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

[Jonathan Edwards]

My understanding is that repeat CPET tests are reproducible (have low variablility) in healthy people, in a number of chronic conditions ... 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.

But wouldn't they then be considered to have PEM?
My understanding is that the reason for doing a 2 day CPET in ME is because it is expected to pick out a very unusual situation of feeling ill hours or days after the exertion whereas in other conditions feeling exhausted occurs at the time and has gone by the next day. (I don't actually know how often people with other conditions like severe cardiac or renal problems get tested on two consecutive days.)

As I think Hutan said, the surprising thing is that if PEM is really as terrible as people say, and I fully believe it is, then how come these people can even start a second CPET test? If I had 'flu' there is no way I would want to get on an exercise bike.

 

[Jonathan Edwards]

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.

Absolutely, I do hope someone takes this on.

I heard yesterday that my wife's cousin has an app linked to a sensor in her ski boots that tells her how good her turning technique is in terms of edging the ski and weight alignment. I get the impression that making a device that would demonstrate 'signature' ME movement patterns ought to be well within current technology.

 

[Hoopoe]

As I think Hutan said, the surprising thing is that if PEM is really as terrible as people say, and I fully believe it is, then how come these people can even start a second CPET test? If I had 'flu' there is no way I would want to get on an exercise bike.

You could do an exercise test if you wanted to even while having the flu or otherwise feeling bad.

 

[Jonathan Edwards]

I suppose it is conceivable that something about a person's breathing might affect when ventilatory threshold occurs and might be altered by a person's psychological state;

I think this is highly possible and I think it is worth discussing in the context of this study. I understand the desire to keep discussions in pigeonholes but my brain is a bit too old to keep dotting about threads once a line of thought has started!!

Breathing patterns are very much affected by mental states relating to concentration on effort during sports. In all the sports I have been involved with - middle distance running, swimming, rowing and especially ski-ing, instructors put a lot of emphasis on attention to breathing patterns because they often become counterproductive. When skiing in deep powder almost everyone stops breathing regularly because of the acute focus on truncal posture control. If you do more than about ten turns that gets problematic.

 

[Andy]

As I think Hutan said, the surprising thing is that if PEM is really as terrible as people say, and I fully believe it is, then how come these people can even start a second CPET test? If I had 'flu' there is no way I would want to get on an exercise bike.

In part, I think it might depend on how severely affected the individual patient might be. The tendency on the forum is for the more, but not most, severe patients to be represented, where PEM is far more disabling than in less severely affected patients, who may well be still able to function even when in PEM. I can certainly imagine being able to take part in two CPET tests, one a day after the first, when I was more mildly affected than I am now.

 

[Jonathan Edwards]

You could do an exercise test if you wanted to even while having the flu or otherwise feeling terrible.

Actually I don't think I could. I think I would vomit and collapse on the floor.
Over the years I have looked after people in hospital with all sorts of reasons for feeling acutely ill and I am quite sure they could not get on an exercise bike and start pedalling. I have assumed that PEM feels much like that situation.

 

[Jonathan Edwards]

In part, I think it might depend on how severely affected the individual patient might be.

Agreed. And I can see the logic of the original experimental design trying to show a dip in function on day 2 by looking for maximal performance twice, studying people who are bad enough to show an effect but not bad enough to find it distressing.

But if the aim is to study metabolic changes following exertion and maybe further shifts in such changes with repeated exertion then it would make more sense to me to look at the sorts of levels of activity normally encountered - at least on the second occasion - rather than push for maximal exertion.

 

[Hutan]

As I think Hutan said,

I'm not sure what I said, but
1. 2 day CPET's don't guarantee that the person feels that they have PEM on the second test. I had PEM (feeling terrible and exhausted, body feeling crushed, glands up, the night after the first test, but felt ok (PEM-free) for the second test (but still showed the characteristic reduction in work at ventilatory threshold, and also lower VO2max on the second test).

