New Exercise Study Brings Both Illumination and Questions

Simon submitted a new blog post:

New Exercise Study Brings Both Illumination and Questions

Simon McGrath looks at new objective evidence of abnormal response to exercise in ME/CFS patients, and the questions that researchers are still trying to answer ...


Exercise testing at Dr. Keller's lab

Given the doubt, scepticism and even denial of benefits that often confronts ME/CFS patients, it’s not surprising that many patients crave clear-cut, objective evidence of physiological problems in the illness. Preferably something that will explain at least some of the perplexing symptoms. Something that will say: “this is real”.

And finally it seems researchers might be closing in on this.

Two-day maximal exercise tests promise to provide objective evidence for the most striking and unusual feature of the illness, the exhaustion and flare of symptoms following exercise, called post-exertional malaise.

A couple of studies by researchers at Workwell showed distinctive abnormalities on these tests, and now another researcher Dr. Betsy Keller of Ithaca College has found them in an independent study.

But, as usual, science is messy, and these studies raise almost as many questions as they answer. While all three studies find substantial abnormalities, key details vary between them.

Furthermore, safety is a big unknown. These tests require patients to push well beyond normal limits twice in two days — exactly the kind of thing patients have found can cause lasting relapses. As yet, there is no hard safety data.

Even so, a little-noticed Social Security ruling in April states that while there is not yet a ‘definitive’ laboratory test, an abnormal exercise stress test, consistent with other evidence in the case record, proves a ‘medically determinable impairment’ in those with ME/CFS. And Keller reports that insurers increasingly accept her tests as evidence of incapacity. The two-day test could help secure a financial lifeline for patients.

Results from the latest exercise study

Keller used a similar two-day maximal exercise test at Workwell. ME/CFS patients exercised to complete exhaustion on a bicycle while their oxygen consumption, work output (pedal power), and numerous other measures were recorded. Then the 22 patients came back one day later to do it all again.

The most interesting measures were oxygen consumption and work output, a key measure of what people can actually do.

Work and oxygen consumption were measured at two key points: peak (usually just before people stopped from exhaustion), and at the anaerobic threshold.This is the point where normal aerobic (oxygen-burning) metabolism can't keep up, so the body has to draw more heavily on anaerobic metabolism to make up the shortfall, resulting in accumulation of lactate in the blood.

For healthy people at least, the anaerobic threshold is roughly the point where it’s still just possible to talk normally while exercising. (Strictly speaking, Keller used the "ventilatory threshold,” calculating it from the ratio of oxygen used to carbon dioxide exhaled, but that’s approximately the same as the anaerobic threshold.)

The patients showed an average fall in day-two oxygen consumption of 14% at their peak and 16% at their anaerobic threshold. Work output fell by similar amounts: patients could do less on day two.

There were no controls in this study, but there are well-established studies going back to the 1950s showing that healthy people can reliably reproduce their performance (within 7%) on two-day tests. Keller says the far greater drop in ME/CFS patients indicates an underlying physiological defect.

In fact, the results are even more striking for individual patients: while some show little to no change, some show very large drops, including one patient dropping 55% on day-two peak oxygen consumption. (It’s worth taking a look at the results diagram, Figure 3A in the paper, to see what’s really going on).

What’s more, those patients who didn’t show a clinically significant fall in peak oxygen consumption instead showed a significant fall oxygen consumption at anaerobic threshold: everyone showed abnormalities.

All patients showed a clinically significant drop on day-two, either for peak or anaerobic threshold oxygen consumption.

A one-day exercise test wouldn’t be enough to reliably show these patients’ true impairment. Using a standard measure of impairment developed for heart and lung patients based on a single exercise test, 13 of the 24 ME/CFS patients were classified as having little or no impairment. But while heart and lung patients can reproduce their exercise performance on day two, the ME/CFS patients could not.
The difference was big enough that half of the ME/CFS patients in this study would be classified as having lower functional ability on day-two results, and five of the thirteen that didn’t show any impairment on day one did on day two. This just highlights something very unusual going on with ME/CFS patients.

The results were so unusual, in fact, that it raised the possibility of faulty equipment. Though Keller didn’t run a control group, separate testing in her lab during the same period found normal results for healthy people, indicating equipment worked effectively.

Workwell included controls in their studies, and Chris Snell said this was mainly to prove the equipment was working (not to demonstrate that healthy controls can replicate performance on day two).

Science is messy

Perhaps these inconsistent results are not so surprising. A complex disease like ME/CFS is unlikely to yield its secrets so easily, and science is messy, especially in the early days.

A good example of messy findings came in the most important discovery in biology of the twentieth century: the structure of DNA.

