NIH post-infectious CFS study

[Sasha]

Don't think for an instant that fibro and chronic pain have a good reputation in the community. Diseases that have a biomarker (MS, rheumatoid arthritis for instance) get much more respect and access to research funding than diseases who rely on self-report or lack biomarkers.

Fibromyalgia is getting some of the same vilification including mentions of 'catastrophizing' and 'patients with fibro should not get access to disability insurance'. Scary.

I realised as I was typing it that it wasn't the best, but what about migraine? Neuropathic pain? Tinnitus? Surely there's a whole ton of stuff that relies on self-report and doesn't have objective markers.

@Jonathan Edwards? What do you reckon to the idea of letting patients off a 2-day CPET and relying on self-report of PEM (using a good instrument, not the usual vague rubbish)?

 

[JayS]

If they do the 2-day exercise test properly, the study will find two groups of people - a group with PEM and a group without PEM.

For all its flaws, the IOM report was specific about PEM being mandatory for the illness. I'm not exactly clear on why they would find 2 groups of people when it seems by definition there should only be one to begin with.

That they wrote that the purpose of the exercise testing was to make patients 'tired' doesn't fill me with confidence that they're approaching this properly at all.

 

[TiredSam]

That they wrote that the purpose of the exercise testing was to make patients 'tired' doesn't fill me with confidence that they're approaching this properly at all.

Do patients need an exercise test to make them feel tired? Surely standing up and walking across the room when their name is called will do that job nicely. Very concerning that anyone running a study doesn't seem to know that already.

Or do they mean by "make them feel tired" "deliberately induce PEM"? Just as concerning from an ethical point of view.

 

[Bob]

I assume the two-day exercise event will be a CPET test, following established protocols, otherwise why would they include a two-day exercise event? I think it should be optional, otherwise the study excludes many moderately affected patients, and the study will be biased towards patients who can better tolerate exercise. A one-day exercise event can also provide very useful information e.g. if they were to test for cellular changes before and after exercise, as the Lights did in the genetic studies.

Sasha, I think you missed Brian's reply to you that the exercise test is not for diagnosis, but it's part of the investigation:
http://forums.phoenixrising.me/inde...infectious-cfs-study.42873/page-7#post-694916

 

[JayS]

Okay, so then how do you prove PEM if the exercise test is only done after the cohort is selected. I know this is kind of picking nits combined with chicken/egg, but if they're selecting patients for whom PEM is not a finding, then what does that say about who they're actually studying, and what they're actually studying.

This brings us back to the idea that if this illness is best characterized by an abnormal response to exertion, then the only way we can prove we actually have it is to engage in an activity that is known to be damaging...which of course invites ethical questions.

But if NOT for the 2-day CPET, then how do we KNOW they're actually ME patients. And what does that say about patients so severe they can't get on a bicycle in the first place.

As horrible as it is to consider, I do believe, not that I am a supporter of the report the IOM produced, but I do think that the best way to prove ME at the moment is the horrible exercise test, which will ;probably kill one of us one of these days as we're trying to prove we're ill with a physical disease. So from that standpoint I have an issue with any study that doesn't require PEM...with the only way to objectively measure that being...the 2 day CPET. I would like to think that a comprehensive study of patients qualifying primarily on the basis of that test plus others such as POTS/NMH is the best route to discovering a marker which can then be used to look at the more severe patients who can't even get on a bike.

But I don't have all the answers, and nobody does. Still, if they can't prove PEM, then all of the protest towards using CCC or ICC or whatever amounts to...what?

 

[Kati]

Okay, so then how do you prove PEM if the exercise test is only done after the cohort is selected. I know this is kind of picking nits combined with chicken/egg, but if they're selecting patients for whom PEM is not a finding, then what does that say about who they're actually studying, and what they're actually studying.

This brings us back to the idea that if this illness is best characterized by an abnormal response to exertion, then the only way we can prove we actually have it is to engage in an activity that is known to be damaging...which of course invites ethical questions.

But if NOT for the 2-day CPET, then how do we KNOW they're actually ME patients. And what does that say about patients so severe they can't get on a bicycle in the first place.