2. So, the feeling of PEM and the lower performance on the second test are different things, although they might be manifestations of the same process, but with different thresholds. (i.e. exertion can cause the drop in performance on the CPET while not triggering the 'emergency alert - you need to rest' of PEM; or exertion might trigger a PEM response that is over before the second test.)

3. The severity of the flu varies a lot, and plenty of people with the flu could get on a bike and pedal for 8 minutes, especially if they had made a commitment to do so and/or felt that their future depended on it.

4. On the potential for the change in breathing during the second CPET, I hope @Snow Leopard comments. There was no anxiety or body pain or anything that would have made me breathe differently on the second CPET. Just maybe there is some adrenalin or something to enable us to get through another exercise challenge? I know I have experienced a sort of 'wired' burst of energy to get through prolonged social events, so much so that I feel ok when I finally get home and start cleaning the kitchen rather than resting - and then get hit with PEM a bit later. But, I don't think it felt like that for my second CPET.

5. I suspect breathing rate, tidal volumes and more - things adding up to dysfunctional breathing - are monitored by the CPET set up. We could look to see if that is different in people with ME/CFS. I don't recall seeing that they are. And we'd still have to have an idea as to why the breathing wasn't dysfunctional on the first test, but was on the second.

 

[Braganca]

As I think Hutan said, the surprising thing is that if PEM is really as terrible as people say, and I fully believe it is, then how come these people can even start a second CPET test? If I had 'flu' there is no way I would want to get on an exercise bike.

I did the 2 day CPET in Ithaca years ago. I had been ill for 18 months. At the time I was moderate but in constant push / crash cycles which would result in severe symptoms. On non crashed days, I could walk about 10 minutes once or twice a day. I could cook for myself, but couldn’t do grocery shop, couldn’t work or drive. I could feel normal for some parts of each day, a half hour to a couple hours maybe if I was at home and not trying to do any activities, pacing. So I could be brought to Ithaca by family member, walk into center and feel and look normal. Even though I was extremely ill.

The exercise challenge takes 6 minutes and I could do it. I blacked out 5 mins after doing the first one which was the immediate abnormal response. Rest of day I was in bed and was actually ok. The next day I felt ok enough to do it again and lay down immediately afterwards in the center to prevent blacking out again. Afterwards I rested for days, staying in bed and my family member taking care of me. But I felt ok, and thought it had gone v well. It was only about 4 or 5 days after when I tried to do the things I could do before that I realized I was not able to without immediate symptoms and PEM. And within 2 weeks I realized I was hugely less functional in that I couldn’t be upright anymore for longer than a few minutes. In the following months I went into a very severe crash. I eventually recovered to be more stable at a severe level, but never recovered to baseline before CPETs. The CPET did show abnormalities (lower V02 max on second test).

Betsy’s team does not track patients after the first week or two. I did let her know I never recovered but I’m not sure it’s documented anywhere. I also emailed Maureen Hanson when I saw they were doing this trial. She said all subjects recovered to baseline after CPET. Sure enough I haven’t really spoken to many other patients who have permanently declined after doing it, which seems bizarre to me.

 

[Sean]

I get the impression that making a device that would demonstrate 'signature' ME movement patterns ought to be well within current technology.

Yep. Gross and fine patterns.

 

[duncan]

I've done the 2-day CPET. Here is my problem with it:

Unless they bring that bike and mask etc to your house, many of us will be crashing when we do the first CPET. I was. Simply traveling to the research site levied a toll. So I did not say anything, but I know my baseline could not possibly have been my normal baseline, i,e, before traveling.

I'm thinking this invalidates the entire PEM part. The deterioration on the second day CPET may speak to our ME/CFS, but for me at least, it isn't the PEM. I felt equally shitty both times on the bike.