X-ray diffraction images of DNA provided key evidence about its structure. Original images of DNA were clear in some parts but blurry in others, making them hard to interpret. This changed when X-ray expert Rosalind Franklin discovered DNA came in two types: A-DNA and B-DNA.

The original images turned out to be for a mixture of A and B DNA. Separate images for A and B revealed the extra information needed to solve the structure of DNA.

The different X-ray diffraction patterns of A and B DNA
Perhaps a similar scenario will play out in two-day testing, if studies are able to identify different subgroups, each with clear and distinct abnormalities - perhaps even a subgroup with none. Given that many researchers believe ME/CFS is likely to be more than one illness, it would almost be surprising if all patients did respond the same way to exercise.

Different differences

Unfortunately, when you compare the results of the various studies, as Keller did in her paper, the story becomes considerably murkier.

First, let’s look at oxygen consumption. Keller’s result, in summary, was that every one of her twenty-two patients had a drop in oxygen consumption either at peak or at anaerobic threshold, but not necessarily both.

The first wave-making 2007 Workwell study found drops in both for all six patients. A 2010 Dutch study found drops in both as well — but they were too small to be confident that they were meaningful.

Last year, a larger Workwell study (51 patients, 10 controls) found that the oxygen consumption at anaerobic threshold dropped significantly (by 11%), but the drop in peak oxygen consumption wasn’t big enough to be statistically or clinically significant (only 5%).

However, this last study also found a huge drop of 55% in work output on day two at the anaerobic threshold for patients.

This was especially surprising because the drop in oxygen consumption was far smaller at 11%, meaning that the patients produced much less work for each unit of oxygen. This inefficiency could point to some major metabolic change.

In contrast, Keller’s new study found a less dramatic drop of 21% in work. While that’s a clinically interesting result, it is broadly in line with the 16% drop in oxygen consumption at anaerobic threshold. It doesn’t suggest that the body is producing less work per unit of oxygen, the way the larger Workwell study did.

The Dutch study found a non-significant drop in work output of 7%, while work wasn’t measured in the first Workwell study.

So three of four published studies find substantial drops in day-two performance (the fourth Dutch study was on the margins of finding a difference), but no clear pattern has emerged as to which are the most important measures.

Is it peak oxygen consumption, anaerobic threshold oxygen consumption, or work output at anaerobic threshold?

Moving beyond messy science

Researchers have uncovered a very promising area for study. What’s needed to build on these findings and find out what’s really going on is further, more thorough investigation. Keller says we sorely need a much bigger study -- and by bigger she means involving hundreds of subjects, which will come with a hefty price tag.

The bigger study will help clarify exactly what changes in response to exercise and for whom. It could even establish thresholds for measures like peak oxygen consumption that could then be used by clinicians in diagnosis. Such guidelines will be crucial if more patients want to take advantage of the test to help with disability claims, as currently only three labs in the United States carry out this work.

Keller is clearly disappointed by the lack of interest in these extraordinary findings from exercise physiologists working outside ME/CFS. She’s not sure why but thinks it may go back to training.

As in so many medical fields, exercise physiology undergraduates learn next to nothing about ME/CFS, while young researchers are deterred by a lack of funding for this area. As things stand, moving the field forward will fall on the shoulders of the existing small group of researchers.

What could be going on physiologically?

Given the mixed findings, it’s hard to know what is driving the problem. The reduced oxygen consumption suggests two possibilities.

Keller thinks that too little blood could be being delivered to the muscles, thus not supplying enough oxygen. There is some indirect evidence to support this, including a modestly reduced heart rate on day two in this study, indicating less blood is being pumped around the body.

Poor autonomic response, says Keller, could be behind reduced blood flow, and there is plenty of research showing autonomic problems in ME/CFS, at least for subgroups.

An alternative explanation is that muscles are simply unable to burn more oxygen, and a study by a Dutch group suggested muscle uptake of oxygen was the problem. The muscle problem in turn could be down to mitochondrial or other energy metabolism defects. Again, it may need careful identification of subgroups before researchers can really get a handle on what’s going wrong.

Is it unique?

We don’t know if these findings are unique to ME/CFS, though it’s certainly unusual. This kind of maximal testing has been used frequently in diseases affecting heart and lungs (where all published results indicate they can reproduce results the second day).

Yet no published data exists on other fatiguing illnesses such as multiple sclerosis, HIV and rheumatoid arthritis. In a pilot study, however, Workwell reported normal reproducibility for one MS and one HIV patient.

The safety question

There will inevitably be concerns from some patients about taking a test that by definition pushes them to their absolute limits, and then does it again twenty-four hours on in the midst of post-exertional malaise.

