Opportunity Lost

The CDC hosted a conference call for ME/CFS patients and advocates today. The highlight of the call was a presentation from Dr. Ian Lipkin about his pathogen and immunology work in ME/CFS. But we received an important update on the CDC multisite study, and it remains to be seen whether advocates will accept what we were given.

You may recall that at the May 2013 CFSAC meeting, advocates were aghast at Dr. Unger’s statement that the CDC multisite study would not use two-day cardiopulmonary exercise testing (CPET) despite the research showing that this protocol produces evidence of post-exertional malaise, metabolic dysfunction, and is a potential diagnostic marker for ME/CFS. When questioned, Dr. Unger said she had not discussed the protocol with Dr. Chris Snell or Staci Stevens (who created it). This seemed like yet another example of CDC having an opportunity to do good science and intentionally choosing not to do so.

On July 22, 2013, eleven groups and thirty-one individuals sent a letter to CDC requesting, among other things, that the multisite study use the two-day protocol. Here’s what they said:

The two-day CPET regimen known as the Stevens Protocol provides gas exchange and other objective and measurable results “which can’t be faked.” With properly trained personnel in place, this test can be done using technology which has been used in hospitals and other facilities for decades. Having CPET testing performed by trained personnel on subjects involved in the multi-site clinical assessment should be considered a TOP PRIORITY in order to maximize standardized data and take advantage of the opportunity provided by this important CDC-initiated study.

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. A combination of data from the two-day CPET test and the on-line cognitive test that is already planned will provide the data needed for effective analysis of this debilitating symptom.

Dr. Unger responded in writing on August 30th, but for unknown reasons the advocates did not receive her response until today. Both the letter and Dr. Unger’s comments on the call today explain why CDC has chosen to do one day of maximal effort testing, followed by 48 hours of cognitive testing and symptom measurements. Especially important (and highlighted in the excerpt below) is Dr. Unger’s representation of Dr. Snell’s opinion on the protocol:

To address concerns regarding the cardio-pulmonary exercise testing (CPET) in the second stage of the study, I would like to share additional details, and the rationale that we used to select the one-day maximal exercise test. Our primary objective is to measure the exercise capacity in as many of the enrolled patients as possible using a standardized protocol, and to monitor the post-exertional response for 48 hours with online cognitive testing and visual analogue scales of fatigue, pain, and symptoms. Maximal CPET with one day of testing and 48-hour follow-up of cognition was developed in consultation with Dr. Gudrun Lang (cognition) and Dr. Dane Cook and Connie Sol (exercise). The exercise protocol was discussed also with Dr. Chris Snell. Dr. Snell favors the two-day test because it gives more information, however he believes the one-day maximal CPET will provide useful information. We chose the one-day test so that more patients could be tested. The two-day test would require an additional overnight stay for those patients who travel long distances to attend clinic and excludes those who are most severely affected because of the heavy physical toll. In developing the protocol, we strived to find a balance between testing that would yield meaningful data in the broadest representation without placing an unnecessary burden on the patients.

I immediately asked Dr. Snell if this was an accurate representation of his comments, and he said it was. He commented:

As you know, we believe that the 2 day test provides important metabolic data as well as potential to objectively document fatigue following physical exertion. I do believe, for most patients, a single max test will elicit PEM which should affect the post-test cognitive scores and fatigue scale scores. The CPET data however may not be a true reflection of physiological function post exertion for all patients.

On balance, I am happy that the CDC chose to use a validated protocol for functional assessment that does incorporate objective measures of effort. This is infinitely preferable to dubious “sub-maximal” tests. I did indicate that the study was still worthwhile even absent the second test. On what may be a selfish note, I am disappointed that the study does nothing to validate the diagnostic value of repeated CPET testing for ME/CFS. It was briefly mentioned that this might be part of subsequent studies.

So is this CDC protocol a reasonable compromise? I’m sure it was influenced by budget, to some degree. CPET testing is expensive (as I can personally attest), and creates a serious burden of recovery. CDC is choosing to compromise by using a single maximal test and then measuring the effect on patients. Will a one day test be sufficient to demonstrate PEM, including the cognitive and physical symptoms of a crash? Will advocates be satisfied, especially in light of Dr. Snell’s support of CDC’s protocol for this study?

