Repeat Test Reveals Dramatic Drop in ME/CFS Exercise Capacity

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Hooked up for a CPET

Simon McGrath reports on Dr Snell's new study demonstrating that ME/CFS patients have a reduced capacity to exercise when they repeat a maximum exercise test one day on - unlike healthy controls.

One of the biggest problems of getting ME/CFS taken seriously is that often we 'look' normal, even though we feel lousy, and most lab tests produce 'normal' findings. How do we prove to the world that we are sick?

A defining feature of ME/CFS is Post-Exertional Malaise (PEM) and a couple of studies have clearly demonstrated PEM in patients [see box]. However, PEM is a subjective experience and one that can only be measured by patient self-report, which won't satisfy everyone.

Dr Chris Snell, Staci Stevens, Dr Todd Davenport, and Dr Mark VanNess's new study aimed to objectively demonstrate the problem of post-exertional malaise, by using a repeat Cardiopulmonary Exercise Test (CPET). As they formally hypothesized in their paper: "an exacerbation of symptoms following the first test would be reflected in physiological responses to the second".


The study

The 51 CFS patients were all women, met Fukuda criteria and also reported PEM. Controls, also female, were similar in age and BMI, and were fairly sedentary. In fact, the results of the first CPET revealed that the controls were in the bottom 10% of published population norms and would count as deconditioned. CFS patients were barely different from controls so were also deconditioned, but, crucially, they were ill while controls were healthy, casting doubt on the idea that deconditioning is responsible for CFS.


CPET: Cardiopulmonary Exercise Testing explained

CPET is the Gold standard for measuring physical capacity, used by athletes wanting to measure the effectiveness of their training programs. It's also used medically e.g. to diagnose cardiovascular, breathing and muscle disorders.



The principle is to get someone to exercise to exhaustion, using a protocol that starts easy and gets increasingly difficult until the subject can do no more. The key measures for this study are the Volume of Oxygen consumed (VO2) and the amount of work done, measured in Watts on the exercise bike.


Anaerobic/Ventilatory Threshold

A critical factor is the anaerobic threshold, the point at which the body has to supplement normal aerobic (oxygen-burning) metabolism with much less efficient anaerobic metabolism, creating lactic acid. This threshold is measured in CPET by finding the point where carbon dioxide (CO2) starts to be produced faster than Oxygen, and is called the Ventilatory Threshold, or VT (strictly, VO2 VT).




VO2 max versus VO2 peak

One challenge of CPET is detecting if the person is using maximal effort, as opposed to trying pretty hard. Data showed that CFS patients and subjects here all went deep into anaerobic exercise and met at least one other measure of high effort. However, as it's almost impossible to be completely sure, the study reported 'peak' measures instead of maximum, e.g. VO2 peak, not VO2 max.

Note there are equivalent thresholds for work output, in watts: W max, W peak and W VT

More: Lannie's blog on PR about her CPET at Pacific Fatigue Labs.


Day 2 results separated patients from controls



A Day 2 CFS patient...

The big differences between the groups emerged on the second maximal CPET test, 24 hours after the first. On average, controls did slightly better on Day 2 (something that has been observed in other studies too) while patients did substantially worse. Interestingly, VO2 peak did not differ significantly between patients and controls, but peak Watts output was significantly lower, as was VTO2 . The biggest difference of all was for Watts output at VT, down for the patient group by over half.

The study found the repeat test could separate CFS patients from controls in this sample with 95% accuracy (3 errors in total). They also used a statistical technique called 'cross-validation', which indicated the test would achieve a 90% accuracy in an independent sample (though see issue with convenience sample below).

This ability of a 2-day repeat test to discriminate healthy but sedentary controls from CFS patients is critical. In theory, doctors can manage this easily enough without a CPET test. However, where there is doubt about the reality of symptoms, as can happen with disability insurance claims, an objective test can demonstrate that a patient really is sick. As Workwell Foundation notes, it's useful in legal or medical disputes; the reduced performance on VT is "impossible to fake", adds Dr Snell.
The study conclusion said:
the post-exertional state in CFS is characterized by objectively measurable deficits in submaximal metabolism and workload that would be nearly impossible for patients to fabricate
In some ways the findings are unexpected, as it was the same group's earlier finding of a substantial drop in VO2 max on the second test that caused such a buzz amongst patients. And the big drop in output at VT wasn't seen in a study (albeit a small one) by a separate research group, though a smaller drop was seen for VT, and VO2 max in a study presented at an IACFS conference. I asked Chris Snell if he was surprised by the finding. "No", came the reply: the initial study was small making the findings less robust, and he said that a much bigger effect on VT than VO2 max has been seen in the clinic too.