As horrible as it is to consider, I do believe, not that I am a supporter of the report the IOM produced, but I do think that the best way to prove ME at the moment is the horrible exercise test, which will ;probably kill one of us one of these days as we're trying to prove we're ill with a physical disease. So from that standpoint I have an issue with any study that doesn't require PEM...with the only way to objectively measure that being...the 2 day CPET. I would like to think that a comprehensive study of patients qualifying primarily on the basis of that test plus others such as POTS/NMH is the best route to discovering a marker which can then be used to look at the more severe patients who can't even get on a bike.

But I don't have all the answers, and nobody does. Still, if they can't prove PEM, then all of the protest towards using CCC or ICC or whatever amounts to...what?

Hopefully soon there will be biomarkers for this disease, other than a 2 days CPET. One would hope that the NIH study does their own research, so to speak, engage with our experts and patient population and be very mindful of the Steven's protocol.

 

[BurnA]

There seems to be confusion. The 2 day exercise test is not for diagnosis. It's for testing purposes.
I think it's a good idea so long as people have PEM and don't suffer too much. AFAIK it would be the first testing done on ME patients during PEM.

 

[Sasha]

There seems to be confusion. The 2 day exercise test is not for diagnosis. It's for testing purposes.
I think it's a good idea so long as people have PEM and don't suffer too much. AFAIK it would be the first testing done on ME patients during PEM.

My bad - I haven't read the proposal.

 

[Sasha]

Cort's view:

http://www.cortjohnson.org/blog/201...fs-the-good-the-bad-and-the-just-plain-weird/

 

[JayS]

Not for diagnosis in what. In this study or in general. And what is this PEM you're describing? The PEM that we only know from the 2-day CPET testing, necessitating that a patient undergo that test to be included in a study that only wants PEM-affected patients? Or the PEM the CDC says they can't define?

After all, so long as the CDC claims that they can't define what PEM is--which is to say they're unwilling to accept any of the testing that's made it into the literature--then how can anyone define exactly what it is. Which leads me to, if I see that there's a study looking at PEM...who's defining what that is, and if the CDC won't accept it, then we're back at square one, what's the difference, and why are we going to make patients sick for something that won't be acceptable as per CDC standards.

I'm trying to be optimistic here. If this study was recruiting for patients with PEM as mandatory, which I think we all agree is a desirable goal, then what besides 2 day CPET would define what PEM is in the first place. Of course, going with Reeves Criteria and doing exercise testing to 'make patients tired' means they're not necessarily looking at patients with PEM in the first place, since they won't know until after they run the testing...assuming they're using a definition of PEM that somebody finds acceptable.

I wish I could be more optimistic. It'd be difficult enough to ponder all this if they did require PEM, which should, I would think, be a minimum requirement. But it isn't. So I don't see much room for optimism, unfortunately. They could have the greatest study designed possible, but if they're not requiring PEM, then how is it an ME/CFS study.

 

[jimells]

I did a 2-day exercise test for my case with Prudential. It wiped me out for a good long while. So I certainly understand the fears. I don't know if I would do the test again for a study. But I don't know how else PEM can be measured.

If one wants to compare symptom severity before and after an exercise challenge with an objective test, this would probably do it. Unfortunately no one has bothered to pursue this research.

Am J Med Sci. 2003 Aug;326(2):55-60.
Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome.
Peckerman A1, LaManca JJ, Dahl KA, Chemitiganti R, Qureishi B, Natelson BH.

BACKGROUND:
Findings indicative of a problem with circulation have been reported in patients with chronic fatigue syndrome (CFS). We examined this possibility by measuring the patient's cardiac output and assessing its relation to presenting symptoms.

METHODS:
Impedance cardiography and symptom data were collected from 38 patients with CFS grouped into cases with severe (n = 18) and less severe (n = 20) illness and compared with those from 27 matched, sedentary control subjects.

RESULTS:
The patients with severe CFS had significantly lower stroke volume and cardiac output than the controls and less ill patients. Postexertional fatigue and flu-like symptoms of infection differentiated the patients with severe CFS from those with less severe CFS (88.5% concordance) and were predictive (R2 = 0.46, P < 0.0002) of lower cardiac output.

In contrast, neuropsychiatric symptoms showed no specific association with cardiac output.

CONCLUSIONS:
These results provide a preliminary indication of reduced circulation in patients with severe CFS. Further research is needed to confirm this finding and to define its clinical implications and pathogenetic mechanisms.

