Plasma metabolomics reveals disrupted response and recovery following maximal exercise in ME/CFS, Arnaud Germain, Maureen R. Hanson et al, 2022

Some of the study findings are discussed in this video:

https://www.youtube.com/watch?v=AomPPtzZHgc

Originally posted by @Jaybee00 here https://www.s4me.info/threads/news-...disease-and-maureen-hanson.20339/#post-409538

 

Haven't read the study (or even the abstract) but my knee jerk reaction is that they could have selected using actimetry combined with a diagnosis of ME/CFS. There are probably plenty of studies which demonstrate how actimetry could be used e.g. Friedberg* and (didn't think I'd even quote this) the dreaded Knoop** who uses it to select participants. Also, OMF (Hanson is part of it) have expetise in actimetry.

*Friedberg F, Adamowicz J, Caikauskaite I, Seva V, Napoli A. Efficacy of two delivery modes of behavioral self-management in severe chronic fatigue syndrome. Fatigue: Biomedicine, Health and Behavior. 2016; 4(3):158-174

**https://www.s4me.info/threads/recov...gnosed-with-covid-19.16227/page-5#post-403544

 

When Workwell did the first studies they commented that the controls complained on the second day but the ME patients "would have walked over burning coals to get proof they had a physical disease"

With ME you are always doing things you do not feel well enough to do. It is one of the worst things about it. When I was moderately ill I actually pushed myself more because now I am worse I look ill so people help me. You push through exhaustion and pain or you do not eat. People give up washing but need to struggle to a toilet.

There is also the adrenalin effect where you can do much more than normal.

The 2 day CPET testing shows that people with ME do not recover from exertion the way it happens in normal people and other diseases they have tested. Exertion causes something in people with ME which makes it impossible for them to exert to the same level the next day.

If PEM is anything it is a shorthand for whatever is going on in the body that accounts for this. It is not a separate symptom but a reflection of something that causes symptoms which can be different between people and within patients on different occasions.

 

If I remember correctly, the clinical trial registration mentioned 90 patients and 90 controls. I presume the pandemic put a dent into the recruitment effort.

 

I continue to be very puzzle by all this CPET stuff. I would like to get to grips with it but fail every time because of the jargon.

If you have pain you may have a reduced ability to do work without altering utilisation of metabolic pathways. You put effort into protecting painful parts, maybe by contracting opposing muscle groups to splint a joint rather than using the joint efficiently to push a peal or whatever.

Can you explain to me @Snow Leopard, in plain English terms exactly what the consistent fining is for 2nd day CPET in ME in terms of process. Is it that despite using the same amount of oxygen, less useful work is one (on the peals or whatever) or that less oxygen is used for a given heart rate or what? I find it very hard to understand how we can be sure this isn't just a nonspecific response to discomfort.

This puzzles me too. How do we now a voluntary reduction does not occur? We know almost nothing of the mechanism of 'voluntary effort'. If I am on an exercise bike and someone asks me if I am doing maximum voluntary effort I don't think I can say. One can get somewhere near to a sense that instantaneously but over a period of many seconds all sorts of things modulate the sense of effort being maximal. Effort isn't actually something we have any way of measuring. And if you feel ill you are in a completely different mindset.

 

The trouble is that this screws up any scientific analysis.

PEM is a symptom pattern - as I understand it of feeling ill after exertion.
If we then want to use the same word to mean what causes PEM we get PEM causes PEM and that opens things up to confusion.

Maybe exertion releases some mediator X which give people a sense of PEM. Having a sense of PEM may generate signal Y which interferes with the ability to do work on a bicycle. So the second day PET does not tell us about X but about Y.

 

I recall Simon M, in a review of a previous metabolic study (by Hanson's group), writing something along the lines of --- we [this study] didn't find anything --- if we were to repeat this study then we'd introduce a stressor --- like exercise.

So they've now done that follow up study i.e. including exercise as a stressor. I just wonder if the forthcoming GWAS study might help to shed some light on the findings in this study e.g. if metabolic pathway X appears to be affected then do the results from the GWAS study suggest a problem and/or does it link to the findings of this metabolic study?

 

OK I am beginning to remember half-understanding this. It seems that the change in work rate at ventilatory threshold could be affected by all sorts of shifts in neural control of the sort I was thinking of. So I am not sure why it should be interpreted as a metabolic phenomenon.

One of the things that worries me is what Mithriel mentioned. PWME go in to this test motivated by wanting to produce an abnormal result - maybe the second result to look different from the first. Knowing just how much frame of mind affects one's physical performance on the running track I wonder how problematic this is.