Evidence of Post-Exertional Malaise from subjective studies
As well as the objective evidence from this new paper, PEM has been shown by self-report measures too. A 2010 study from Pacific Fatigue Labs found that only 1 of 25 female CFS patients recovered from a maximal exercise test 48 hours later while all 23 sedentary controls did. Another study using a moderate exercise test found that fatigue and pain increased in the 48 hours after exercise in CFS patients - while it returned to normal in that time for both healthy controls and Multiple Sclerosis patients.

Committed to Maximal CPET

Given that it's hard enough for people with ME/CFS to do one maximal test, let alone two, these results create the temptation to just run the second test as far as the Ventilatory Threshold and forget about VO2 max. But Chris Snell stressed that the Workwell Foundation remains committed to the repeat-maximal approach. First, VT can't be measured on the fly so they wouldn't know when to stop the test. And perhaps more importantly, the post-exertional effect appears to differ by patient, with some showing a greater effect on peak measures and others at VT. Dr Snell suggested that varying post-exertional responses may well reflect different underlying pathologies.


Unique to ME/CFS?

Is this the killer test that uniquely identifies CFS patients? Dr Snell has reported that their clinic has tested patients with numerous illnesses including Multiple Sclerosis and Congestive heart failure, but have only seen the problem in ME/CFS patients. Published studies show normal repeat CPET performance for sarcoidosis, angina, Chronic Airflow Obstruction, Pulmonary Hypertension and heart disease. I’ve seen no studies showing failure to reproduce CPET results in other illnesses, but it’s probably too soon to say if this is unique to ME/CFS, or just very unusual.


What might cause the exercise problems?

The authors suggest that a synergy of small effects across multiple systems could be responsible for the poor exercise performance of the individuals with CFS. Lower oxygen carrying capacity could result from low blood volume, while low oxygen consumption could also result from autonomic dysfunction and reduced ventilation. But research into the causes is needed.


No study is perfect...
  • There were only 10 controls, though as the repeatability of CPET results is firmly established (with 94% reliability between tests), in some ways controls mainly serve to demonstrate that the protocol and equipment is working properly.
  • The CFS patients were a convenience sample, rather than, for example, consecutive referrals to a secondary clinic. This, and the fact that patients had agreed to a repeat maximal exercise test, means the results might not generalize to the patient population as a whole.
  • The earlier study by this group, and the other studes from independent groups, didn't find the dramatic changes with workload at the ventilatory threshold, so further replication would help to confirm the nature of the changes.
These findings, which make visible the hallmark ME/CFS problem of post-exertional malaise, have potentially huge importance. Replication of this study, perhaps with a more representative sample of CFS patients and some sick controls, should in my view be a priority for the research community. Stage two of the huge CDC multi-clinic study could provide the perfect opportunity for this.

Simon McGrath tweets on ME/CFS research





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Comments

Simon I have something I would like your opinion and that of others on in relation to this kind of testing; and that relates to safety.

Let me take this from Jennie's wonderful blog, it doesn't cover all my point, but does exemplify it to some extent:



When we talk about 'exercise' and most especially GET we express concern and alarm that some practitioners, clinicians, might lack the necessary understanding of ME and push people to exercise above their safe ability etc.

With the Snell test, as I understand it, patients are told to push it as much as they can for the duration of the test, and it could be said that, in order to prove you have ME you must crash on the next day.

Is this safe? Is it safe for everyone or for only some? Is it safe for the undiagnosed? How might it be viewed in light of widespread concerns over the misuse of GET?

We are essentially saying 'Prove you have ME by crashing' and that this is the best (one of the best) objective measures. Is it not rather extreme? Could it be achieved any other - less intrusive - means?

Any thoughts? I refer of course to the scenario of having this test in it's current state used outside of research in a clinical setting as part of a process for diagnosing ME; and to calls for it being incorporated in the existing CDC data collection project.

I believe that you said yourself, Snell's work needs replication. So maybe we are not there yet with something that could or even should be considered for mass-use?

