Reprinted with the kind permission of Simmaron Research .
By Cort Johnson
A Big, Deep Fishing Expedition
“We’re throwing every known sophisticated technology at these patients.” ~ Avindra Nath, MD – Lead Investigator of NIH Intramural Study on Chronic Fatigue Syndrome
The NIH’s Intramural Study on ME/CFS now underway is almost certainly the most comprehensive chronic fatigue syndrome (ME/CFS) study ever done. In fact, it may be one of the more multi-faceted studies done in any disease. It’s breadth is astonishing. Besides the blood, urine, fecal matter and saliva gathered, participants will spend a night in a metabolic chamber, get their brains scanned, have their their immune systems transplanted into mice, and their neurons grown in a petri dish. After years of patient advocacy – at least in this one study – ME/CFS has abruptly transitioned from being one of the poorest studied diseases of all to getting an array of cutting-edge technologies thrown at it.
Featuring top researchers at the NIH’s big research hospital its results are guaranteed to get noticed. This one study won’t solve ME/CFS – no one study can do that – but it could and really should provide dramatic new insights into it, and, most importantly, provide the foundation for years and years of study into it. Nath, for instance, recently suggested the study could produce the bio-signature we’ve been seeking for years.
The study is basically a huge fishing expedition, an anomaly for an institution known for its strict adherence to hypothesis testing. The NIH is looking (and building data) just about everywhere in patients.
We probably have NIH Director Francis Collins to thank for that. Collins has more control and discretion over the intramural site than any other part of the NIH and it shows. Collins got this study started before the NIH allocated money for the research centers. He wanted and got Avindra Nath – a highly prestigious researcher specializing in neuro-infectious diseases – to lead it and he got the NIH to bring out its fishing poles and fish.
Round One: The NIH’s “Deep Phenotyping Exercise”
Not only is the breadth of the study unusual, but the rigor with which it’s being run is unmatched. The first part of the study (participants come in for two rounds of testing) is partially being done to ensure that only one kind of patient participates. This is an important point since the ME/CFS disease population is very heterogeneous and mounting studies are identifying distinct subgroups.
In order to capture post-infectious ME/CFS patients, the study requires participants to have a sudden flu-like onset that’s been documented in a doctor’s files. After taking questionnaire after questionnaire, a complete review of a patient’s medical records are being made by a panel of ME/CFS experts. Dr. Dan Peterson noted that one patient’s file ran to 191 pages (he said read every one). Dr. Peterson, longtime expert ME/CFS clinician and Simmaron Scientific Advisor, is reviewing patient selection for the NIH Intramural study.
Even the ME/CFS doctors reviewing the patient records have been taken aback at times with the strictness of the study. Dr. Peterson relayed one incident where Brian Walitt’s questioning of whether a patient should be included in the study raised eyebrows. (Walitt is the clinical lead investigator. Wallitt promptly dug into the Canadian Consensus Criteria to show the exact criteria the patient didn’t meet.)
Dr. Peterson noted that the reviewers have debated how “sudden” a sudden onset needs to be for someone to be included in the study. Does a patient have to remember the exact date they became ill or is something more general sufficient?
Another interesting twist concerns the rigor with which prospective patients have been tested. ME/CFS doctors that do more testing that others are more likely to find something that could kick a patient out of the study. That same patient coming from an ME/CFS doctor that doesn’t do a lot of testing might get into the study.
The first part of the study is apparently an attempt to level the playing field. Test after test after test is being done during the nine days a) to gather data and b) to ensure that nothing other than ME/CFS (and specified co-morbid diseases) is going on in these patients. At least in these early stages anything that looks off is being investigated. The NIH is calling the visit a “deep phenotyping” exercise.
An ME/CFS Patient Reports: Brian Vastag on Round One of the Intramural Study
It was fitting that Brian Vastag be one of the first ME/CFS patients to go through the first part of the study. He did after all, play a role in getting it started.
Vastag’s “Dear Dr. Collins: I’m Disabled. Can the N.I.H. Spare a Few Dimes?” piece effectively used Vastag’s personal story to highlight the devastating funding problem and, importantly, provide a way out of the problem that was probably very appealing to Collins. (The dark humor in the piece didn’t hurt either.)
Vastag used to work for the NIH; in fact, Vastag worked with John Burklow, Francis Collins’ right hand man for communications for years. Vastag also worked with the Journal of American Medical Association (JAMA), and then reported for the Washington Post on science and medical issues. He knows the NIH well and used his personal connection to Collins to lobby for more funding.
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He got in the study the old-fashioned way – by emailing the study recruiter. In the months leading up to his stay, Vastag reported he had several conversations with the lead clinical investigator, Dr. Brian Wallitt, provided his medical records, was fully informed what he was in for and was provided several opportunities to bow out if he chose.
