

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.

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.

 

[Hutan]

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:

IL-1β as well as elastase can be viewed as markers of the inflammatory response. IL-1β leads to widespread transcription of cyclooxygenase-2 in neurons, resulting in prostaglandin production, which in turn augments neuronal excitability in somatosensory pathways and triggers hyperalgesia [22]. In addition, IL-1 activates the hypothalamus pituitary adrenal-axis [23]. Cortisol and corticotropin-releasing-factor, two crucial players in the hypothalamus pituitary adrenal-axis, are both involved in pain sensitivity [24, 25]. Patients with ME/CFS have mild hypocortisolism, a blunted adrenocorticotropin response to stressors and an enhanced negative feedback, possibly explanatory for chronic widespread pain [reviewed in 26, 27]. A deficient hypothalamus pituitary adrenal-axis functioning might foster pathological immune activation with release of pro-inflammatory cytokines [28] like interleukin-1β, provoking a so-called ‘sickness response’ [29]. Too vigorous exercise might be one of the frequent stressors triggering IL-1β release and subsequent increased pain experience in patients with ME/CFS. Therefore, it was hypothesized that submaximal exercise as opposed to self-paced, physiologically limited exercise, triggers IL-1β release and related pain increases in people with ME/CFS but not in healthy sedentary controls.

So, their hypothesis doesn't seem to be well supported by IL-1B levels.

 

[Hutan]

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:

The level of complement C4a following submaximal exercise was identified as a clinically important biomarker of postexertional malaise in people with ME/CFS.

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.

Baseline elastase activity, but not complement C4a level, was found to be higher in the ME/CFS group compared with the control group (P = 0.013). However, neither immune variables changed in response to the self-paced and physiologically limited exercise (P > 0.05) (Table 5). There was no group × time interaction for either immune variables (refer to Fig. 3 for complement C4a level changes).

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.

We were unable to find evidence in support of immune alterations in response to either type of exercise, in either group. This might indicate that the biological parameters measured are not involved in the pathogenesis of postexertional malaise. However, previous studies showed that people with ME/CFS respond to an exercise challenge with increased expression of the lectin pathway (C4 and mannan-binding lectin serine protease 2) in PBMC’s, resulting in significant increase of C4a spilt product [10, 16]. However, our results are not in contradiction with those earlier reports. First, the increase in complement C4a split product became apparent at 6 h after exercise [10]. In the present study, peripheral blood levels of C4a were measured only at 1 h after exercise, a time-point at which Sorensen et al. [10] were unable to find changes in circulating C4a levels either.

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.

Both types of exercise triggered postexertional malaise in people with ME/CFS. However, neither types of exercise altered elastase activity, IL-1β or complement C4a split product levels in people with ME/CFS or healthy sedentary control subjects. Furthermore, the change in complement C4a level was strongly related to the increase in pain and fatigue 24 h following the self-paced, physiologically limited exercise. Postexercise elastase activity level and the change in elastase activity level were inversely related to the fatigue increase 1 h following the self-paced, physiologically limited exercise. The level of complement C4a following submaximal exercise was identified as a clinically important biomarker of postexertional malaise in people with ME/CFS.

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.

The self-paced, physiologically limited exercise protocol applied strategies used to implement ‘safe’ exercise therapy and self-management for people with ME/CFS [2, 15]. In a previous study, we applied a similar but less stringent approach to limit postexertional malaise in people with ME/CFS: it was shown that the use of exercise limits (limiting both the intensity and duration of exercise) prevents important health status changes following a walking exercise in people with ME/CFS, but was unable to prevent short-term symptom increases [14]. Based on that experience, we made the exercise limits more stringent by decreasing the intensity to 80% of the heart rate corresponding to the anaerobic threshold of the first (submaximal) exercise. Nevertheless, it was unable to prevent postexertional malaise in the women with ME/CFS studied here. These results highlight the fact one should be cautious when using exercise in people with ME/CFS.

A typo:

However, elastase activity was not triggered in either groups, suggesting that exercise will not have delirious consequences on the ribonuclease L enzyme either, although this requires further empirical testing.

(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.)

 

[rvallee]

Ugh. Not exactly stellar, then. And the complement thing is nonsense, a single result from a single study.

The self-paced, physiologically limited exercise protocol applied strategies used to implement ‘safe’ exercise therapy and self-management for people with ME/CFS

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.