I am wondering whether if researchers are looking for metabolic shifts, rather than performance shifts, it would make more sense to study the sorts of level of activity that PWME engage in day to day and look at the metabolic profiles. As far as I can make out the only reason to use maximal exertion is in order to use work output as your outcome measure. If you are studying shifts in metabolism directly this would not seem to be necessary. Presumably metabolic shifts are only relevant to ME if they occur during normal daily activities for PWME.

 

This is not anything worth worrying about. People with ME want a test that will give proof that something is going on to show they are not imaging they are ill. I doubt if it is possible for someone who has not experienced it to know how it feels to be made to doubt yourself for decades, there is no comparison with running performance. No matter how much you say to yourself it is wrong you are genuinely ill that worm of doubt is there all the time. We continually try to prove we are not slackers or hysterical. Other researchers have noticed this too, people doing standing tests for POTS have been amazed at the endurance of ME patients.

There is more likelihood of patients pushing themselves more on the second day. In fact patient stories often say they believed they did just as well until they were shown the results then they were surprised. It is not about performance it is about endurance and effort so it can't be compared to athletes.

if anything, controls are more likely to be fed up on the second day and not put so much effort in but they still achieve the same results as on day 1.

PEM was imposed on us as part of the criteria for CFS put in as a sop to the ME people who believed that exercise caused ME to flare up. None of the criteria were researched or laid down because of careful examination of patient experience.

We have been left with it as the best we have but I do not think it is accurate or very helpful as a concept. Exercise causes us damage and that damage has consequences for our health. To talk about a broken leg using the concept of "unable to load bear" and drawing a graph of recovery tells you something but much better to talk about the healing of the bone.

Asking whether a patient gets worse after exertion, particularly if it is delayed is only a way of separating out ME from other fatiguing illnesses so we can get at what the actual physiology of the disease is doing. The delay before PEM shows that exercise is causing damage long before it is expressed. That is the damage we need to work out.

Though CPET testing has shown a deficit exists it is not ideal and can't even be necessary as damage must occur in usual daily living. It is not ethical to exercise patients to exhaustion but patients volunteer knowing the risks. The psychology people refuse to accept exercise is damaging so they do not accept any risk exists. Another way ME research is screwed up.

 

Some thoughts on the CPET.

I agree that the CPET might not be a good test because it doesn't replicate exactly what happens in daily life. Usually what causes crashes for me is not things that resemble a CPET, but more doing too much over a day or several with inadequate rest. It's almost never a single instance of exercise until exhaustion.

I haven't really been able to figure out what aspects of exertion contribute the most to crashes. The narrative that it has to do with intensity of exercise (as per the advice sometimes given "don't exceed a certain heart rate") doesn't seem to be true for me

 

From what you say it seems there might be a big difference in mental state between patients and controls. And in hormonal responses over the 48 hour period and so on. Cortisol levels are likely to behave very differently, as well as adrenaline. Vagal control of respiration might well differ. And so on.

 

Such things may affect metabolites but people are sent for single CPET tests every day and the results are taken as evidence of heart disease or lung disease with no one worrying about their mental state. The protocols for annual testing of Cystic Fibrosis patients does not say anything about mental attitude or hormone levels.

There is no good reason for people with ME to have their mental state or willingness to do the test properly doubted.

 

It is isn't a matter of doubting willingness to do the test properly. It is recognising that if you are feeling ill you may be in a mental state that affects repeated tests differently from healthy controls. And if you are worried that you will not be believed that may well affect mental state too.

The end point for standard cardiac and lung patients is something quite different - simple capacity to do work I guess. The ME findings appear to depend on a complicated relation between ventilatory rate changes and measured work.

If there is a reproducible difference between PWME and controls then it is likely to reflect what is going on in ME in some way but I am concerned that there is confusion about the way changes should be interpreted.

 

Given that the vast majority of the PEM experienced by patients is induced by daily living activities, this makes sense to me.

I still think it would be worthwhile investing in the development of an app that could capture ME-specific data from commonly used devices such as sports watches. For instance, my swimming app crunches data from my watch in such a way that it not only distinguishes reliably between several different pull strokes, but also measures how far each pull moves me forward. It must therefore be pretty straightforward to pick up basic information such as whether or not someone's moving their arms (indicating activity rather than complete rest) even if they're sitting or lying down.The app is more important than the source device, because it can be tailored to process info in ways that might not be of interest to any other type of user.

 

My understanding is that repeat CPET tests are reproducible (have low variablility) in healthy people, in a number of chronic conditions (reportedly includes for cardiovascular disease, lung disease, end-stage renal disease, pulmonary arterial hypertension and cystic fibrosis) and in deconditioned people. But this is not the case with ME which fails to reproduce on subsequent tests. Presumably some of those patients with other chronic illnesses also feel ill.

Given they are measuring physiological parameters, with one being RER (ratio of VCO2/VO2) to demonstrate maximal effort, I wouldn't think mental state would affect physiological measures only in ME but not in those other chronic conditions.