I think CDC will capture good data this way, but it won’t be a complete demonstration of PEM and the metabolic dysfunction that characterizes ME/CFS. The second day of testing captures the significant drop in VO2max, oxygen consumption at the anaerobic threshold, peak workload, and workload at the anaerobic threshold. The second day results differentiate ME/CFS patients from other illness groups. It is possible that the CDC multisite results will not do so without that second day of testing. In my opinion, that is a huge missed opportunity.


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21 Responses to Opportunity Lost

  1. Kati D says:

    i agree also, Jennie, missed opportunity and also failure to get objective results and not self-report of symptoms. Who knows what the cognitive test will be, especially if it is done in patients’ homes. For instance, my cognition is much better in bed than sitting up.

    And won’t they draw blood post exercise to look for specific biomarkers?

  2. Tina says:

    agreed. They could do it for those willing to do it. It doesn’t have to be all of them. I still want it. I think it has great diagnostic value and if it isn’t included in this study looking at how to identify (define or characterize) the disease, in addition to subgroups, it’s a missed opportunity to do something important.

  3. Otis says:

    I just posted on a thread on Phoenix Rising that I didn’t concur with the approach or the rational.

    Too fried to repeat it all but I don’t believe watering down the test is valid.

    I think most patients who can do one day (not to mention travel) can do the second day. Secondly, the sickest can’t travel or ride a bike even once.

    I believe this is a lose-lose.

    I also wonder about the funding aspect of this.

  4. Maxine says:

    In principle, I agree with the vital impact that further validation of test/retest V02Max could have for the M.E. community. On the other hand, I continue to have serious concerns about Test/retest reliability, PARTICULARLY in the more severely affected. Other than the obvious issue of the most severe patients being unable to do one, let alone 2 tests, he more severely impacted patients, including me, are ALREADY in PENE, simply from the effort of planning, packing for and travelling to the first test. This occludes any Test 1 to Test 2 drop, because that drop has ALREADY occurred by the time of the first test. Indeed my first and second tests showed negligible difference, even though my anaerobic threshold and V02Max were pathologically low, and even though I meet all the International and CCC criteria for M.E. – including neuro, I might add.

    I continue to have serious concerns regarding the forceful advocacy to position the Stevens/Snell Test-Retest protocol as diagnostic, or as a biomarker, unless meticulous care is taken to control for PENE happening simply as a result of preparing for or traveling to the test itself. Indeed this is corroborated by word-of-mouth findings that other researchers are unable to document this drop in their more involved patients. And I’d bet my bottom dollar that this inability is simply due to crashing from prep/travel to the test. This caveat needs to be addressed, and urgently, before we can rely on the innovative and brilliant Stevens/Snell protocol as a biomarker.

  5. rivka says:

    is there any harm in replying to unger that we patient advocates are not at all satisfied with this one-day test, as it will make the study results less acceptable to the patient community? we’d be on the record saying such, and it is true: we are not satisfied and it will make the results less accurate.

  6. Robert Morley says:

    I think there’s some degree of validity to the proposed method, but it’s definitely not as good as the two-day method. The main reason that I think the two-day method is preferable is that there’s no questioning the physical results. By relying on patient reports of pain, fatigue, etc., it’s immediately susceptible to variation and so forth in that what I consider 7/10 may not be what you consider 7/10 which may in turn be totally different from what the researchers think of a 7/10 being.

    There’s also the fact that everyone’s a bit different. After a significant physical strain, my cognitive function goes down for the rest of the day, but at least nowadays, it’s usually back up to normal by 24 hours later, so if that’s the focus of the testing, it makes it look like I’m not so badly off. Physically, however, I can take days to recover.

