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

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.

 

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?

 

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.

 

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.

 

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.)