The same pretty much holds true with cognitive testing, but, although it was divided into two days as well, I felt markedly worse the second day, my crash was more pronounced since I was deeper into it (Day 3 of severe PEM), and I fared worse. Interestingly, my first day at the research facility a neurologist gave me a MOCA test, and I scored 22. The susbsequent two days I had more orthodox cognitive testing and no MOCA. I would have liked a MOCA on the third day just to see that value.

 

[Jonathan Edwards]

And we'd still have to have an idea as to why the breathing wasn't dysfunctional on the first test, but was on the second.

Yes, I agree with all your points, but there remains the key point that if we are tracing a complex series of cause-effect interactions then it is unwise to assume they can be treated as a simple;
'exertion'>>'PEM '
relation and interpret findings as if it were. The 2day CPET is often quoted as documenting PEM but your case seems to show clearly that this is not the case.

And maybe the breathing was dysfunctional of the first test and not on the second and so ventilation threshold occurred at lower work rate?

 

[Jonathan Edwards]

It was only about 4 or 5 days after when I tried to do the things I could do before that I realized I was not able to without immediate symptoms and PEM. And within 2 weeks I realized I was hugely less functional in that I couldn’t be upright anymore for longer than a few minutes.

Betsy’s team does not track patients after the first week or two.

Another interesting example of the CPET not correlating with PEM in time scale - but the other way around.

I go out of my way to be sceptical because it is the way to get debate going and I am happy to believe that there is some consistent finding on the 2day CPET of relevance to what is going on in ME. I have to say that I was disappointed, however, on the one occasion when I was expecting Betsy Keller to explain the CPET story at an IiME meeting and instead she scrubbed her presentation and just got the audience to do some fun exercises!

 

[Medfeb]

But wouldn't they then be considered to have PEM?
My understanding is that the reason for doing a 2 day CPET in ME is because it is expected to pick out a very unusual situation of feeling ill hours or days after the exertion whereas in other conditions feeling exhausted occurs at the time and has gone by the next day. (I don't actually know how often people with other conditions like severe cardiac or renal problems get tested on two consecutive days.)

I understand from discussions with people at Workwell that the test has been shown to be reproducible in various diseases by repeat testing. This is one example of a study in pulmonary arterial hypertension where they used two tests 1 to 3 days apart and then repeated that up to 6 times and concluded it was reproducible.

Kelller has said that when she first tested an ME patient, she thought her equipment was broken because the test did not reproduce on the second day.

 

[JemPD]

If I had 'flu' there is no way I would want to get on an exercise bike.

But if you had some degree of flu every day for 20yrs, and it had decimated your life and getting on that bike might give you a chance to get your life back, to regain all the things you had lost. To have a 'life' again. You would give it a damn good go, because while you might not 'want' to get on the bike, you want to carry on with the non-life you're 'living' even less. Dont underestimate the power of grief, frustration, utter desperation.

Over the years I have looked after people in hospital with all sorts of reasons for feeling acutely ill and I am quite sure they could not get on an exercise bike and start pedalling. I have assumed that PEM feels much like that situation.

Yes you assume correctly, for me at least, thats exactly what happens to me when i'm in PEM and i try to get up & walk, the exertion makes me vomit & collapse. But i am severely affected and could not get to the testing site without making myself bad. So none of the participants can be severely affected (as i understand SA to mean) in the first place.

Careful not to compare a severe person's description of PEM with a 'mild' sufferer's description of it. Not commenting on that, i have very limited understanding of what PEM is like when you're 'mildly' affected. But perhaps it's not 'try to stand up = vomit & collapse'.

But i must say, that even in that state, try to stand/walk = vomit & collapse, i would think nothing of attempting, through sheer bloody minded determination to get on that bike & push my feet down the pedals. Because i am so f*ing miserable that i would do anything, anything if thought it might lead to a treatment so i could escape this torment, and go to work/shopping/horse-riding/the pub, again.

I'm not saying i could do it... you'd have to hold me up on the bike and wear plastic overalls to protect from the puke, but i'd do my upmost to do it.
I dont imagine i'm alone in that, but for sure before i got ME, if i felt like that ill back then, i'd have said 'no way i cant'. But my perspective is different now. I'd suffer anything to make this stop. I wouldnt have done back then because until you've experienced it you cant imagine the emotional/psychological hell of being trapped in it.

