New Dr Snell paper on exercise and CFS

[Bob]

Firestormm, my understanding is that Dr Snell's tests are objective biomarkers. He confirmed this as his opinion, in his FDA presentation. Subjective factors, such as effort, motivation and fear etc., do not feature in these tests. So if these results are replicable, then they are very helpful.

I'll explain what I understand about ATWL (aka VTWL), although I'm still learning about it, so I might get some details wrong.

Dr Snell uses a cycle machine, and using CPET (Cardiopulmonary Exercise Testing), he measures the anaerobic threshold for each participant. The anaerobic threshold is the point at which the body starts utilising anaerobic energy production. For athletes, the anaerobic threshold is relatively very high because they are very efficient at producing energy by utilising oxygen. But fitness is fairly irrelevant in this study, because Dr Snell is looking at the differences between first-day thresholds and second-day thresholds, and not the absolute threshold level, and he used sedentary controls.

When the anaerobic threshold is reached, a note is made of the amount of work being carried out on the cycle machine, measured in Watts.

So, it gives you a measure, in Watts, for the point at which each participant reaches their anaerobic threshold.
This is an objective measure, independent of subjective factors such as motivation etc.
If the participant doesn't/can't put in enough effort, then they won't reach the anaerobic threshold, so their results won't be part of the study.

This is really helpful, for various reasons, including that it is an objective biomarker, and because all subjective issues (motivation, pain issues, fear, accusations of laziness etc.) are irrelevant to the results. It objectively demonstrates that CFS patients simply are not as efficient at utilising oxygen, or producing energy, as healthy people. And it also helpfully and objectively demonstrates a post-exertional symptomatic reaction to exercise.

It makes me think of Julia Newton's recent research in which muscle tissue from CFS patients produced 20 times as much (lactic?) acid as healthy controls, when grown in a lab and subjected to simulated exertion via electric shocks. Lactic acid is produced by anaerobic energy production.


Thinking about post-exertional malaise, notice that, on average, the work-load at anaerobic threshold for healthy controls increased on day two (i.e. their fitness improved), whereas the work-load at anaerobic threshold for CFS patients decreased (dramatically) on day two (i.e. their fitness deteriorated)... See 'VTWL' in graph, below...

 

[Simon]

I think that some of the objective results (oxygen uptake?) are completely biological results, and lower levels can't be reflective of a lack of effort. And there's also blood tests of proteins and such, showing objective abnormal results for ME/CFS patients, presumably compared to controls doing a similar amount of exertion.

Bob's right, but it is a little more complicated when it comes to "VO2 max" the maximum oxygen uptake.

How do you know if the peak oxygen uptake is actually the maximum the individual can do? There are several ways usually used to address this (generally, not specific to CFS studies), including:
1. Verbally encouraging subjects to continue when they tire is usually a standard part of the protocol
2. using the Borg scale to measure perceived exertion: on the 6-20 scale a score of 17 equates to 90% of maximal effort, and in trials I've seen CFS patients usually score the same as controls.
3. Studies often also use reaching >85% of age-predicted heart rate as a measure of maximal exertion. This is a bit vague since a) 85% isn't maximal and b) age-predicted heart rate is only an estimate and not that accurate - but it is easy to calculate
4. Measuring repsiratory ratio (ratio of CO2 exhaled vs O2 consumed) is a more exact way of doing this, though there are different measures and slightly different thresholds too.
5. Think repeatedly measuring blood lactate levels is the 'gold standard' of maximal exertion, but isn't popular...

So it would be useful to see the protocol to see exactly what was done.

However
That said, the metabolic efficiency (watts per O2 consumed) is purely objective, and this appears to be very different in the new study. Similarly the anaerobic threshold is an objective measure.

Also Chris Snell commented on the high level of motivation of CFS patients generally when it comes even to the Day 2 exercise test, something they don't always see in sedentary controls.

