A rough sketch of the NIH’s Clinical Center study for chronic fatigue syndrome (ME/CFS) has been posted. The good news about the study is that when Francis Collins said they were serious about ME/CFS he apparently wasn’t kidding. This looks to be the most comprehensive study ever done on chronic fatigue syndrome.

There’s also a bit of weirdness in the study which will make it more difficult for some to fully embrace. That’s unfortunate, because aside from that, all the indications to this point demonstrate that this is just the type of effort that we’ve been waiting for.

The Good

Post-Infectious Illness – The NIH’s focus on post-infectious illness; i.e. those whose disease was triggered by an infection, selects out what is probably the most important subset in this illness. Plus the researcher leading the study, Avindra Nath, is an expert in the central nervous system infections. The NIH got its priorities in this area right.

The Tests

The NIH will be throwing the veritable kitchen sink at the participants.

Two Day Exercise Tests – The specific kind of exercise testing that will be done was not clarified, but the fact that the NIH is going with a two day exercise test could have profound ramifications for this field.

It will be very important that the tests are done correctly, but if they are and the results are positive they could and should be a game changer. Staci Stevens, Betsy Keller and other exercise physiologists have stated that the drops in energy output seen in a significant number of ME/CFS patients have not been seen in any disease before. In fact they’re so unusual that they have to be seen to be believed.

One Canadian group reportedly visited Staci’s lab last year as skeptics and left agog at the results. If the results from the two-day exercise tests are positive it’s hard to see how the exercise study alone in this highly visible study won’t transform this field.

These tests, of course, are hard on patients and they must be done correctly. Staci Stevens and the Workwell Group know how to do these tests as safely as possible and have developed standardized protocols (the Stevens Protocol). Hopefully the NIH will bring in members of the Workwell Group and/or Betsy Keller to make sure the tests are done as safely as possible and according to protocol. This is an opportunity not to be missed.

Other Tests

Autonomic Nervous System – sweating and breathing, being upright (apparently tilt table), blood pressure, and heart rate.

Cortisol (presumably) – saliva test

Cognition

Heart monitoring

Breath tests overnight – (small intestinal bacterial overgrowth?)

Transcranial magnetic stimulation

Functional MRI – the participants will do thinking AND exercise tasks in the MRI

Spinal Tap

Microbiome – gut, saliva and skin

Blood Testing – the blood tests weren’t listed but given the comprehensiveness of the rest of this study one imagine many blood tests will be done

The Bad – Little Outside Participation

It’s hard to imagine that anyone (outside of the CDC) would have signed off on the criteria used to select patients (see below) and it doesn’t appear that any ME/CFS experts have been consulted. When that happens you can run into some problems – which this study has.

The Weird

Avindra Nath and the Clinical Center team have done something no one outside the CDC has done in the past ten plus years: they’re going to use the Empirical or as they call it “The Reeves Criteria” of 2005 to help define patients. That was kind of a jaw-dropper.

The ME/CFS research community rejected it, the IOM poo-pooed it, and Lenny Jason tore it to pieces and the NIH resurrected it. It’s just the weirdest thing. After putting together what looks like a study everyone can embrace, the NIH somehow happened to pick the one thing guaranteed to drive the ME/CFS community nuts – they’re going with the Empirical definition.

Reeve’s plan with the definition seemed like a good one at the time. He would bring ME/CFS into the modern age by using questionnaires like the SF-36, Multidimensional Fatigue Inventory (MFI) and the CDC’s symptom severity list to quantify the symptoms in it.

The Empirical definition, however, has been suspect ever since Dr. Reeves invited ME/CFS experts to the CDC to prepare the ground for a new definition, and then disappeared with a small team to create the criteria for it (Ooops).

The plan ran into two major roadblocks. First, as Reeves was trying upgrade the ME/CFS definition using standardized quantitative assessments, the rest of the ME/CFS community was coalescing around highlighting post-exertional malaise. Second, some of Reeves criteria were so loose as to defy credibility. Reeves, for instance, set the functional criteria in the SF-36 needed to qualify for ME/CFS, at just 75% of norms – far above that typically found in other, less functionally disabling diseases such as asthma.