  7. Molly says:

    I agree with this commentary. The Test/Retest is the best method to get all the results as quickly as possible and begin immediate interventions targeting the core of the physiological health deficits. “IF” a patient has any physical barriers that would make that person a risk for emanate heart failure, or exacerbate an injury (such as requires a joint replacement), then of course some individuals should only be considered for the one day or no test

    However, the Test/Retest with Cognition Testing may require an overnight stay, the end results are well worth the expected prolonged recovery time. It is most definitely a cheaper and more effective diagnostic tool than the pathetic “rule-out matrix. It is really hard to fake this horrid misery for decades.

    My primary question is in the timing. If the two day CPET tests were ordered early in the first Six months of medical affliction followed with years of unproductive diagnostic “rule-outs”, how many ME (et al) Patients would never become housebound or bedbound to the degree that travel is overwhelming. My guess is after 2, 6, 13 or 30 years of living with the constraints of no interventions resembles the CDC once again creating critical developmental stages of no hopeful recovery.

    This to me is intentional “history repeating itself.” Again, the CDC now has the opportunity to develop a standard that would bring understanding and consensus to the medical care of people afflicted. Dumbing down the benefits of the CPET Test/Retest w/Cognitive testing is a CDC methodology to minimize the devastation that this disease costs each of us, who have to watch our Quality of Life become a mockery of human potential. We lose our Integrity, our Family, Careers, and Futures while the CDC recreates tactics that keep us in this InvisiDisability (my reality). It creates grief, lost and despair with rapid financial ruin without ever allowing patients their individual Civil and/or Patient Rights to Equal Health Care Treatments.

    I question if Dr. Unger has carefully crafted a convoluted response that puts Dr Snell and his Professional Team Excellence on the defensive if they even hint at disagreeing with her white- washed translation of his incredible work. A few months back she didn’t even know of his work. There is a hidden agenda, just as sure as the Asst. Sec. of HHS projects smiley faces with empty platitudes at the CFSAC meetings while negotiating secretive contracts with Private Government Contractors who will spend millions to spin the development of a Case Definition denying True, Consistent and Representative Diagnosis’ of the patients misery.

  8. Ess says:

    Wow, Maxine–have you ever raised a very important point that has not been considered in this–all the effort it takes to get ready, packed and out the door–then travelling!!!! :(–never mind the exercise–everything is a PUSH–and arriving and testing haven’t even begun — we are depleted before we even start.
    Reallllly—the powers that be ‘don’t know that/don’t get that’—HELP!!!!!


  9. michel says:

    I am also disappointed that they will do only 1 day test. I think that the majority of the patients who would be able to do 1 day test they would be able to do also 2 days. The sickest patients will not be able to do 1 day test. So this is not a good “excuse” for not doing 2 days test. I think we should keep advocating for 2 days test.

    Also we are listening all the time from NIH that for CFS there is enough money but there are not enough good applications. So now is the time to confront NIH with these words and ask to fund Lipkin studies. It was already mentioned – i would also like to see our advocates to prepare a letter with Lipkin´s cooperration to ask moey from federal agencies and then we will attack them with the letters

  10. Waiting says:

    Does anyone have a copy of Dr. Unger’s response to the July 22nd advocate letter? I’m assuming it could be posted and made public. I’d like to see the point by point argument for NOT including the 2nd day test.

    The omission of the 2nd day CPET is a big mistake. It makes no sense to me whatsoever. This is not the test to skimp on. It is objective data and we appear to be a unique group of patients in our inability to reproduce our CPET results on the 2nd day. Decades have gone by while we waited for a test like this that clearly assesses our degree of disability. Why on earth is the CDC not taking full advantage of this test’s availability and the ready expertise of Staci Stevens, Chris Snell at the Workwell Founation?

    I don’t think we should drop this issue: it’s too important.

