Reprinted with kind permission of Cort Johnson, Health Rising, Sept 15, 2013
In July, eleven ME/CFS groups and thirty-one advocates requested the CDC use the two-exercise protocol in phase two of their multi-site study. Their letter stated:
"The two-day CPET regimen known as the Stevens Protocol provides gas exchange and other objective and measurable results “which can’t be faked.” …Having CPET testing performed by trained personnel on subjects involved in the multi-site clinical assessment should be considered a TOP PRIORITY…
We cannot over-emphasize the importance of measuring and understanding post-exertional malaise (PEM) in this study. PEM is most often the largest obstacle to activities of daily living, gainful employment, exercise, and more."
During the CDC Conference Call on Tuesday, Sept 10, Dr. Unger nixed any chance of meaningfully measuring exercise capacity in this study by her decision to do the 1-day exercise test. A brief look at the results from latest two-day ME/CFS exercise study will illuminate what was lost.
The One-Day Two-Day Question
The first exercise test suggested the ME/CFS patients had the same capacity to do exercise as the healthy controls After the first exercise test the ME/CFS patients looked as healthy as the healthy controls. The ME/CFS patients’ ability to produce energy (at ventilatory threshold) dropped a full forty percent during the second exercise test. The healthy but deconditioned controls maintained their energy production. These findings demolished the ideas that deconditioning and lack of effort played a role in ME/CFS patients’ ability to exercise, and pointed a dagger at their energy production system.
Workwell’s ability to accurately determine who was healthy and who had ME/CFS 95 percent of the time simply by looking at the difference in results between day 1 and day 2 suggested they’d found a diagnostic biomarker.
Eliminating that second day means deconditioning will remain on the table as a possible explanation for ME/CFS. The idea that metabolic dysfunction is involved in ME/CFS will take a hit. Getting at the cause of the exercise problems in ME/CFS has been sidelined. Instead, what we have is a study that will determine whether ME/CFS patients’ symptoms and cognitive functioning get worse after exercise.
Dr. Unger gave up a lot when she gave up that second day. Let’s see why she made that decision.
The CDC’s Reasons
Dr. Unger’s rationale for dumping the two-day test was surprising to me. Questions about expense, about different staff doing the tests correctly, whether the sites had access to the equipment and personnel needed to do the test, whether the ME/CFS centers wanted to do two day tests–all the seemingly tough stuff–disappeared. Here are the reasons she provided in a response to the advocates.
(1) The CDC wanted to measure “exercise capacity” in as many patients as possible.
But they’re not really measuring exercise capacity, are they? They’re measuring the ability of ME/CFS patients to exert themselves fully on one day, and that’s NOT exercise capacity. Exercise capacity is the ability to engage in exercise day after day after day.
The ME/CFS patients' ability to exercise plummeted during the second exercise test; the deconditioned controls were able to exercise at their normal rates The ability (or rather inability) to do that is what gives people with ME/CFS so much difficulty. The beauty of the two-day testing protocol is that it captures what happens to people with ME/CFS in real life.
This study won’t do that. It’s not measuring exercise capacity in a meaningful way.
We know from past studies that most people with ME/CFS blow through the first exercise test with flying colors. We know that the real metabolic abnormalities in ME/CFS don’t show up until the second day. This study is not about measuring ‘exercise capacity’; it’s about determining what symptoms and cognitive problems occur as a result of exercise.
Unintended Consequences Could Spell Problems
We know researchers have used results from one-day exercise tests to assert there are no underlying metabolic problems in ME/CFS. We know that the two-day test was developed, in part, to counter those claims, which brings up the question of whether this study might not do more harm than good. A large study that finds no significant changes in exercise capacity could inadvertently provide ammunition to those who propose no metabolic issues exist in ME/CFS…
If past studies are any guide, this large study will almost surely conclude that most people with ME/CFS do not have significant problems with energy production. It will probably be published in a widely-read journal. It will certainly eclipse the smaller efforts, published in more obscure journals, that found significant metabolic issues using two-day exercise tests.
After this study if your doctor knows anything about energy production in ME/CFS, he will know that it’s probably not the issue. He’ll probably recommend that you exercise.