Pushing beyond normal limits has triggered many a relapse, and sometimes patients never bounce back. But how big are the actual risks for a two-day test?

Keller says that most people in their tests report recovering to baseline in seven to 21 days, though some take longer. She also points out there is a lack of published data on long-term effects even for a one-day test, let alone two-day tests.

What’s needed, she says, is long-term follow-up looking at both symptoms and activity levels, to establish how long it takes patients to recover to baseline symptoms and activity. And she wants to use actometers (activity sensing devices) to ensure objective measurements of patient activity. This would also allow researchers to see if changes in patient activity matched the physiological changes seen on day two.

If these tests do cause extended relapses in some patients, they may never be appropriate to use for all patients in the clinic, even if they fulfil their promise to unravel some of the mechanisms of the disease. And in that case, there’s a cruelty in the new disability ruling. The only way that patients can prove their disability might be by risking making it worse.

The promise of exercise stress tests

To me, these are extremely interesting findings, because they have found substantial effects linked to the central feature of ME/CFS, abnormal response to exertion. It’s not just these two-day tests either: in Utah, the Lights’ fascinating gene expression studies are particularly interesting as they only uses a single, moderate test to reveal differences between patients and controls.

This is closer to real-world exertion by patients, as well as probably carrying less risk of relapse. The Lights’ initial findings have apparently been replicated in a larger NIH-funded study, but have not yet been published.

Clearly this isn’t a done deal yet, but the biological response to exercise is becoming an important new front in helping to unravel ME/CFS.

Simon McGrath tweets on ME/CFS research:

Picture credits: Exercise testing photo courtesy of Dr Betsy Keller; Exhausted pose drawings by JoeyGates on deviantART, Creative Commons CC BY-NC-ND 3.0; X-ray photos By I.C. Baianu et al. [GFDL or Creative Commons CC-BY-SA-3.0], via Wikimedia Commons.

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You are a class act. Great piece. In addition to being clear and concise, I really enjoyed your images and links. I also really liked that you put credits at the end and a creative Commons copyright. Very thorough.

Have you ever heard of anybody speculating on what's going on using both the Lights results and these today exercise test? For example, the Lights gene expression studies show what's going on after a one day test, and what in the Lights results could lead to the decrease in oxygen consumption etc. on a two day test?
One of the great deficits in ME and CFS studies is the size of the studies. As always we need larger studies. It would be very interesting to combine the 2 day CPET with many days of testing of the gene expression profile as well. Further, I wonder what would happen if they retested CPET at ten and twenty days.

Yet all of this is inadvisable for severe patients, and impossible for the very severe. The Light's research is one alternative. Another I have pointed out is gas analysis without exercise in severe patients.
@Simon Absolutely wonderful article!!! I often get lost in these scientific articles but this one was very clear and well-written and a brilliant summary of the current research.

I did a one-day exercise echocardiogram test today for diagnostic reasons where I completed the test which lasted for four minutes. I can't imagine doing it at maximal capacity, which I wasn't, and then having to repeat it the next day! :eek:

If PWC's were forced to do this in order to get disability, it seems unethical to me. But I like that people have the option to take it and agree that we need studies with larger sample sizes. Another major hurdle is the cost of the test which is not covered by insurance (as far as I know)

Also, I was confused, does gas analysis test without exercise for very severe PWC's currently exist? (what Alex mentioned?)

@NK17 Best wishes for your CPET test and I will be sending very positive thoughts & prayers your way for a successful test and recovery :hug::hug::hug:.
Thought people might like to see the detail of that SS ruling on exercise tests

Social Security Ruling, SSR 14-1p; Titles II and XVI: Evaluating Claims Involving Chronic Fatigue Syndrome (CFS)
Effective Date: April 3, 2014.

PURPOSE: This SSR clarifies our policy on how we develop evidence to establish that a person has a medically determinable impairment (MDI) of CFS and how we evaluate this impairment in disability claims and continuing disability reviews under titles II and XVI the Social Security Act (Act).

Laboratory findings. At this time, we cannot identify specific laboratory findings that are widely accepted as being associated with CFS. However, the absence of a definitive test does not preclude our reliance upon certain laboratory findings to establish the existence of an MDI in people with CFS. While standard laboratory test results in the normal range are characteristic for many people with CFS, and they should not be relied upon to the exclusion of all other clinical evidence in decisions regarding the presence and severity of an MDI, the following laboratory findings establish the existence of an MDI in people with CFS:

Any other laboratory findings that are consistent with medically accepted clinical practice and are consistent with the other evidence in the case record (for example, an abnormal exercise stress test or abnormal sleep studies, appropriately evaluated and consistent with the other evidence in the case record).
Thanks @voner @NK17 @SOC @Gingergrrl for those kind words :). And good luck @NK17.