There is also the cost of course but I would like to talk a bit about concerns over safety and whether or not such a test could possibly be considered suitable for all with ME or who need a diagnosis.

Thanks :)

All very good points. From that perspective, the test is actually medically unethical, as it violates the "do no harm" dictum.
 
All very good points. From that perspective, the test is actually medically unethical, as it violates the "do no harm" dictum.
Not exactly. :) Doctors do surgical biopsies and spinal taps when necessary for diagnosis. Both these procedures cause some degree of "harm". Some amount of trade-off is accepted.

The relevant difference between the CPET test and GET is that the CPET is a one-time diagnostic(theoretically) from which one can recover, although it takes time. GET is presented as a continuing therapy, constantly stressing the system and not giving it time to recover.

That said, I agree that 2-day CPET testing is not ready to be used as a universal diagnostic. First, it needs to be confirmed. Second, there's still a lot we don't know about it and its usefulness. My hope is that using 2-day CPET testing in research will provide enough information that someone will be able to develop a less "destructive" test for diagnosis.

I have never done the 2-day test. I did the one-day maximal test while I was mild-moderate and had a moderate crash that was a week or two long. Not fun, but not catastrophic. I've had as bad, and worse, crashes from other activities and infections. It wasn't so bad that I wasn't willing to do it again about 5 years later. The second test was not maximal, though, only to VT and was easy -- no crash afterwards.

We've all had crashes. We get up, we move on. I'm willing to crash (as a one-time event), if necessary, to improve the knowledge base in this illness, especially if it's a planned crash so I can arrange my schedule, and maybe stick a few meals in the freezer. ;)

Maybe we need to hear, all in one place, from some of the people who did the 2-day CPET -- what their condition was before the test, if they crashed and for how long/badly, what their condition was after the crash. Anybody willing to chime in with their experience?
 
Sometimes people don't recover, though, or more commonly, don't recover fully. I think as long as that very real danger exists, it's a bit unethical to test in this way. I guess as long as the patient in an experimental or research setting consents that's one thing, but if a test like this were to become standard for diagnosing CFS/ME, I think it would have the potential to cause a lot of harm, and that obviously less dangerous testing through blood, etc. (or even spinal puncture) would be preferable. It would be psychologically very distressing if nothing else for patients to know they had to subject themselves to a 2- or more day exercise test to get any validation from the doctors.
 
At the most recent CFSAC meeting, Beth Unger seemed to suggest that they might be including (one-day) post-exercise resting heart rate measures for the CDC's study. (I think it was suggested that CFS/ME patients' heart rates take a long time to return to normal after exercise.) Perhaps this is a good compromise, if she won't include two-day testing for ethical and practical reasons, but I'm not familiar with any post-exercise resting heart rate studies.
 
...
That said, I agree that 2-day CPET testing is not ready to be used as a universal diagnostic. First, it needs to be confirmed. Second, there's still a lot we don't know about it and its usefulness. My hope is that using 2-day CPET testing in research will provide enough information that someone will be able to develop a less "destructive" test for diagnosis.

I have never done the 2-day test. I did the one-day maximal test while I was mild-moderate and had a moderate crash that was a week or two long. Not fun, but not catastrophic. I've had as bad, and worse, crashes from other activities and infections. It wasn't so bad that I wasn't willing to do it again about 5 years later. The second test was not maximal, though, only to VT and was easy -- no crash afterwards.

We've all had crashes. We get up, we move on. I'm willing to crash (as a one-time event), if necessary, to improve the knowledge base in this illness, especially if it's a planned crash so I can arrange my schedule, and maybe stick a few meals in the freezer. ;)

Maybe we need to hear, all in one place, from some of the people who did the 2-day CPET -- what their condition was before the test, if they crashed and for how long/badly, what their condition was after the crash. Anybody willing to chime in with their experience?
I agree that this is very important research, and that CPET testing should be carried out with willing volunteers, who know that they will not suffer from long-term consequences from an exercise test.

But I don't agree that "we get up, we move on" after crashes. Obviously, it's different for everyone, but my ME is very reactive and my crashes tend to be severe, deeply distressing and long-lasting, and I spend my whole life trying to avoid them. I would never agree to any exercise testing unless I was in a very stable period of remission and I was absolutely confident that the exercise was within my safe limits. (Safe enough to avoid a crash.)
 
I agree that this is very important research, and that CPET testing should be carried out with willing volunteers, who know that they will not suffer from long-term consequences from an exercise test.