When a CDC study using the new criteria bumped prevalence up fourfold, it was clear something was wrong. Jason’s demonstration that criteria could possibly allow significant number of people with depression as having ME/CFS into studies, hammered another nail in the criteria’s coffin.

Why Reeves never went back to the drawing board to retweak the criteria, only he knows. Eleven years later, though, his criteria has never to my knowledge been used by non- CDC researchers – until now.

Not Garbage In – Garbage Out

Of course the use of the Empirical Definition, i..e the “Reeves criteria” is causing great dismay. Garbage in, they say, garbage out some say. Calls have been made for the study to be boycotted and petitions have begun. I think the criteria should be replaced but I don’t think the criteria is the study killer some are making it out to be. In fact, my guess is that this study is structured in such a way as to make the criteria mostly a non-issue.

The main worry about the Reeves criteria was the possibility that people with depression but not ME/CFS could be mistakenly end up in ME/CFS research studies. That issue is most concerning in randomized sampling studies that pluck their participants out of the population at large. In those efforts the criteria is the only filter.

In other studies which get their participants from doctors office or by asking for people with ME/CFS to enroll, filters are already in place to weed those people out. The Clinical Center study comes with three filters that I believe will make it very hard for anyone who doesn’t have ME/CFS to get into this study.

Filter #1 – ME/CFS Diagnosis – The study is calling for people diagnosed with ME/CFS to apply. The depression issue is only an issue if people with depression get misdiagnosed as having ME/CFS and then apply to be in the study. Most of us know from personal experience, however, that doctors are prone to misdiagnose ME/CFS as having depression.

The reverse – that people with depression are getting misdiagnosed as having ME/CFS is surely very rare. Most doctors simply don’t know enough about ME/CFS to make that mistake. When they see a patient suffering from mood problems, fatigue, etc. they’re going to diagnose them with depression – not the reverse. A horde of depressed patients masquerading as ME/CFS patients just isn’t out there.

Filter #2: Infectious Onset – the NIH requires doctor certified infectious onset be required to be in the study. The fact that an infection started off the disease has to be in the doctors records. Infectious onset is common in ME/CFS but the percentage of people with depression who’s medical file states that their depression can be traced back to an infection is surely miniscule.

Filter #3: The Reeves Criteria – Jason’s study suggests that the Reeves criteria could misdiagnose 38% of people with depression as having ME/CFS. That’s not good news but it means hat the criteria rejects over 60% of depressed patients. So even if someone with depression but not ME/CFS somehow got past the first two filters they would probably get knocked out by the last one.

These three filters appear to make it almost impossible for someone with depression but not ME/CFS to get into this study. First you would have to get misdiagnosed as having ME/CFS, then you’d have an infectious onset to your depression documented in your medical records, and then you have to make it past the criteria. For those reasons I don’t see the Reeves criteria being a particular problem in this study.

Postexertional malaise (PEM) – the Reeves criteria does not require PEM. Does that mean people without PEM are going to show up in this study? Because PEM is very common in the ME/CFS population, people who have already been diagnosed with this disease are very, very likely to have it. Plus I would imagine that almost everyone with infection triggered ME/CFS experiences PEM. This study should be loaded with patients with PEM.

Using the Canadian Consensus Criteria

Still, I think we should push for use of the Canadian Consensus Criteria (CCC). Why? The CCC focuses on post-exertional malaise and the IOM report – which started all of this – endorsed a definition that focuses on PEM. CFSAC recommended it be used and it (and the Fukuda Definition) were required during XMRV testing.

The CCC reflects the experience of the ME/CFS community; the Reeves Criteria does not. The CCC was put together by a team of doctors and researchers with vast experience with this disease; the Reeves Criteria was put together by a smaller group with less experience. The CCC has its problems but its largely been accepted by the researchers and doctors associated with the disease. The Reeves Criteria has been a total flop.

The CCC, then, is the natural choice for this study. You don’t lose anything that I can tell of by using it. If you do use it everyone can rest easy and will accept the results. That’s important. Plus, the NIH earns some trust, is acknowledged for their flexibility, and an excellent study moves forward without a pall hanging over it.

Update!