Thus far the reviews of Dr. Walitt from two people (Dr. Peterson, Vastag) participating with him have been positive. Dr. Peterson said he found him attentive and interested, and Vastag, who said he spent a lot of time with him, found him available and dedicated.
Vastag spent five or six hours relaying his medical history to Dr. Walitt and nine full days in the NIH hospital. The history, he said, was very detailed.
Some people have worried that the ME/CFS patients well enough to participate in the NIH’s intramural aren’t sick enough to get results. Brian Vastag is exhibit number one why that hopefully is not the case.
When Vastag got sick he got really sick. At one point, he was 98% bedbound and had to be pushed around in a wheelchair. On his eighth or nineth doctor journey, Vastag saw neurologists and got checked out at a multiple sclerosis clinic. Now he’s probably moderately ill for an ME/CFS patient and has to limit his walking to about 2 blocks a day; e.g. Vastag cant work at all, and he’s functionally very limited.
My guess is that if you can only walk two blocks a day without getting whacked there is something seriously, seriously wrong with you. Ditto with work; if you can’t work without getting hammered you have something seriously wrong with you that should be discoverable.
Having moderately ill people (by ME/CFS standards) participate in a study may not get the sickest patients in the study but it also brings with it the bonus that researchers don’t have to worry about the confounding factors that severe deconditioning brings. If there’s something to find in the testing the NIH is doing it should be found in these patients.
“I can’t believe they are letting us do all this stuff”. ~ Brian Walitt, MD MPH
The NIH is after all, throwing a lot of new technology at this disease. Vastag was told the intramural researchers have the green light to do a deep exploration of this disease and to let the evidence take them where it will. They also have carte blanche to add to the study if the need arises.
The head of Clinical Neurology at the Intramural Center, Avindra (Avi) Nath, heads the study. Nath has co-authored hundreds of journal articles and is on the editorial board of several journals. His main research focus – on the effects of infection on the brain – couldn’t be better suited to ME/CFS.
His latest paper on the cerebral spinal fluid in the survivors of the Ebola epidemic is exactly the kind of post-infectious work he’s been tasked with doing in ME/CFS. His 2016 review of Ebola survivors highlighted the functional declines seen in those who survived the outbreak. The study also noted that joint and muscle pains were “persistent problems” in more than half the 200 plus survivors assessed.
“Tellingly, the survivors reported a functional decline when compared with before the EVD outbreak. In comparison with the household contacts, the survivors were more likely to report a decline in both overall health (70% vs 18%) and ability to work (70% vs 7%).”
Nath told Dr. Peterson, after Peterson’s NIH talk on epidemic presentations of ME/CFS, that the Incline Village outbreak was probably an infectious encephalitis type of outbreak but that the technology at the time wasn’t up to diagnosing it. Nath has also collaborated often with Dr. Ian Lipkin on infectious diseases, and we know Lipkin’s work in ME/CFS is refining our understanding of immunity in the disease. Nath’s 2015 review paper demonstrated that the HIV virus may be able to survive in reservoirs in the brain indefinitely.
Nath will oversee a huge amount of work and do some cutting-edge work of his own. Using a new technique developed in his lab, Nath will knock out the immune systems of transgenic mice and give them the immune systems of ME/CFS patients. He’ll also turn white blood cells from ME/CFS patients into “brains in a dish” neurons grown in the lab that Nath can then test. This technique, pioneered by Nath for other neurological diseases, can point highlight certain types of cellular problems.
A ton of data is being gathered in the first part of the study. Besides his half a day of questionnaires, Vastag had standard labs done, provided his spinal fluid, did a sleep study, got 3.4 billion white blood cells drawn for Nath’s experimental studies, had his blood drawn for the Sea horse (mitochondria/energy production) study, had an EMG done to rule out muscle myopathy, did a tilt table test( positive for POTS), an MRI, and gave samples for the metabolomics part of the study. Just about every “tissue” possible, from blood, to urine, to cheek swabs to cerebral spinal fluid was gathered.
Some results may already be showing up. The Seahorse study results from just three patients were unusual enough that the intramural mitochondrial expert came down to Brian’s room and chatted with him.
Part II of the study will require a week’s stay and include an exercise test on a stationary bicycle, sleeping in a metabolic chamber, cognitive testing, and more blood and other tests.
The study’s only down-side appears to be its size and the time it is taking. Vastag reported that Nath expressed regret that the study was taking so long and told him that he was trying to speed things up. A couple of months ago, Vastag said he was the fourth patient to go through the study. At the NIH Telebriefing Nath said ten people have now gone through the first part of the study and one will start the second part at the end of July. Since the second part of the study was originally slated to begin in fall, it appears that Nath may indeed have speed things up.
Some researchers and doctors have expressed concern about the study’s forty-patient size, but Nath is convinced he can peel off any subsets with the patient group he has to work with.