  11. Ess says:

    Molly—such an accurate well-worded description with all that you have said—Your words speak volumes of truth and reality. All of these years and years AND continuing years of ‘medical’ ‘politics’ are a devastation to the ME/CFS community of MILLIONS world-wild AND our families. Please, with all due respect, it’s time to ‘cut’ the politics/hidden agendas and truly get to the answer and cure. This is a cruel and unjust way to ‘leave us’ with our lives–in all facets– stolen away because of chronic debilitating illness/disease that has been swept under the carpet for decades. AND the global result—an EPIDEMIC–that is why Epidemiologists are on the research train!!!!! WHY and how could this happen?? In actual fact, it is costing MUCH MORE to NOT find the answers than it is to ignore us—there is a global epidemic that is spreading!! Medical people know that there are also MANY thousands (locally) and millions (globally) persons with ME/CFS than are UNdiagnosed!!! Please–let’s drop the ‘medical politics’ here and really HELP US!!! @Molly

  12. Ess says:

    Sorry (brain fog after yesterday’s outing)—in my response, Molly, the second last sentence should read—In actual fact, it is costing MUCH MORE (dollar-wise to the economy) to NOT find the answers (to ME/CFS) than it would to find the answers—because there is a global epidemic that is spreading!! @Molly

  13. Garrett says:

    A one day CPET is unexceptable to use in this study given the fact that a two day Stevens protocol is multitudes more rich in objective data. The study set up now is based purely on subjective measures and the data collected can be messaged into meaningless psychobabble which is the CDC’s modus operandi. Also I dont think we have to worry about the patients who show up with travel induced pre-PENE because those patients results would not show a significant abnormality using the 2day Stevens protocol and therefore these results could be teased out of the final data set used.

  14. Waiting says:

    You and your readers might be interested in the poll I just created on Phoenix Rising. The poll question is: “IF you were a CDC Multi-Site Study participant, would you agree to do the *2-day* CPET?”


  15. John says:

    Hi Jennie, it sounds like getting the 2-day CPET exercise test studies replicated by an independent group is becoming a top priority. Do you think the CAA would consider possibly changing or alternating from their usual strategy of receiving study applications and go for a direct route of commissioning a study in this case?

    • Jennie Spotila says:

      John, good question. I honestly don’t know if the Association’s current funding model includes contracting for research in this way.

  16. The Walking Dead says:

    Molly hit the nail on the head, they have heard all our signs and symptoms for over a decade now. Their actions speak so loud, that I can’t even hear what the committee is saying anymore. The only thing that makes sense is they have no intention of furthering this cause, because not doing a diagnostic tool like the 2 day stress test that PROVES metabolic failure on the 2nd day shows that Dr. Unger is not for our cause. I mean this is proof on a lab/diagnostic level that physicians can understand, that ME/CFS patients don’t have a mental disorder, or are lazy, I mean its proof. Why wouldn’t she be shouting it out loud, and pushing for mandatory 2 day stress test, not to even mention mandatory write ups in medical journals, and reviews that physicians will be reading. Why would they do this to such a sick, weak group of people? I am starting to just feel like I’m being BULLIED by the stronger.

  17. Maxine says:

    @Ess, you know what makes this even scarier, is that I have heard that some ME/CFS researchers are SURPRISED that they can’t replicate the Stevens Protocol in their more involved patients. And the scuttlebutt I have heard is they see this as discrediting the Stevens Protocol, which IMO is ludicrous. My take – this is just professional jealousy. But is is spite that could set our research field back, and hold the Stevens/Snell team back from further great work. The Stevens Protocol is brilliant- its work just needs to be somehow expanded (rigorous controlling for rest prior to Day 1 testing… maybe enforced bedrest after travel; plus post-test-One gene expression and/or cognitive testing?), so that we can capture PEM/PENE in the more severe patients.

    But in my case, I needed a few months to recover from the whole ordeal, and I hazard a guess that I would have needed at least a week of enforced bedrest after travelling to California, BEFORE doing Test 1, so I was “fresh” enough. Clearly that’s not practical, so we need some proxy measures, I think.

    So as you so rightly point out, this is scary stuff. Seriously… any researcher worth their salt should just be nodding their head: “Yup, this makes sense – the sickest M.E. patients either can’t do the 2nd test, or they are already crashed just getting to the first test.” As to the researchers who don’t get it… maybe it’s time to listen to those patients again.

  18. Waiting says:

    Follow up: I sent the results of the poll on Phoenix Rising to HHS and CDC, as accessed on Wednesday ..93.3% of voting members said “yes”. Snce then there are a few more “yes” votes. The text of the email I sent is here (post #34):


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