 

[Firestormm]

Much obliged. I shall have a more thorough read through tomorrow I think. Thanks

 

[urbantravels]

I'm quoting directly from the report I got after testing at the PFL in 2011, from the section where they assess whether the subject was indeed putting in maximal effort (i.e. not deliberately holding back):

Assessment of Maximal Effort
As established by the American Thoracic Society and the American College of Chest Physicians (ATS/ACCP), two of the below criteria must be achieved in order to meet criteria for maximal effort.
Maximal Test Criteria
RQ greater than or equal to 1.1
RPE greater than or equal to 17
Plateau in VO2 (yes/no)
HR greater than or equal to 85% of predicted
Tester Determination (yes/no)

RQ = Respiratory Quotient, mine was 1.28 on Day 1 and 1.49 on Day 2. This is a ratio of CO2 eliminated/Oxygen absorbed. My notes say that any number above 1 means you have exceeded your aerobic capacity.
RPE = I forget. Mine was 19 on Day 1 and 20 on Day 2. **
Plateau in VO2 - this is the only one I did not meet either on Day 1 or Day 2.
HR needs to be at least 85% of predicted: mine was 94% on day 1 and 90% on Day 2.
"Tester determination" I think is the only one with any subjectivity: it just means the person(s) administering the test give their opinion on whether maximal effort was expended. It certainly wouldn't work as the only criteria since you can't eliminate the possibility of subjectivity or bias. I think if you were designing a clinical trial you could possibly leave this one out.

Another bit from my notes that may be of interest: the second day of testing is (in the PFL's view) essential to evaluate functional capacity EXCEPT in severe cases. So, assuming a person with severe disease could even get up on the bike and complete the test, the abnormalities would already be striking on a single test when compared to healthy sedentary controls and the second test would not be necessary. The people who can't even get up - well, I suppose you couldn't test them this way at all.

** Edited to add: RPE is Rating of Perceived Effort. So that's the bit where you have the card with the numbers on it and they ask you where you are on the scale at intervals. So that one does depend on your self-report, but I don't even know how you could "game" it. If it doesn't correlate with your actual oxygen consumption, that would be a clue I guess.

 

[urbantravels]

Thinking about post-exertional malaise, notice that, on average, the work-load at anaerobic threshold for healthy controls increased on day two (i.e. their fitness improved), whereas the work-load at anaerobic threshold for CFS patients decreased (dramatically) on day two (i.e. their fitness deteriorated)... See 'VTWL' in graph, below...

By my notes, this is not actually an "increase in fitness" (one test 24 hours ago is not enough to change your actual fitness levels) but an expected "learning effect". Both healthy controls and other disease groups are expected to show this, at least a little. One test is enough for your body to start to "familiarize" itself enough with the test (in terms of coordination, muscle memory, etc.) enabling a slightly more efficient performance the next time you try it.

However, in our disease it seems the "PEM effect" is much, much more powerful than the learning effect. So we probably also experience the learning effect, but it is far outweighed by the much larger deterioration caused by PEM mechanisms.

This "learning effect" is kind of fascinating. It's been noted that ME/CFS patients adopt many unconscious strategies for saving energy wherever we can, even in tiny bits here and there - more efficient movements, etc. Every little speck of energy matters to us.

I remember reading once, a long time ago, a study that examined how many calories were burned by people who had to be physically active all day for their work - postal carriers and such. They found that these workers actually expended less energy than expected for their activity level. The hypothesis was that a physical worker adopts unconscious efficiencies in their movements to save energy. This isn't 'laziness' but an unconscious adaptation to make sure you can get through your required work from day to day without exhaustion.

 

[Bob]

By my notes, this is not actually an "increase in fitness" (one test 24 hours ago is not enough to change your actual fitness levels) but an expected "learning effect".

Thanks for the info. I did wonder if I was right to assume it was increased 'fitness'.

 

[alex3619]

On postpolio syndrome and PEM, its entirely possible that polio is a cause of ME, just as we think the related enteroviruses might cause ME now.

 

[Firestormm]

urbantravels many thanks for your additional explanations. Do you think it will be feasible to adapt these tests in some way in order to apply the PEM to severe patients in order that PEM can become a distinction applicable to the disease - as opposed to groups within the spectrum as it were? If so, how might you consider this could be achieved?