This study was done in the NJ Cooperative Research Center. All three research centers were closed a few months after this study was published in 2003. Of course it is purely coincidental. No doubt it is routine for NIH to shut down researchers just as they are publishing promising results.

I remember reading someplace (sorry, no reference handy) that Social Security asked Peckerman's group to develop an objective way to measure impairment for disability benefit claims, and this is what they came up with, and apparently it was buried by ????

 

[jimells]

Although what little we know looks awful, without the full trial protocol there is no way to really evaluate what they have chosen to do. We don't even know what hypothesis they are supposed to be testing, beyond "we expect to find differences between groups". Or are they looking for similarities?

 

[viggster]

Here's a bit of clarifying information, from a solid source.

- The trial protocol was made public prematurely. Someone at NIH (don't know who) sent it to Clinicaltrials.gov [EDIT: Not clinicaltrials.gov, but a website about ongoing NIH Clinical Center studies) without realizing that it would automatically be made public.
- This is important because the communications folks at NINDS are preparing a web page with detailed additional information on the trial. This page was supposed to be published at the same time as the protocol. The NINDS folks have been told by members of the patient community that it is in their best interest to publish this web page ASAP.
- Patients will be referred to the study by known ME/CFS experts in the US, including Susan Levine and others whose names you will all recognize. I think it's safe to say these will be "real" patients.

 

[viggster]

We don't even know what hypothesis they are supposed to be testing,

It's not a hypothesis-testing study. It's a hypothesis-generating study. It's the same approach Ron Davis is taking. Gather as much data as possible & see what pops out.

 

[Kati]

It's not a hypothesis-testing study. It's a hypothesis-generating study. It's the same approach Ron Davis is taking. Gather as much data as possible & see what pops out.

Let's just hope they can refine the language and make the protocol clearer. Who they are comparing with matters and can be quite telling too.

If it was put up by mistake, then it would be best if it was taken down.

 

[jimells]

- Patients will be referred to the study by known ME/CFS experts in the US, including Susan Levine and others whose names you will all recognize. I think it's safe to say these will be "real" patients.

Except the "Functional Movement Disorders" cohort, since by definition they have Mind Magic illness.

 

[jimells]

It's not a hypothesis-testing study. It's a hypothesis-generating study. It's the same approach Ron Davis is taking. Gather as much data as possible & see what pops out.

I recall there was a study from one of our top researchers that was rejected by NIH because there was no hypothesis. Dr Davis' study on the severely ill, perhaps?

His study only has one group. I'm certainly no expert on research design, but it seems to me that if there are comparison groups there must be some theory behind the selection of those groups and how they are going to be compared. We would like to know what it is.

 

[viggster]

@A.B. - thanks for posting this.

(bolding is original to NIH post, not added by me)

The words "fatigue" and "syndrome" are in BOLD because the link on the very first post in this thread is a link to a query result on those search terms. The search engine BOLDS search terms in the resulting pages.

 

[jimells]

Response To NIH Rejections Ron Davis

ME/CFS/SEID Biomarker Discovery Grants

3. NIH: There was a lack of clear hypotheses to be tested and many felt there was a
lack of detail provided in the proposal.

Response: There is not a clear hypothesis because this is not a hypothesis-testing
proposal but a hypothesis-generating proposal in the form of observations. The scientific
method starts with observation, then hypothesis. Without first observation you cannot
formulate a good hypothesis. I’m extremely surprised that NIH does not know this.
Furthermore the Human Genome Project had no hypothesis and was one of the most
important projects accomplished by NIH in its history.

 

[alex3619]

With today's technology, is there a way to avoid post exertional relapse? Could they not study the more severely affected and pick up 'disease signals' without doing any harm?

No, not really. This is one of the things they hope to uncover.

However its possible to bypass a one day CPET in severe patients. I have said before, many times now, that they can just do a gas analysis. I predict many severe patients will be at or over their anaerobic threshold by just existing. That is why they are bed bound, or so my hypothesis goes. Yet this is not validated research. There is no validated PEM research other than the 2 day CPET that I know of.

Many avenues of research might get there in time, especially studies using molecular markers post exercise, such as those by the Lights.