Have you ever heard of anybody speculating on what's going on using both the Lights results and these today exercise test? For example, the Lights gene expression studies show what's going on after a one day test, and what in the Lights results could lead to the decrease in oxygen consumption etc. on a two day test?
I haven't, and it's a very interesting point. Seeing how these two different approaches tie up is something that I hope researchers will look at in due course.

@DanielBR raised the same question about the recent epigentic study, and if the results would change after exercise, and @alex3619 suggested doing the same re gene expression.

One of the great deficits in ME and CFS studies is the size of the studies. As always we need larger studies.

Yet all of this is inadvisable for severe patients, and impossible for the very severe. The Light's research is one alternative.
Always bigger studies :). The Lights have a large on (150-ish) on gene expression response to exercise completed but not yet published - perhaps when it is it could be the basis of a new test.
Another I have pointed out is gas analysis without exercise in severe patients.
New to me: how does that work?
As I said on another thread, I had gas analysis without exercise in 1993. Its the same technology. What is not sure is how useful it is. Its an open question. I do know it can be used to measure metabolic rate.

In my case it showed a low metabolic rate. Brain scans looking at brain metabolism also showed a low metabolic rate for me.

This wont show the energy crash post exercise, but it will show disability in severe patients, I think. It does however leave the door open to how the low metabolic rate will be interpreted. However it also could be used as a noninvasive and nondangerous marker for improvement or worsening, giving us a tool for improving patient care.

Indeed this is how it was being used in 1993 - to measure if interventions improved or worsened individual patient capacity. This was the work of Dr Andriya Martinovic, who was in my view unfairly targeted for treating CFS and forced out of treating or researching it.

I also put a message on the Workwell Facebook page some time ago - the question I have in mind is whether or not severe ME patients are permanently in anaerobic metabolism, and whether this test would then be useful. I have had no reply to date.
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I agree. An excellent article Simon.

I think that there had been some previous convoluted (to me anyway) discussion on these mixed findings and I ended up pretty confused as to how they agreed and differed. This article cleared things up no end.

Going forward I recently came across an article that suggested that heart rate variability may be a simpler and non-invasive measure on anaerobic threshold which might make this type of testing more feasible outside of specialist exercise physiology labs :

Noninvasive method to estimate anaerobic threshold in individuals with type 2 diabetes
I had some testing done and I have viral activation, I have my AT at 115BPM. I will get the second day one done to see the reduction in my case. But I wonder what would happen if you do it for a whole week/?????? If our energy lowers exponatially. I will see if they wanna use me as a case study so I try to do it more than 2 days in a row.
I had some testing done and I have viral activation, I have my AT at 115BPM. I will get the second day one done to see the reduction in my case. But I wonder what would happen if you do it for a whole week/?????? If our energy lowers exponatially. I will see if they wanna use me as a case study so I try to do it more than 2 days in a row.
You have ME/CFS? I was wondering about those who don't, but just have a transient virus.
I am being treated for POTS, but first all the tests. Where do I begin. First I can only do a few tests at one time. So it's been three appointments and only once a month. It actually takes me longer to recover but I'm in this, really in this.

Tilt table test, blood volume test, hemodynamic test, autonomic reflex test, and my personal favorite the stress test on a treadmill that put me in bed for a week and got some abnormal results and mortality rates 5-10% in 5 years depending on which institution you are going by.

I know I'm a mess but now they know it. I will get the final results on 8/25 but they are wondering why I'm not doing the exercises with the heart rate gizmo. Well I haven't recovered from the tests yet and I won't do them until all results of tests are given to me and then a plan is made.

I must say I never thought my life would be this hard, not in a million years. (real tears).
One of the difficulties must be that each of us has a different mix of long and short fibre muscle, which (if I remember correctly) correlate to marathons versus sprints. The initial mix depends upon genetics, but the balance can be adjusted through training. What if (pure speculation here) some people with ME have a muscle balance that, after several years of the disease and careful "nudging the envelope" have increased their short fibre muscles? What effect would that have on measurements such as this?

I ask because I have "classic" ME, and sit somewhere in the middle severity range. I used to cycle a lot (it is very hilly here), but was useless at sprints. A little while ago I was sent to have my heart irregularity checked on a treadmill (on the understanding that I could stop at any time), but I actually managed a fast uphill walk without more than a day's payback (of course, in my pre-ME days I would have laughed at how trivial the test was).

I appreciate that this comment is muddled, but it does puzzle me that I seem to get less payback problems these days for going a little over the physical limits than for going over the concentration limits, something that just wasn't true for the first ten years or so of the illness.