Relationship between Cardiopulmonary, Mitochondrial and Autonomic Nervous System Function after an Ind. Activity Prog;2021 Newton,Morten

Relationship between Cardiopulmonary, Mitochondrial and Autonomic Nervous System Function Improvement after an Individualised Activity Programme upon Chronic Fatigue Syndrome Patients

Katarzyna Buszko

Sławomir Kujawski
Jo Cossington
Joanna Słomko
Monika Zawadka-Kunikowska
Małgorzata Tafil-Klawe
Jacek J. Klawe
Djordje G. Jakovljevic

Mariusz Kozakiewicz
Karl J. Morten
Helen Dawes
James W. L. Strong
Modra Murovska
Jessica Van Oosterwijck
Fernando Estevez-Lopez
Julia L. Newton
Lynette Hodges
Paweł Zalewski
on behalf of the European Network on ME/CFS (EUROMENE)

Abstract
Background: The therapeutic effects of exercise from structured activity programmes have recently been questioned; as a result, this study examines the impact of an Individualised Activity Program (IAP) on the relationship with cardiovascular, mitochondrial and fatigue parameters.
Methods: Chronic fatigue syndrome (CFS) patients were assessed using Chalder Fatigue Questionnaire (CFQ), Fatigue Severity Score (FSS) and the Fatigue Impact Scale (FIS). VO2peak, VO2submax and heart rate (HR) were assessed using cardiopulmonary exercise testing. Mfn1 and Mfn2 levels in plasma were assessed.

A Task Force Monitor was used to assess ANS functioning in supine rest and in response to the Head-Up Tilt Test (HUTT).

Results: Thirty-four patients completed 16 weeks of the IAP. The CFQ, FSS and FIS scores decreased significantly along with a significant increase in Mfn1 and Mfn2 levels (p = 0.002 and p = 0.00005, respectively). The relationships between VO2 peak and Mfn1 increase in response to IAP (p = 0.03) and between VO2 at anaerobic threshold and ANS response to the HUTT (p = 0.03) were noted.

Conclusions: It is concluded that IAP reduces fatigue and improves functional performance along with changes in autonomic and mitochondrial function. However, caution must be applied as exercise was not well tolerated by 51% of patients.

https://www.mdpi.com/2077-0383/10/7/1542

 

From the paper,

Study Limitations

We have noted a considerable withdrawal rate (35 from 69 patients) from the intervention which was mainly due to the development of PEM. Sixteen patients were unable to complete CPET at baseline and therefore we were unable to incorporate this subgroup in all comparisons. Mitofusins level were analysed using ELISA, which has limits in its precision of measurement level [81]. Moreover, some samples were frozen longer than others, as patients did not start the physical activity program simultaneously. Recently, it has been shown that time of samples being frozen could confound the results [82]. A significant limitation for this study was that PEM was not measured. Moreover, further studies should use questionnaires to examine effects of therapy on potential CFS comorbidities such as anxiety and depression. Due to the relatively small sample size, results on effects of IAP should be replicated in further studies. Additionally, no control group was applied in the above study, limiting the conclusions that can be drown from this study. Future research study should incorporate daily or weekly questionnaires assessing PEM in ME/CFS patients undergoing aerobic exercise program.
Future studies on mechanism underlying PEM should consider a crossover-type trial of a supervised physical activity programme with low load for 12 weeks followed by 12 weeks of high load, to ensure that individuals who take part in the study could be their own controls.


So my initial interpretation would be that that this study shows that using Fukuda can result in a misdiagnosis rate of up to 51% (which is the withdrawal rate noted above), and that this study is looking at whatever we want to call non-ME (i.e. PVFS, idiopathic chronic fatigue, etc).

 

Over half dropped out because of PEM. Only Fukuda criteria.

The "benefits" are basically trivial. It does not seem to take any consideration of whether the small increase came at the expense of everyday activity, which is almost always the case.

There are useful conclusions to be extracted from this, but the interpretation is terrible. It is not acceptable to conclude benefits when literally over half drop out because of deterioration. Very disappointing coming from Morten.

Then why bother doing this in the first place? Seriously, what is this nonsense? They did not evaluate the drop-outs, only two mentions and that's it.

EUROMENE, again proving they are not part of the solution. What a disaster this group has been.

 

What would be the reasoning for that conclusion?
If 51% had PEM maybe 49% did not have ME? But then some PWME may have battered on.