But I don't agree that "we get up, we move on" after crashes. Obviously, it's different for everyone, but my ME is very reactive and my crashes tend to be severe, deeply distressing and long-lasting, and I spend my whole life trying to avoid them. I would never agree to any exercise testing unless I was in a very stable period of remission and I was absolutely confident that the exercise was within my safe limits. (Safe enough to avoid a crash.)
I completely agree with Bob. Unless there is a likelihood of some positive therapeutic benefit, I personally wouldn't subject myself to the almost certain crash that would happen from this type of test. I spoke to people at Pacific labs and was told that some people have crashed for as long as a few months. This seems like a poor trade off just to prove my disease exist.

Gary
 
I completely agree with Bob. Unless there is a likelihood of some positive therapeutic benefit, I personally wouldn't subject myself to the almost certain crash that would happen from this type of test. I spoke to people at Pacific labs and was told that some people have crashed for as long as a few months. This seems like a poor trade off just to prove my disease exist.

Gary
Few months? Don't think I've ever got over a relapse that fast. Never mind the malaise, I typically lose over half of my function, and it comes back very slowly. And of course, people like me will self-select themselves out of such a test, making it very hard to know how safe the test would be in general use - as opposed to those willing to volunteer, who are probably people who know their worst case loss is a few months. If I knew that was the worst case for me, I would be more willing to give it a go.
 
I had the test for disability documentation. I can't speak to how they did it for clinical trials, but the disability test includes a symptom questionnaire that asks you about symptoms for a week after the test. I did have PEM symptoms for more than a week, but I think a week's cut-off is practical for the purpose of documenting disability...meaning that being sick for a week after exertion is enough to interfere with your ability to work full-time consistently week to week, and after that going on to be sick for more days isn't relevant for that purpose. Also, self-report of symptoms, as we all know, isn't measurable and objective, so it has only a little usefulness in the context of the whole test. It's more in the nature of supporting evidence.

I had no permanent or long-term setback from the test. I think I was fully back to baseline within 5 or 6 weeks and the really bad symptoms only lasted about 4 days. I am fortunate in having no particular responsibilities beyond basic self-care, so with preparation (lots of food laid in and everything otherwise arranged so I didn't have to go out or do anything but rest) the recovery period was long, but not agonizing or stressful. I was hitting my pain pills far more than usual due to muscle pain - that is, flu-like muscle pain, not muscle strain from unaccustomed exercise, although of course I had that too. Easy to tell which muscles got overworked from a bike test. But the muscle strain went away real fast compared to the PEM muscle pain.

The worst crash symptoms actually did not fully set in until four days after the test. I actually felt OK on the second day in terms of general malaise symptoms - better than I expected. In fact, I got home OK (short flight Sacramento --> Los Angeles, accompanied by my dad) and was all settled in for my recovery period before I started feeling really sick.

But - and this is important - I still had a *huge* plummet in my performance (workload at ventilatory threshold went down 60%) from Day 1 to Day 2 even though I certainly didn't *feel* 60% worse at that point. From this, I think it's possible that PEM symptoms do not track exactly with the decrease in your energy production capability - the decrease in ability to seems to happen quickly, but all the inflammatory-type symptoms may take longer to fully build up.

I don't know how this fits with the Lights' findings that pro-inflammatory cytokines go up within hours of an exercise challenge. It may be that the cytokines don't have their full effect for a while after they start being produced. Or, it could be that the cytokines continue to rise after the Lights' relatively short follow-up time...meaning that what the Lights are measuring actually isn't yet enough to provoke major symptoms, but it indicates the disease process is kicking off. Or that the body can clear the cytokines for a while at first but is eventually overwhelmed by them. I don't think this is a fault in their research. They are not looking at the entire life cycle of a PEM episode, but for a biomarker that distinguishes people with the disease from people without it.
 
But I don't agree that "we get up, we move on" after crashes. Obviously, it's different for everyone, but my ME is very reactive and my crashes tend to be severe, deeply distressing and long-lasting, and I spend my whole life trying to avoid them. I would never agree to any exercise testing unless I was in a very stable period of remission and I was absolutely confident that the exercise was within my safe limits. (Safe enough to avoid a crash.)
Good point. I was a bit too flip there with the "we get up, we move on". Every crash I had in my viral-ish days left me little bit worse. Because my illness wasn't as well-managed in those days, I never lasted long enough between crashes to recover that little bit back. Every crash made me a tiny bit worse, and the accumulation was a slow but steady downhill slide.