Has anyone considered - am trying to frame this appropriately but can't this morning - how it seems to others that people with - I presume - mild to moderate ME are able to even complete this exercise testing given general patient opposition to exercise regimes?

I can answer my own question of course; but I do not believe I could even contemplate this kind of activity at the moment and I consider myself mostly outside of 'severe'. So how would someone in my shoes demonstrate objective PEM on the basis of these kind of tests?

If intense aerobic exercise is achievable in these tests without significant difference from healthy controls - I think these studies need to better account for sustainable ability i.e. whether or not patient compared to controls were able to continue to exercise with as much intensity over a period beyond 24/48 hours.

It goes back I suppose to the comment I made about wishing a study over at least a week. But really I guess a more longitudinal study is called for here. If the only way to objectively measure 'output' is through intense aerobic activity; I wonder if this is really something we want to continue with - is it realistic?

Or can we do something else that will produce similar results in relation to PEM but is more conducive to 'daily life' for someone who is sick?

I know this is a study in isolation, I was thinking outside of this one. How eventually, can you see a test being developed that - presuming it endorses PEM as a distinct clinical feature of ME - might be practically used in a diagnosing physicians surgery.

Thanks.

 

[Valentijn]

I know this is a study in isolation, I was thinking outside of this one. How eventually, can you see a test being developed that - presuming it endorses PEM as a distinct clinical feature of ME - might be practically used in a diagnosing physicians surgery.

I doubt exercise testing (in its present form) will be used for diagnosis. I think PEM exertional testing is more useful in a research setting for understanding abnormalities and physiology, things which might lead to PEM-related biomarkers (and treatments or lifestyle adjustments such as heart rate-based pacing).

Exercise testing's considerable contributions currently come more from 1) refuting BPS theories of psychosomatism and/or deconditioning, and 2) proving disability on the individual basis to get disability benefits in the USA. PEM research has already pretty successfully debunked BPS beliefs, and hopefully the ongoing PEM research will help to find an easier way to document disability without risking relapse.

 

[alex3619]

The repeat VO2max is designed to measure the crash. Its not a pleasant test, but for some of us its very useful.

I think most severe patients could be tested in bed without exercise, or with modified exercise. The equipment would have to be modified to move to them. Hmmm, some student could get a PhD out of this. I think that severe patients hit the AT from just being awake and not moving much. This should be testable, and of course I could be wrong. Less severe but still mostly bedbound might be able to use a supine exercise bike device. Its not about them being able to do a lot of exercise, its about the exercise they are doing being measured at critical thresholds.

What will stuff this up is if the inability to exercise in severe patients has nothing to do with oxygen or AT, or if they were unable to tolerate a facemask or that much activity in the room. It would involve at least one person interacting with the patient.

 

[MeSci]

I remember reading once, a long time ago, a study that examined how many calories were burned by people who had to be physically active all day for their work - postal carriers and such. They found that these workers actually expended less energy than expected for their activity level. The hypothesis was that a physical worker adopts unconscious efficiencies in their movements to save energy. This isn't 'laziness' but an unconscious adaptation to make sure you can get through your required work from day to day without exhaustion.

If it weren't for PEM, I think this may also be the case for those of us with ME who have learned more energy-efficient ways of doing things. For example, I adopted a trudging gait quite early on in my illness, which was less exhausting than lifting my legs normally when walking (although had the adverse effect of increasing the risk of tripping on things!). So for those people, the decrease in exercise capacity on the second day would be less than if they hadn't adopted such techniques. Assuming that the exercise was sufficiently similar to activities for which they had adopted such techniques. Am I making sense? It's early!

 

[MeSci]

On postpolio syndrome and PEM, its entirely possible that polio is a cause of ME, just as we think the related enteroviruses might cause ME now.