Bob and Courtney Miller have a way of getting answers fast- and they got some good ones: Robert and I had a well-timed chance to discuss with NINDS some questions about the protocol that was posted this weekend for the NIH Clinical Center study. There will be additional information posted on a website for patients and the community which may take a week to be live, they said. We asked questions about the criteria for enrollment, reference to Reeves criteria in the protocol, role of ME/CFS experts and the choice of control groups. According to the principal investigator of the study: Enrollees will meet all definitions for ME/CFS, including Canadian Consensus Criteria, IOM, Fukuda and Reeves, in addition to post-infectious onset.

Post-exertional malaise (PEM) is a criteria, and will be specifically studied with extensive testing before and after exercise challenge.

The SF-36 criteria to measure functional impairment stated in the protocol online is inverted mistakenly. “Greater than” is meant to be “less than” in the SF-36 measures.

Dr. Ian Lipkin of Columbia University’s Center for Infection and Immunity has been advising the investigators on the study design and protocol.

Expert clinicians will be used in patient selection.

Control groups: Asymptomatic Lyme was chosen to contrast post-infectious ME/CFS patients to patients who recovered from an infection. Functional Movement Disorder was chosen to contrast post-infectious ME/CFS patients with a very well-studied group of patients with clear psychological illness with neurological presentation.

They seek to have 40 PI-ME/CFS patients, and they will study them longitudinally, hoping to learn how and whether the disease changes over time.

Testing will be extensive. We are very excited to know that the NIH intramural study is moving forward, and that it will deeply study patients with infectious onset against a battery of biological tests. We are reassured by these answers, and eager to have this kind of data to move our disease toward discovery.

Control Groups

The study will also compare ME/CFS patients people with Lyme disease without fatigue (that must be a typo, and not the first one) and people with functional disorders which respond to psychiatric treatment. These extra control groups bear the mark of other researchers wanting in, and getting into this Clinical Center trial.

Lyme disease patients would be an excellent control group, and I’m not worried about the functional disorders control group. ME/CFS first had to “prove itself” against depression and it did and I have no doubt that it will do the same against functional disorders. (Psychiatric treatments, as we know, are no panacea). Showing itself to be distinct from functional disorders that will simply provide further validation for ME/CFS.

Questions

The outlines of the study given were sketchy and questions are pouring into the NIH about this study from The Solve ME/CFS Initiative and advocates. We don’t know why they chose to use the Reeves criteria, how many ME/CFS patients will be involved, what blood tests they are going to do, what tests are going to be given before and after the exercise tests, etc.

Vicky Whittemore Holets has agreed to answer them as quickly as possible.

The Best Study Possible

It’s critical that the study be done correctly. Standard cognitive tests don’t show up all the abnormalities found in ME/CFS. Nor do some kinds of exercise tests. Herpesvirus tests require different procedures than other viral tests. In some ways ME/CFS is different.

Plus much of what will be hot in the next year or so hasn’t made it to publication yet. How about querying our top researchers about unpublished data that could inform this study? What does their intuition tell them about where to search for answers?

The End ME/CFS Scientific Board with its clutch of Nobel Prize winners, for instance, is having wide ranging discussions about what’s next for ME/CFS. They’re laying out a pathway for discovery. There’s simply no way that the NIH group – as talented as they are – can match the experience that groups like this have. When you’re casting a broad net like the NIH is, you want it to land in the most fertile waters possible.

Conclusion

The use of the Reeves criteria introduces a bit of weirdness into this study but the key thing for me is that the study indicates that Francis Collins was indeed serious when he made his promise to move aggressively on ME/CFS. The NIH is not going through the motions here; they’re employing one of their top researchers to lead the deepest and most comprehensive study of ME/CFS than has been done.

The study will make waves in the way that others have not. A major issue for this field has been small studies done by less well known researchers landing in less-respected journals. Even when the results are positive they simply don’t get the impact they should.

That’s clearly not going to happen with this study. The results from a study of this size lead by a researcher of Nath’s ilk will surely land in a prestigious journal. Any positive results will lay the foundation for future studies. The exercise study results alone could transform this field.

If this kind of study portends what our future with the NIH is like we have something to look forward to. The new era is off to a good start.