I am not convinced this study can tell us anything. It is such a pity that studies are set up in such a confused way. Without controls I don't think it tells us anything because we know nothing about the time-dependent conditions of enrolment. If fitness improved then so what, because they did exercise. That is not an indication that ME improved (any more than it might have done anyway).

If further studies are not done a lot better - and the suggestions do not bode well for that since crossover is not the answer - I don't think they are warranted.

The point of doing research is not to do research. It is to get useful answers.

 

Exercise is a dead end because there's no reason to think the disease has much to to with low fitness. That's just an idea popularized by the early CBT/GET papers which sought to rationalize the treatment.

 

Yep, exactly that. Yes, some pwME may have gritted their teeth and stayed in the study, but we have no evidence one way or the other. I think I might actually mean up to 49%, but I'm afraid I'm too tired to get my head around it tonight.

Another separate thought I had is that the percentage dropout is very similar to the percentage who report harms from GET in patient surveys. Perhaps this study show that approx 50% of patients can benefit from exercise but then would a drug get licenced on those kind of odds?

 

How was the CFS cohort assessed/ selected ( given the known high rate of misfiagnosus)?

 

So 34 completed out of 92 enrolled in the trial. That's awful and renders the conclusions frankly absurd, even with the caveat.

 

A drug would certainly get licensed on those odds but this study does nothing to indicate that anyone benefited from exercise because it has no controls. Patients probably said they had less fatigue to be polite and if they were fitter who cares if their ME is the same?

 

But...but...jobs! We have a Research-Industrial Complex to support!

Seriously, this 1000x. I wish NIH and MRC would erect neon signs with these two short sentences outside their buildings. And beat it into every grad student, program administrator, journal editor, etc.

 

This study neatly demonstrates the pitfalls of using Fukuda.

1) We have a cohort selected by Fukuda which is likely to consist of 2 groups, one which experiences PEM and another which does not (but this paper doesn't report this detail).

2) We have an exercice programme where a large number dropped out due to PEM.

The very first question that springs to mind is this: were the participants who managed to complete the exercise programme Fukuda-minus-PEM and the participants who dropped out Fukuda-plus-PEM?

This would have been an interesting question to answer. It's not addressed in this paper. All it would have taken was to record PEM+ or PEM- at enrolment and then see if that could predict who would benefit and who would drop out. A missed opportunity.

Of course the participants who managed to complete the exercise programme may just have been better at balancing activity, i.e. they may have dropped some of their usual activities to allow for the exercise programme. The reported improvements weren't exactly overwhelming.

The only thing this paper tells us for sure is that when you ask pwME to exercise, a lot of them get PEM. Not exactly news but at least it was reported very clearly - which is a lot more than what certain other papers have done.

 

It's difficult to get excited about this study but what I've understood is that in Poland you get zero funding for biomedical research. Doing a GET or exercise study was the only way to get funding going. At the time this study was conducted they used it to also take objective measures.

Furthermore, since those who dropped out, dropped out due to PEM and that the recent criteria all include PEM as a mandatory symptom. Exercise doesn't seem to be a good option for patients with ME and PEM.

 

Well at least they were honest about the PEM dropout.. I dont think they can conclude as they did though (that the individualised activity treatment helped)

 

Right, and even BPS researchers now argue against their early claims by claiming that (alleged) treatment effect of CBT/GET is not mediated by increased fitness which is how they are able to dismiss no improvement on fitness measures. GET is just graded exposure therapy.

 

Unfortunately that’s all research is these days with rare exceptions. Almost every paper I read on pubmed makes me disgusted and demoralised.

 

Though I agree with @Jonathan Edwards in principle that “The point of doing research is not to do research. It is to get useful answers.” I would also argue that in practice the way British University Departments are funded means there is also an important secondary purpose of research and that is to get grants and to publish papers regardless of whether this leads to ‘useful answers’ or not.

 

Funny story about that, I can't remember the context but one time Sharpe responded to someone criticizing PACE by saying his job is to write clear papers. Indeed it is, well except the clarity part, or maybe it's that it's clear that they are pointless busy-work. Still, he sees his job as producing stuff that gets name recognition and that's it, because it's all funding institutions care about. Literally no one expects anything useful to come out of this process. And it shows.

 

I don't see that as a secondary purpose of research but as a self-interest of researchers. It is perfectly possible to stick to research that gets useful answers - as long as you (a) do not see research as an exercise in self-aggrandisement (b) you know what you are doing. Spending other people's money is not a useful purpose. Yes, you have to ignore all the idiots around you who think it is, but life was always like that.