In addition, i have to use that kind of determination to get to the bathroom on occasion, crawling along the floor puking as i go, so it becomes bordering on 'normal'.

But i also want to flag up the effect of excitement/anxiety/adrenaline - I can go from that 'try to stand/walk = vomit & collapse' state, to being able to stand & walk slowly & unsteadily for a few yards, within 5-10mins of someone making me frightened or angry. I know lots of other pwMP have 'adrenaline' related improvements so one wonders what impact that has on CPET performance/results etc. Maybe none, I'm just musing.

but since no doctor has ever seen me crawling/vomiting, because the mere act of seeing a dr makes me anxious = adrenaline = improvement, i dont suppose we will ever find out.
sorry rambling

 

[Mithriel]

You have described it so well Jem

 

[Jonathan Edwards]

Keller has said that when she first tested an ME patient, she thought her equipment was broken because the test did not reproduce on the second day.

That sounds a bit weird. I thought the post of doing it twice was to show a difference?

 

[Jonathan Edwards]

ut if you had some degree of flu every day for 20yrs, and it had decimated your life and getting on that bike might give you a chance to get your life back, to regain all the things you had lost. To have a 'life' again. You would give it a damn good go, because while you might not 'want' to get on the bike, you want to carry on with the non-life you're 'living' even less. Dont underestimate the power of grief, frustration, utter desperation.

When I have flu I don't actually have a choice. I collapse shivering if I try to do anything vigorous. But my point was exactly this - that to overcome feeling so ill you need to be in a very particular mental state supported by adrenaline and cortisol and goodness knows what and that may matter.

 

[ukxmrv]

When I have flu I don't actually have a choice. I collapse shivering if I try to do anything vigorous. But my point was exactly this - that to overcome feeling so ill you need to be in a very particular mental state supported by adrenaline and cortisol and goodness knows what and that may matter.

I went to work sick for decades (working off and on in permanent then contract jobs, part time or evenings if I could) with sore throat, glands, a temperature, going to the loo to vomit, falling off a chair when weak, fainting at work or on the way. I collapsed shivering as well and had to sit at my desk and work until I could no longer sit up or move my hands or talk. Had to live close to work and catch taxis when needed. Personal hygiene and wardrobe a problem.

There was always an end to the job when I could no longer get out of bed and they sacked me or I had to leave because I was to become homeless etc.

When i was hit by a motorcycle I still got up (was knocked out), refused to go to hospital and tried to get to work. My work life stopped when I fell down a spiral staircase and got further injured.

There would have been a high level of determination and a lot of help to get some of these people to the appointments for the 2 days. A wheelchair, someone to wash and dress them, a helper, aids to block out noise and light, a hotel close to the hospital, taxis which would have made it possible.

Then there would have been people who simply could not get there who were simply unable to get out of bed on that particular day because their level of sickness was producing the symptoms that mean standing and being able to get on an exercise bike were impossible. My guess is that this test included some who could do it due to a mixture of luck and a lot of help.

 

[duncan]

I am confused by the exertion=exercise assumption. I think I understand their goal: provoke PEM through amplified exertion, and demonstrate that through metabolite comparisons. That sounds reasonable.

But how would metabolites come into PEM caused through mental exertion?

If PEM=PEM, then something should be consistent in that abnormal response regardless of whether its cognitively, physically, or emotionally provoked. If you're looking at metabolites as a specific metric for demonstrating PEM, shouldn't it hold up for all three types of catalysts?

Maybe not. Maybe there are different types of PEM.

Regardless I think they need to accommodate cognitively-induced PEM somewhere, and I'm concerned we are missing something in assuming extreme exercise translates into the kind of exertion necessary to provoke PEM.

But I'm thankful they are trying.