I have often wondered whether polio vaccines could be the cause in some cases. As stress increases the permeability of the blood-brain barrier, the stress caused to young children by having needles stuck in them could increase the likelihood of vaccine contents entering the nervous system. I was absolutely terrified out of my wits of needles as a young child, and used to scream the place down when being vaccinated. I probably had the Salk polio vaccine, batches of which were found to be contaminated with monkey virus SV40.

 

[Firestormm]

The repeat VO2max is designed to measure the crash. Its not a pleasant test, but for some of us its very useful.

I think most severe patients could be tested in bed without exercise, or with modified exercise. The equipment would have to be modified to move to them. Hmmm, some student could get a PhD out of this. I think that severe patients hit the AT from just being awake and not moving much. This should be testable, and of course I could be wrong. Less severe but still mostly bedbound might be able to use a supine exercise bike device. Its not about them being able to do a lot of exercise, its about the exercise they are doing being measured at critical thresholds.

What will stuff this up is if the inability to exercise in severe patients has nothing to do with oxygen or AT, or if they were unable to tolerate a facemask or that much activity in the room. It would involve at least one person interacting with the patient.

I suppose we really need to do more work in better understanding the 'phases' of this disease. I suspect from experience that these borders are not fixed but are as flexible as this condition's symptoms are fluctuating.

Still, a better accounting for 'severe' would be most welcomed by everyone I think.

Exercise is of course only one way in which objective accounting can be gleaned, and in illness generally I don't think many would question someone who is unable to leave their bed; but ME does attract this 'malingering' label still (as Tom's article most recently mentioned).

And I suppose for those whose severity does confine them to bed (not everyone of course with severe/acute ME is wholly confined to bed); there is a more pressing need than in other more short-term conditions; to present a more believable explanation than 'simply' the patients' word.

So maybe not exercise in the same way as exercise can be applied to the 'moderate' or 'mild' patient. But some form of measuring the impeded ability to exert objectively.


OK. Thanks

N.B. I can't help but think that whatever might be thought of could be applied equally to any condition that leaves someone sick for longer than is expected.

I am reminded of Star Trek. I often am when we discuss being able to prove things. You remember that gadget that Dr McCoy would hold in his hand and wave up and down in front of someone?

It would perhaps make some noise, and 'bones' would know what was wrong. Easy-peasy

But cripes! There would be nowhere to hide. And Big-brother... Who programs the gadget? The Department for Work and Pensions?

 

[Bob]

I am reminded of Star Trek. I often am when we discuss being able to prove things. You remember that gadget that Dr McCoy would hold in his hand and wave up and down in front of someone?

It would perhaps make some noise, and 'bones' would know what was wrong. Easy-peasy

That'll be the TriCorder! Don't they have a TriCorder app for the iphone now?

 

[Ember]

"Two Is Better Than One: "

The Physical Therapy Journal has made the author manuscript available (behind a paywall), and so that version [Jennie reviews] is not necessarily the final version that will be published by the journal....

The CFS patients were diagnosed using the Fukuda criteria, and they also reported symptom exacerbation after activity. All subjects completed two maximal effort CPETs conducted 24 hours apart....

The controls performed the same or even better on the second test. But the CFS patients demonstrated a drop in VO2max, oxygen consumption at the anaerobic threshold, peak workload, and workload at the anaerobic threshold. The mean for the last value – workload at the anaerobic threshold – dropped by more than 50%. Respiratory measurements prove that all subjects gave a maximal effort in both tests, so the reduction is not due to lack of effort....

The authors state that it "could be utilized diagnostically as an objective indicator of abnormal post-exertional response, and possibly even a biomarker for this condition."...

This study showed that for many CFS patients, even activities of daily living require them to push past their anaerobic thresholds....

While there were differences between patients and controls on the first day, only the CFS patients demonstrated a dramatic drop in performance on the second day....

The authors say, “It is very possible that a synergy of small effects across multiple systems is responsible for the poor exercise performance of the individuals with CFS in this study.”...

I hope its publication will lead to wider use of the two day maximal CPET protocol, particularly in research like the CDC’s multisite study.