I guess I was thinking of participating in research -- I would plan ahead for a crash and do everything I could to ensure I had the opportunity to go into mega-rest mode for up to a couple of weeks afterward. This is what I've done for other important things -- my mother's funeral, for example. Not exactly "we get up, we move on" :whistle:. More like, we sometimes do what we have to do.

No ME/CFS patient should be required to do a two day CPET. The potential consequences are too high to require that from anyone. I hope some people at all stages of ME/CFS will choose to do the test for the sake of forwarding our knowledge. I also hope those patients will be under the care of a good ME/CFS doc who will help deal with the symptoms involved in the crash -- autonomic dysfunction, infections, cardiac problems, whatever they are. To plan research on severe patients without that kind of post-test support borders on unethical.
 
That's sort of what I was trying to say in my post - creating a big cushion of rest and recuperation both before and after an expected stressor can help minimize the effects and possibly shorten the crash period. So it's important to be able to do that. I'd hate to have a big exertion and resulting PEM happen on top of one of those sort of "snowballing" crash periods. when something keeps happening to set you back a bit more each time. Pile a huge PEM on top of that and you might have a very protracted crash on your hands.

I'm not sure what deathly things could happen to you once you are done with the test and are recuperating at home that would require specialist medical intervention. I think people often imagine a huge risk of permanent damage from taking the exercise test and I just don't see that happening. But the only way to know for sure would be to do long-term follow-up on a group of patients.
 
More like, we sometimes do what we have to do.
I always tell healthies that I'm actually capable of rapid movement in an emergency, though I couldn't sustain it for long and would pay consequences later. I kept saying "I could run from a bear if I had to" so often that my friend asked me if bear attacks were a big problem in my neighborhood. :eek:
 
The worst crash symptoms actually did not fully set in until four days after the test. I actually felt OK on the second day in terms of general malaise symptoms - better than I expected. In fact, I got home OK (short flight Sacramento --> Los Angeles, accompanied by my dad) and was all settled in for my recovery period before I started feeling really sick.
I found this particularly interesting. In the days when I was still doing the push-crash thing, my delay was 4 days, which seems longer than most people are reporting. I usually hear of people crashing 24-48 hours after over-exertion. I did wonder if the 2-day CPET would catch my more delayed reaction, but it sound like it did for you, which is promising.

That was a clear and complete description of your reaction to the test. Thanks for that! Your description of a shorter "acute" phase of PEM, followed by a longer phase where you get back to baseline resonates with me. It's very much the way my (now rare) crashes work, but I've never described it that clearly.
 
I'm not sure what deathly things could happen to you once you are done with the test and are recuperating at home that would require specialist medical intervention. I think people often imagine a huge risk of permanent damage from taking the exercise test and I just don't see that happening. But the only way to know for sure would be to do long-term follow-up on a group of patients.
I'm thinking of things like viral reactivations or some kind of resurgence of infections. That seemed to happen to me with crashes when I had a pack of chronic infections. Antivirals and abx might be helpful under those circs. I'm also wondering if some people have some kind of autonomic crash after overexertion that could be alleviated with, I dunno, IV saline or meds...?

For me, the one-day tests have not been bad. You described it quite well. No long-term effects. I never did one when I was in the bedbound stage, though, so I don't know what it might have done to me then. Still, having done one before I was bedbound, I don't think I would have been afraid of trying it when I was. It might have been miserable, but I've been miserable with this illness, so that's not a big deal. I wouldn't have expected any permanent damage.
 
Good point. I was a bit too flip there with the "we get up, we move on".
Yes, I had the feeling that you'd experienced worse crashes than it appeared from your comment.

I guess I was thinking of participating in research -- I would plan ahead for a crash and do everything I could to ensure I had the opportunity to go into mega-rest mode for up to a couple of weeks afterward. This is what I've done for other important things -- my mother's funeral, for example. Not exactly "we get up, we move on" :whistle:. More like, we sometimes do what we have to do.
Yep, we all plan for big days, by resting before-hand etc., but a day visiting family, for example, is completely different to a maxed out exercise test. I've been through long periods of my illness where I only have to take a short walk and I crash severely. I can't think of anything worse for me than a maxed out exercise test!