The two day test-retest studies suggest otherwise, but the lack of traction given them concerned ME/CFS advocates enough that they produced a major lobbying campaign to get them included in the CDC’s study. The advocates don’t necessarily believe the test-retest results are clear, but they do believe they’re clear enough to warrant significantly more study. This large study appeared to be a perfect launchpad for more extensive research into this area.
Unfortunately, it could do the opposite.
(2) Doing the two-day test would cause people who are traveling long distances to stay an extra night, causing additional costs that might cause them to not participate in the study.
What??? The study centers exist in major metropolitan areas. It’s not clear why many people would a) need to travel long distances to get to them, or b) if they are willing to do that, why they wouldn’t be willing to stay an extra day, and c) what proportion of the total study population this problem would affect anyway.
Four hundred and thirty-five people participated in the study. Even if you cut that number down dramatically you’d still have the biggest exercise study ever done in ME/CFS.
But there’s no reason to cut the study down dramatically. Let’s say 10% of the study participants have to fly in. Let’s say 25% of them decide not to participate because they don’t want to pay for another night. That would mean one-fourth of that 10%, or 2.5% of all study participants, would be dropped from the second test. But 97.5% would remain!
The two-day study would exclude the most severely affected.
Of course it would, but only from participating in the second test. Since the most severely affected will probably show metabolic dysfunction on the first exercise day, they don’t need to do the second test. Adding the second exercise test doesn’t exclude the more severely affected it simply includes include the less severely affected.
The weak reasons given for not doing the test-retest protocol suggests Dr. Unger and/or the centers in the study, simply didn’t want to do a two-day exercise test, and that we still don’t really know the reason(s) why. In fact, Dr. Unger’s decision not to consult the experts in the field until after the study design was finished suggests that two-day exercise testing was never on the table.
CDC Choses Not to Use the Experts in the Field.
Dr. Unger’s discussion with Dr. Snell, a published expert on exercise testing in chronic fatigue syndrome, took place only after eleven organizations and thirty advocates implored the CDC to do the two-day exercise tests. It took place months after Dr. Unger, at the FDA Workshop, stated two-day testing was not on the agenda. It took place well after the study design had been decided. It was a sop to ME/CFS advocates.
Two of Workwell’s PhDs, Snell and Van Ness of Workwelll, have published extensively on exercise in ME/CFS. Staci Stevens developed the two-day exercise protocol for ME/CFS. When Stanford’s Dr. Montoya needed to ensure that his exercise studies were done correctly, he went to Workwell. They would seem to be the natural consultants for a study on ‘exercise capacity.’
When Dr. Unger needed advice on exercise testing, she went to Connie Sol, a fine exercise physiologist, but who is not a PhD and has no long record of research (1 study). It turned out, though, that Connie was perfectly adequate to this task because it appears that the CDC had no intention of understanding exercise capacity or examining energy production issues in ME/CFS.
This study has always been about measuring symptom exacerbations and cognitive declines after exercise.
A Difference of Opinion
In my opinion we’re simply dealing with a difference in opinion. Dr. Unger clearly has reservations about doing two-day exercise tests. She believes different kinds of testing are more valuable.
ME/CFS advocates are baffled why the test-retest strategy was not used in this study ME/CFS advocates, on the other hand, believe the two-day tests could be a game-changer. They recognize there are issues, but the possibilities presented are too significant not to pursue them further. The two-day exercise tests are a priority for them.
They’re completely baffled as to why the CDC (or other researchers) doesn’t see it the way they do. They just don’t get it. Dr. Unger’s explanation is so weak that some are beginning to think diabolical motives are in play.
Once again the CDC, which has done so much under Dr. Unger to allay fears and repair bridges, is under attack. That’s unfortunate, but she has to bear some responsibility for that; the explanation she gave simply didn’t help.
The chronic fatigue syndrome research field needs game-changers. It needs results that smack researchers between the eyes so hard that they finally sit up and take notice. Any study that eats up a year of one of our largest research effort’s budgets should be focused on possible game-changers. Let’s look at this study and see if it provides any.