 

[urbantravels]

I can't really say whether it's practical to use the two-day exercise testing protocol as a diagnostic test more widely. It's a large amount of effort and expense, and of course it's very hard on the patient. But I was able to do it. The anticipation was really worse than the reality. I was not a part of a study; I did it to document my disability. It's one thing to have the disease diagnosis, but there isn't any other way to objectively demonstrate the *severity* of the disease and how physically limited you are.

There was a prolonged crash afterward - really almost a week, and still not back to baseline for a while after that - but I did not have any permanent deterioration in my baseline. I can't say what might have happened if I was not in a position to just get in bed and wait it out. Being required to exert myself during that period might have prolonged the crash or even snowballed it into a longer term deterioration.

My report at the time, with more information than I can remember now: http://forums.phoenixrising.me/inde...ab-disability-testing.6174/page-3#post-129769

And in following posts on that thread.

I think it might be easier (though still more involved than a simple blood test) if a test could be developed that is something like the Lights' protocol - one single exercise challenge (and theirs isn't to maximum effort...is it?) and then blood draws at intervals thereafter showing the abnormal gene expression. If it could be established through clinical studies that the two forms of testing are similarly able to show severity of impairment, then the shorter test might allow a level of severity to be assigned as a "proxy" for what the full two-day test would show.. You'd still have to hang around a clinic basically all day, but that's not unknown in tests for other diseases.

I think it's theoretically possible to design a CPET test for the bed-bound, if they can move at all they must be reaching or exceeding their aerobic thresholds just from that, and you could maybe use an arm exercisor (those things like bike pedals that you crank with your hands.) There are multiple big computers that go along with the exercise device itself, and those would be challenging to transport as well. This is very expensive stuff. Since CPET is used in many other conditions, maybe someone has already produced a more portable set-up for CPET and that could be used.

Otherwise an arm exercisor + blood draws at intervals could be used on bed-bound patients if that protocol were confirmed for diagnosis. That would be far less involved than dragging in the face mask and all that and having to repeat the test at 24 hours. It would still be very expensive but not quite as bad.

 

[Bob]

At the most recent CFSAC meeting, some of the panel members (or at least one of them) who were urging Unger to consult Dr Snell, were also urging Unger to include post-exercise resting heart-rate tests in the CDC's study. I think they were suggesting that the heart rate of CFS patients takes a long time to return to normal compared with healthy people. I haven't read any research about it but perhaps it has potential as a one-day alternative test.

 

[SOC]

My hope is that someone will find measurable blood markers, say, a massive increased in inflammatory cytokines, that could be figured out based on exercise testing in moderate/severe patients. Once that abnormality was identified, very severe patients might easily show those markers without doing any exercise. Even their limited activities of daily living are likely to be too much exercise and therefore show the measurable marker. I'm not sure I explained that clearly..... Just thinking that research using exercise could produce markers that don't need CPET ultimately to diagnose or evaluate disability.

 

[alex3619]

My hope is that someone will find measurable blood markers, say, a massive increased in inflammatory cytokines, that could be figured out based on exercise testing in moderate/severe patients. Once that abnormality was identified, very severe patients might easily show those markers without doing any exercise. Even their limited activities of daily living are likely to be too much exercise and therefore show the measurable marker. I'm not sure I explained that clearly..... Just thinking that research using exercise could produce markers that don't need CPET ultimately to diagnose or evaluate disability.

I suspect that we will not find constant cytokine markers of this kind, though it would be nice if we could. What I think we will find is better ways to induce problems. That is what exercise does, it induces problems that can be measured. Julia Newton induces problems in muscle tissue that are measurable. Other fibromyalgia research (I forget the details, cytokines I think) induces problems in blood tissue that are measurable. Taking a sample and stressing the cells in the right way may well lead to induced changes that are characteristic of ME. We react to stressors, isolating the right stressor and using it in a test is important. Exercise is only one such stressor.

 

[Firestormm]

alex3619 very good. "Exercise is only one such stressor" Yes indeedy. If you could 'test' a cell rather than test the human and reach the same diagnostic conclusions; that would indeed be marvelous