Obviously many patients might feel confident that an exercise test is OK for them to participate in. But we've all got to safely make that decision for ourselves.


I think people often imagine a huge risk of permanent damage from taking the exercise test and I just don't see that happening. But the only way to know for sure would be to do long-term follow-up on a group of patients.
Each individual is different. A number of us here seem to be saying that an exercise test would be really bad for us. For myself, it could mean years of added distress if I had a bad crash. And it's very likely that I would have a bad crash if I exercised to the max, just once. Two days could be asking for a life time of hell. Remember that we're all different, and so the extent and severity of flare ups, in reaction to exertion, is different in all of us.

I'd like to see this research taken forwards, but it's got to be done safely, and not every one will be suitable to get involved.
 
Well, then the reasonable question would be: for those who have had crashes lasting months or longer, how often have they started from baseline (i.e you were at your personal average level of unwellness, not already extra unwell) and been triggered by one single episode of over-exertion?
 
My worst "crash" was after a 3 month prolonged overdoing under severe stress, while my Dad was dying (in a hospital 70 miles away). I did not stabilise to a new, but lower baseline than I had been at before, for 6 years.

I have just come home from a 6 day period of big overdoings - travelling a long way to cram as many friends and family members into the short space of 4 days (2 full days travelling).
I got home early Tuesday am. (this is now Friday afternoon)

I haven't crashed yet. I will monitor what happens and report. :)

Normally, I try to ignore it as much as I can. I had a lot of fun and it was very mentally uplifting. I anticipate a bout of depression as part of it (getting happy has its costs:cry: ) But I most sincerely hope it does not happen.

I generally find resting as much beforehand, taking a carnitine supplement daily while away, and carrying on with the carnitine supplement when I get back really does help to minimise suffering, and I have been doing that.
 
I would like to see the results if they waited longer between tests... 36 hours, 48 hours, perhaps more.

Some doctors are bound to say that the results can be faked. The terrible ones who think we want to be sick.
 
SickofSickness said;
"Some doctors are bound to say that the results can be faked. The terrible ones who think we want to be sick."

You mean the ones that are already "faking" their results? Possible. They would, I'm sure, expect everybody else to be as deceitful as they are. :p

However, I don't think these are the sorts of results that CAN be faked, SoS. Honestly! :)
 
It's important to define what information you are looking for and why. Since the two-day exercise test is cumbersome, expensive, stressful, and contraindicated for many people, I certainly don't want and don't expect it to become the standard diagnostic test to confirm the presence of ME/CFS...or at least the ONLY test available.

A blood test for cytokines after a mild exercise challenge may become accepted as diagnostic. That would be quicker and cheaper and much more widely applicable. (Actually I've no idea how cheap it is to measure what the Lights are measuring, which is, as I understand it, activation of the genes that produce certain cytokines, not the cytokines themselves.)

Here's one problem though, drawn from my personal experience, that goes beyond the need to diagnose. For a disability claim, they may acknowledge that you have CFS, but refuse to accept that it is as severe as you say it is, or severe enough to prevent you from working. So in that situation, you need some way to objectively demonstrate how much your functional capacity is impaired by the disease, not just the fact that you have it. Being able to measure the severity of disease would also be useful for research. The really tricky bit would be developing a test that shows impairment of functional capacity without requiring the patient to do anything, or a test that "measures" a PEM without provoking a PEM. Unless it turns out that the most severe patients are in a more or less permanent state of PEM, which might be measurable.
 
It's important to define what information you are looking for and why. Since the two-day exercise test is cumbersome, expensive, stressful, and contraindicated for many people, I certainly don't want and don't expect it to become the standard diagnostic test to confirm the presence of ME/CFS...or at least the ONLY test available.

A blood test for cytokines after a mild exercise challenge may become accepted as diagnostic. That would be quicker and cheaper and much more widely applicable.
This is why it's especially important to have this test included in the research. By seeing which patients have the non-deconditioned abnormal response, they can look to see what non-exercise-induced markers are present in those patients. Then every patient can benefit by having the results of a blood test stand in as indicating vulnerability to exertion, versus having to do the two day exercise challenge themselves to prove that they're ill.

They are NEVER going to take our word for it that exertion makes us sick. There has to be objective, unfakeable, physical testing clearly associated with the quick-and-painless testing methods that we want to be developed.