The ME/CFS field needs game-changers but nothing in this large study, almost two years in planning, suggests it will produce a game-changer for the ME/CFS Community. Before we start let’s note that Dr. Unger’s explanation of the study is very confusing. In it she states that the study will “Enroll patient for the protocol on combined cognition and cardio-pulmonary exercise testing (CPET), with 48 hour follow-up of cognition, pain and symptom measures to identify post-exertional changes.”
A bullet point she includes below that says ‘blood sampling for gene expression changes’ suggests gene expression changes are going to included–somewhere. In the header, though, she states the 48-hour post-exercise follow-up tests will include cognition tests and symptom measures.That suggests gene expression change tests are not part of the 48 hour post-exercise period.
The study will attempt to identify cognitive declines in patients after exercise. Let’s be clear about one thing: as distressing as the cognitive declines are for ME/CFS personally, no-one in the research world is grasping just how horrible the cognitive declines are in ME/CFS. This is because they appear to be fairly mild relative to disorders known to produce significant cognitive problems. It’s possible that one fifteen minute exercise period to exhaustion will produce off-the-charts cognitive dsyfunction in ME/CFS over two days, but I doubt it.
My guess is that reading the results will not cause outside researchers to gasp, clean their glasses, and then read the study again to make sure they got it right.
Besides the cognitive tests, the CDC will examine pain and symptoms. Increases in these after exercise have been abundantly documented by other groups.
That’s it! Unless the description of the study is sloppily written, other testing is not going to be done in the 48 hour post-exertional testing period.
Gene Expression (?)
If gene expression studies are being done in the 48 hour post-exercise period, then validating Dr. Klimas’s unpublished results suggesting autonomic nervous system changes trigger an immune cascade, or Dr. Light’s results, would be a major step forward.
Identifying any subgroups based on gene expression would be a step forward. Gene expression is a hot but complex topic with a mixed record of success in the ME/CFS field My guess is that gene expression has great value but that it’s going to take years to come to fruition. The last six gene expression studies have found increased sensory, adrenergic, etc. gene expression, nothing, increased GRK2 and NPAS2 (in subgroups), increased sensory, adrenergic, etc. gene expression, increased WASF3 and HDAC7A, concluded that misclassification of genes meant gene expression could not be used as a diagnostic tool, and one that talked about hundreds of upregulated genes.
The last Kerr gene expression study blew the results of his two previously positive studies out of the water which meant the ruin of years of work, and Kerr left the field shortly afterwards. The Light gene expression studies have been the most successful, but even there gene expression varies remarkably from individual to individual. Disentangling those complex but encouraging results to provide treatment options for ME/CFS is going to take work and time. (Dr. Vollmer-Conna of the Dubbo group in Australia recently told me they’ve been unable to duplicate the Light gene expression study results.)
Gene expression studies, for all their promise, are a gamble at this point. For me, the choice between a possibly difficult to interpret gene expression result and clear evidence of metabolic dysfunction using exercise technology that’s been with us for decades, and has a good track record in ME/CFS, is an easy one.
Natural Killer Cell Dysfunction/Morning Cortisol
It appears that NK cell function tests and morning cortisol tests are not part of the exercise study, but part of the larger study. We know cortisol levels are mildly reduced in this disorder–particularly in the morning–but it’s hard to see how another low cortisol finding, particularly another mildly low cortisol finding, is going do anything significant for ME/CFS.
Natural killer cell dysfunction is clearly an important facet of ME/CFS, yet we might ask here too what finding more NK cell dysfunction will do that hasn’t been done already. Yes, it highlights a major issue in ME/CFS. Hopefully it will point to more immune research, but will another NK cell dysfunction finding be a game changer? My guess is no.
Demonstrating that ME/CFS patients’ ability to produce energy declines during a second bout of exercise is an eye-opener for me. It comports with my experience. It’s easily understandable. It doesn’t require complicated programs to understand it. It’s like being hit with a mallet over the head. It has the possibility of being an immediate game-changer for this disease. Nothing else in this study provides that kind of possibility that I can see.
Little in this study appears to be novel. The idea to study ME/CFS patients who see expert ME/CFS practitioners was a good one, but I believe the CDC is missing an opportunity.
Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising.