The European ME/CFS Biomarker Landscape project

Posted on 08/09/2017 by wames

The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE, by Carmen Scheibenbogen, Helma Freitag, Julià Blanco, Enrica Capelli, Eliana Lacerda, Jerome Authier, Mira Meeus, Jesus Castro Marrero, Zaiga Nora-Krukle, Elisa Oltra, Elin Bolle Strand, Evelina Shikova, Slobodan Sekulic and Modra Murovska in Journal of Translational Medicine 2017, 15:162 [Published: 26 July 2017]

Review Abstract:

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a common and severe disease with a considerable social and economic impact. So far, the etiology is not known, and neither a diagnostic marker nor licensed treatments are available yet.

The EUROMENE network of European researchers and clinicians aims to promote cooperation and advance research on ME/CFS.

To improve diagnosis and facilitate the analysis of clinical trials surrogate markers are urgently needed. As a first step for developing such biomarkers for clinical use a database of active biomarker research in Europe was established called the ME/CFS EUROMENE Biomarker Landscape project and the results are presented in this review.

Further we suggest strategies to improve biomarker development and encourage researchers to take these into consideration for designing and reporting biomarker studies.

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Severe ME remembrance day, 8 August 2017

Posted on 08/08/2017 by wames

Stonebird: the experience of severe ME

At the Stonebird website you can find resources to help you understand the experience of severe ME and how to care for people with it.

The Stonebird represents the idea that you don’t have to do anything to be of beauty and value in the world. Even if you cannot move, even if you cannot communicate, even if you cannot think, still you are precious and your presence matters.

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Trial by Error: The Science Media Centre’s desperate efforts to defend PACE

Posted on 08/04/2017 by wames

Virology blog, by David Tuller, 2 Aug 2017: Trial by Error: The Science Media Centre’s Desperate Efforts to Defend PACE

This week, the Journal of Health Psychology published a special issue containing a raft of commentaries on the PACE trial. Most of them slammed the study for its many, many unacceptable flaws. Not surprisingly, Sir Simon Wessely’s lackeys at the Science Media Centre immediately posted three comments from “experts” lauding the trial and criticizing the JHP commentaries. I thought it might be helpful to deconstruct these rather pathetic efforts at defending the indefensible.

I’ve posted all three statements below, followed by my comments. I decided to keep them relatively brief, although I could have gone on much longer.

Read more

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Two radically different immune subsets in ME/CFS?

Posted on 08/04/2017 by wames

Health rising blog post, Cort Johnson, 15 July 2017: Early Results Suggest Two Radically Different Immune Subsets Present in Chronic Fatigue Syndrome (ME/CFS)

Subsets, Subsets, Subsets
Everyone with ME/CFS who’s been around a bit must ask themselves at some point, “Do I have what she or he has?” Some people do great on treatments that others fail on. Some people get really, really sick while others maintain at least a modicum of health. The variety of symptoms, treatment responses, illness progressions, even illness triggers is astonishing. For every person who remembers the exact day their illness came crashing down, there’s another who doesn’t remember the day, week or even month they became ill, because their illness came on gradually.

There’s the relapsing-remitting group which gets better and then worse, the plateaued group in which things remain much the same for decades and the progressive group where the illness gets progressively worse – sometimes to levels rarely seen in any nonlethal disease.

Most researchers concluded decades ago that ME/CFS must be littered with subsets. Just what those subsets are is a critical question, because as Jared Younger notes – a treatment that works for one subset probably won’t work for another.

Some subsets appear to be showing up. Dr. Peterson’s atypical subset typically has an unusual onset, an unusual course, has unusual comorbidities and is sicker than the rest of us. The immune systems of short duration patients (one subset) are on fire while the immune systems of longer duration patients (another subset) have run out of gas.

Jared Younger, in an unusual move, has released some early results from his big daily immune monitoring “good-day, bad-day” study to spread some early news on his findings.

Younger’s “good-day, bad-day” study is an example of what the NIH does best: throw a boatload of money (> $1,000, 000 over three years) at a complex study. Younger’s study allows him to track which immune factors track with a person’s fatigue. A substance that rises and falls depending on how fatigued a person is, very likely has something significant about it.

The scale of testing is extraordinary. The study includes seventy people with ME/CFS, 20 healthy controls and 20 fatigued people with thyroid issues. The study involves twenty-five straight days of blood sampling from all 110 people, and each sample is tested for 51 substances associated with inflammation.  If my math is right, that’s approximately 140,000 tests for inflammatory substances over the life of the study. Each person will also report their fatigue levels daily on a personal handheld computer. All this data will be thrown into a computer to see what patterns emerge.

It’s still early yet – the study is slated to run for several years – but in his YouTube video, Younger reported that some patterns may be starting to emerge.

The Infection Group?
C-reactive protein (CRP) levels are tracking with fatigue in about thirty percent of the ME/CFS participants. This suggests that a significant number of ME/CFS patients may have an underlying infection that’s popping out during their bad days.

 C-reactive protein is an “acute-phase” protein produced by the liver which shows up early in an infection, in cancer or in response to a tissue injury. Once immune cells called macrophages come into contact with dead or dying (infected) cells they release a substance called IL-6 which triggers the production of CRP (and fibrinogen) by the liver. When CRP binds to the surface of those cells, it gets the complement system involved which, in turn, helps more macrophages to find, engulf (phagocytyze) the infected cells and begin clearing them away.

The key to high C-reactive protein levels is plenty of dead or dying cells – something which usually occurs in the context of some infection (bacterial, viral, fungal), inflammatory diseases, malignancy or injured tissues. A very large (n=1125) fibromyalgia study recently found increased CRP levels in FM. It’s not clear how high the CRP levels in the ME/CFS subset was relative to other diseases. but what is clear is that the high CRP levels would probably be swamped by the lower CRP levels in the two other ME/CFS subsets; i.e. CRP would not be elevated in the group as a whole.

Autoimmune diseases like lupus, Scleroderma, polymyositis, and dermatomyositis, on the other hand, generally have little effect on CRP levels.  (In fact, one researcher proposed that CRP protects against autoimmune diseases.) That brings up the next group.

The Autoimmune/Autoinflammatory Group?
A substance called fractalkine – which is elevated in many autoimmune and inflammatory disorders – is tracking with the fatigue levels of another third of ME/CFS patients. Fractalkine, whose release is also triggered by damaged cells, promotes the production of pro-inflammatory cytokines.

CRP and Fatigue: Check out how closely CRP levels track with fatigue levels
Fractalkine is released by T-cells and other immune cells, endothelial cells and, most prominently, in the central nervous system.

In contrast to CRP, fractalkine is elevated in autoimmune diseases like rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, and scleroderma, as well as diseases associated with systemic inflammation. In rheumatoid arthritis fractalkine directs immune cells to the joints. Fractalkine is also elevated in systemic inflammatory diseases like atherosclerosis and inflammatory cardiomyopathy.

Because fractalkine appears to be intimately involved in producing pathological pain, one wonders if these are the fatigue and high pain patients. One study has found increased fractalkine levels, not in the blood, but in cerebral spinal fluid in fibromyalgia. The study suggested that damaged neurons were triggering fractalkine release.

Because fractalkine plays a prominent role in producing inflammation, anti-fractalkine agents are being examined. Several existing drugs and supplements (baclofen, Apo-A1, resveratrol, epigallocatechin-3-gallate) may be able to suppress fractalkine production.

The Non-Immune Group?
In the last third of patients, Younger hasn’t yet found a pattern, which suggests that the fatigue symptoms of this group may not be driven by the immune system. This, Younger suggested, could be a metabolic or other group.

Conclusions
Younger’s “Good Day – Bad Day” study is looking for biomarkers in an entirely new way. Very different from the one-time shots at assessing immune problems that we usually see, Younger’s study is tracking immune changes as they occur over time and pulling out the immune factors shown to be most associated with fatigue. Many other symptoms exist in ME/CFS, but as Dr. Lerner used to say, when the fatigue lifts the other symptoms follow.

Thus far the study suggests that the fatigue in ME/CFS may be being produced differently in the three subsets of patients: by an ongoing infection in one, by an autoimmune or autoinflammatory process in another, and by something outside the immune system in the third.

The most intriguing thing about Younger’s study is its intensity. No one has examined the immune basis of fatigue in ME/CFS with Younger’s intensity. It’s no surprise, then, that Younger is getting results (CRP, fractalkine) new to ME/CFS – results that also, interestingly enough, fit with what we already know. Infection and autoimmunity, after all, have long been thought to be present in ME/CFS. Younger’s early results suggests that they are present – but in different sets of patients.

If Younger’s early results prevail and are validated, we should ultimately see radically different treatments for the two different subsets – immune activators and anti-pathogen treatments for one, and immune suppressants for the other. We’ll also see studies focused on each subset and that could make all the difference in research.

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The Big Fishing Expedition: report from the NIH Intramural Study on ME/CFS

Posted on 08/03/2017 by wames

Simmaron research blog post, by Cort Johnson, 24 July 2017: The Big Fishing Expedition: Report from the NIH Intramural Study on ME/CFS

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.

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.  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.

Cutting-Edge Technology

“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.

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Scientists trade insults over myalgic encephalomyelitis (ME) study

Posted on 08/02/2017 by wames

Times article, by Tom Whipple, 1 Aug 2017: Scientists trade insults over myalgic encephalomyelitis (ME) study

An acrimonious scientific row has broken out after a £5 million publicly funded study investigating treatments for chronic fatigue syndrome was condemned as “deeply flawed” and a “textbook example of a poorly done trial”.

The dispute led to mass resignations and an exchange of insults so intense that in emails seen by The Times one scientist referred to another as a “disgusting old fart neoliberal hypocrite”.

An entire edition of a health journal was devoted yesterday to attacking a landmark study called the Pace trial, published in The Lancet in 2011. It claimed to show that people with chronic fatigue syndrome (CFS) could improve their condition with simple lifestyle changes.

This has formed the basis of treatment of the condition, also known as myalgic encephalomyelitis (ME), in Britain, but provoked a backlash among some sufferers who feared that it implied the illness had a psychological rather than physiological origin. Others said that exercise, far from helping, made them worse. Academics have criticised the trial too, particularly after a freedom of information request revealed all the patient data. Some have argued that it showed the statistical methods were flawed, and that the criteria for deeming the trial a success were changed midway through.

The editors of the Journal of Health Psychology said it was clear that “the results are, at best, unreliable, and at worst manipulated to produce a positive-looking outcome”. They did not justify the “extraordinary sum” charged to taxpayers.

Read more

See also:

The Times article, by Oliver Moody, Tom Whipple, 1 Aug 2017: Behind the story – A battle of prescriptions

One lot of scientists is mocked as stooges of a free-market conspiracy to dismantle the welfare state. The other stands accused of marshalling a bloody-minded and ideologically driven “witch-hunt”.How did an argument about a clinical trial become so personal?

The first thing to understand is that chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a very real and traumatic illness affecting about a quarter of a million Britons.

Mail online article, by Stephen Matthews, 1 Aug 2017: ‘Disgusting old fart, neoliberal hypocrite’: Angry scientists throw insults at each other over the results of a £5 million taxpayer-funded study into chronic fatigue syndrome

  • One journal dedicated its August edition to ripping apart the ‘unreliable’ trial
  • The PACE study was published in The Lancet in 2011 – but was ridiculed by many
  • It claimed to show those affected could improve with simple lifestyle changes
  • The Journal of Health Psychology launched a scathing attack on the British study
  • Three editors resigned before its ‘unacceptably one-sided’ issue was published
  • But a co-editor hit back and called one ‘disgusting’ and told him to f*** off

Science media centre blog post, 31 Jul 2017: expert reaction to Journal of Health Psychology’s Special Issue on The PACE Trial

Prof. Malcolm Macleod, Professor of Neurology and Translational Neuroscience, University of Edinburgh, said:

“The PACE trial, while not perfect, provides far and away the best evidence for the effectiveness of any intervention for chronic fatigue; and certainly is more robust than any of the other research cited. Reading the criticisms, I was struck by how little actual meat there is in them; and wondered where some of the authors came from. In fact, one of them lists as an institution a research centre (Soerabaja Research Center) which only seems to exist as an affiliation on papers he wrote criticising the PACE trial.

“Their main criticisms seem to revolve around the primary outcome was changed halfway through the trial: there are lots of reasons this can happen, some justifiable and others not; the main think is whether it was done without knowledge of the outcomes already accumulated in the trial and before data lock – which is what was done here.

“So I don’t think there is really a story here, apart from a group of authors, some of doubtful provenance, kicking up dust about a study which has a few minor wrinkles (as all do) but still provides information reliable enough to shape practice. If you substitute ‘CFS’ for ‘autism’ and ‘PACE trial’ for ‘vaccination’ you see a familiar pattern…”

Read more

inews blog post, by Paul Gallagher, 1 Aug 2017: ‘You’re a disgusting old fart neoliberal hypocrite’ – scientists in furious row over ME study

A furious row has erupted between scientists after a medical journal dedicated its entire August edition to ripping apart a “deeply flawed” £5m taxpayer-funded study investigating treatments for chronic fatigue syndrome (CFS).

The dispute led to three editors at the Journal of Health Psychology (JHP), who are all scientists, resigning. Professor George Davey Smith resigned before this month’s issue of the journal, which criticised the “extraordinary sum” of the study, was published. It is unsure how long the clinical epidemiologist, based at Bristol University, had been on the board for before leaving his post.

He said the journal displayed “unacceptable one-sidedness”, but an upset co-editor of the journal hit back. James Coyne told Professor Davey Smith to “f*** off” for his “attempted bullying”, leaked emails obtained by The Times show.

Read more

 

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Researchers identify biomarkers associated with CFS severity

Posted on 08/02/2017 by wames

Stanford Medicine News Center press release, by Bruce Goldman, 31 July 2017: Researchers identify biomarkers associated with chronic fatigue syndrome severity

Stanford investigators used high-throughput analysis to link inflammation to chronic fatigue syndrome, a difficult-to-diagnose disease with no known cure.

Researchers at the Stanford University School of Medicine have linked chronic fatigue syndrome to variations in 17 immune-system signaling proteins, or cytokines, whose concentrations in the blood correlate with the disease’s severity.

The findings provide evidence that inflammation is a powerful driver of this mysterious condition, whose underpinnings have eluded researchers for 35 years.

The findings, described in a study published online July 31 in the Proceedings of the National Academy of Sciences, could lead to further understanding of this condition and be used to improve the diagnosis and treatment of the disorder, which has been notably difficult.

More than 1 million people in the United States suffer from chronic fatigue syndrome, also known as myalgic encephomyelitis and designated by the acronym ME/CFS. It is a disease with no known cure or even reliably effective treatments. Three of every four ME/CFS patients are women, for reasons that are not understood. It characteristically arises in two major waves: among adolescents between the ages of 15 and 20, and in adults between 30 and 35. The condition typically persists for decades.

“Chronic fatigue syndrome can turn a life of productive activity into one of dependency and desolation,” said Jose Montoya, MD, professor of infectious diseases, who is the study’s lead author. Some spontaneous recoveries occur during the first year, he said, but rarely after the condition has persisted more than five years.

The study’s senior author is Mark Davis, PhD, professor of immunology and microbiology and director of Stanford’s Institute for Immunity, Transplantation and Infection.

‘Solid basis for a diagnostic blood test’

“There’s been a great deal of controversy and confusion surrounding ME/CFS — even whether it is an actual disease,” said Davis. “Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.”

Many, but not all, ME/CFS patients experience flulike symptoms common in inflammation-driven diseases, Montoya said. But because its symptoms are so diffuse —sometimes manifesting as heart problems, sometimes as mental impairment nicknamed “brain fog,” other times as indigestion, diarrhea, constipation, muscle pain, tender lymph nodes and so forth — it often goes undiagnosed, even among patients who’ve visited a half-dozen or more different specialists in an effort to determine what’s wrong with them.

Montoya, who oversees the Stanford ME/CFS Initiative, came across his first ME/CFS patient in 2004, an experience he said he’s never forgotten.

 “I have seen the horrors of this disease, multiplied by hundreds of patients,” he said. “It’s been observed and talked about for 35 years now, sometimes with the onus of being described as a psychological condition. But chronic fatigue syndrome is by no means a figment of the imagination. This is real.”

Antivirals, anti-inflammatories and immune-modulating drugs have led to symptomatic improvement in some cases, Montoya said. But no single pathogenic agent that can be fingered as the ultimate ME/CFS trigger has yet been isolated, while previous efforts to identify immunological abnormalities behind the disease have met with conflicting and confusing results.

Still, the sporadic effectiveness of antiviral and anti-inflammatory drugs has spurred Montoya to undertake a systematic study to see if the inflammation that’s been a will-o’-the-wisp in those previous searches could be definitively pinned down.

To attack this problem, he called on Davis, who helped create the Human Immune Monitoring Center. Since its inception a decade ago, the center has served as an engine for large-scale, data-intensive immunological analysis of human blood and tissue samples. Directed by study co-author Holden Maecker, PhD, a professor of microbiology and immunology, the center is equipped to rapidly assess gene variations and activity levels, frequencies of numerous immune cell types, blood concentrations of scores of immune proteins, activation states of intercellular signaling models, and more on a massive scale.

Finding patterns
This approach is akin to being able to look for and find larger patterns — analogous to whole words or sentences — in order to locate a desired paragraph in a lengthy manuscript, rather than just try to locate it by counting the number of times in which the letter A appears in every paragraph.

The scientists analyzed blood samples from 192 of Montoya’s patients, as well as from 392 healthy control subjects. The average age of patients and controls was about 50. Patients’ average duration of symptoms was somewhat more than 10 years.

Importantly, the study design took into account patients’ disease severity and duration. The scientists found that some cytokine levels were lower in patients with mild forms of ME/CFS than in the control subjects, but elevated in ME/CFS patients with relatively severe manifestations. Averaging the results for patients versus controls with respect to these measures would have obscured this phenomenon, which Montoya said he thinks may reflect different genetic predispositions, among patients, to progress to mild versus severe disease.

When comparing patients versus control subjects, the researchers found that only two of the 51 cytokines they measured were different. Tumor growth factor beta was higher and resistin was lower in ME/CFS patients. However, the investigators found that the concentrations of 17 of the cytokines tracked disease severity. Thirteen of those 17 cytokines are pro-inflammatory.

TGF-beta is often thought of as an anti-inflammatory rather than a pro-inflammatory cytokine. But it’s known to take on a pro-inflammatory character in some cases, including certain cancers. ME/CFS patients have a higher than normal incidence of lymphoma, and Montoya speculated that TGF-beta’s elevation in ME/CFS patients could turn out to be a link.

One of the cytokines whose levels corresponded to disease severity, leptin, is secreted by fat tissue. Best known as a satiety reporter that tells the brain when somebody’s stomach is full, leptin is also an active pro-inflammatory substance. Generally, leptin is more abundant in women’s blood than in men’s, which could throw light on why more women than men have ME/CFS.

More generally speaking, the study’s results hold implications for the design of future studies of disease, including clinical trials testing immunomodulatory drugs’ potential as ME/CFS therapies.

“For decades, the ‘case vs. healthy controls’ study design has served well to advance our understanding of many diseases,” Montoya said. “However, it’s possible that for certain pathologies in humans, analysis by disease severity or duration would be likely to provide further insights.”

Other Stanford co-authors of the study are clinical research coordinator Jill Anderson; Tyson Holmes, PhD, senior research engineer at the Institute for Immunity, Transplantation and Infection; Yael Rosenberg-Hasson, PhD, immunoassay and technical director at the institute; Cristina Tato, PhD, MPH, research and science analyst at the institute; former study coordinator Ian Valencia; and Lily Chu, MSHS, a board member of the Stanford University ME/CFS Initiative.

The study was funded by the National Institutes of Health (grant U19AI057229), the Stanford ME/CFS Initiative Fund and an anonymous donor.

Stanford’s departments of Medicine and of Microbiology and Immunology also supported the work.

Reaction to the study:

The Telegraph: ‘Yuppie flu’ an inflammatory disease which blood test could easily diagnose, say scientists

New Scientist: Blood biomarkers may help diagnose chronic fatigue syndrome

Medscape: New Chronic Fatigue Syndrome Biomarkers in the Pipeline

Sciencemag: More clues link immune system imbalance with chronic fatigue syndrome

Shots, Health News From NPR, by Miriam E. Tucker, 31 Jul 2017: Scientists Edge Closer To Elusive Lab Test For ‘Chronic Fatigue Syndrome’

Science alert blog post, by Signe Dean, 1 Aug 2017: We’ve Found Even More Proof That Chronic Fatigue Syndrome Is a Real Disease

Reuters Health News, by Lisa Rapaport, 31 July 2017: Molecular profile hints at inflammatory processes in chronic fatigue

Science media centre: expert reaction to cytokines for Chronic Fatigue Syndrome

Science daily: Chronic fatigue syndrome: Biomarkers linked to severity identified

Smithsonian mag blog post, by Ben Panko: New Study Gives Hope to Victims of Chronic Fatigue Syndrome

Futurism blog post, by Karla Lant, 3 Aug 2017: We Might Be Closer to a Lab Test for Chronic Fatigue Syndrome

 

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Cytokine signature associated with disease severity in CFS patients

Posted on 08/02/2017 by wames

Cytokine signature associated with disease severity in chronic fatigue syndrome patients, by Jose G. Montoyaa, Tyson H. Holmes, Jill N. Anderson, Holden T. Maecker, Yael Rosenberg-Hasson, Ian J. Valencia, Lily Chu, Jarred W. Younger, Cristina M. Tato, and Mark M. Davis in PNAS July 31, 2017

Significance:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) devastates the lives of millions of people and has remained a mystery illness despite decades of research. It has long been suspected that inflammation is central to its pathogenesis.

Although only two cytokines were found to be different (TGF-β higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity. Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years. Only CXCL9 (MIG) inversely correlated with fatigue duration.

Research abstract:

Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system.

Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity:

CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

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Muscle injections with lidocaine improve resting fatigue and pain in patients with CFS

Posted on 08/01/2017 by wames

Research abstract:

Muscle injections with lidocaine improve resting fatigue and pain in patients with chronic fatigue syndrome, by Roland Staud, Taylor Kizer, Michael E Robinson in Journal of Pain Research, Vol. 2017, #10, pp 1477-1486 [June 26, 2017]

Objective

Patients with chronic fatigue syndrome (CFS) complain of long-lasting fatigue and pain which are not relieved by rest and worsened by physical exertion. Previous research has implicated metaboreceptors of muscles to play an important role for chronic fatigue and pain.

Therefore, we hypothesized that blocking impulse input from deep tissues with intramuscular lidocaine injections would improve not only the pain but also fatigue of CFS patients.

Methods

In a double-blind, placebo-controlled study, 58 CFS patients received

20 mL of 1% lidocaine (200 mg) or normal saline once into both trapezius and gluteal muscles. Study outcomes included clinical fatigue and pain, depression, and anxiety. In addition, mechanical and heat hyperalgesia were assessed and serum levels of lidocaine were obtained after the injections.

Results

Fatigue ratings of CFS patients decreased significantly more after lidocaine compared to saline injections (p=0.03). In contrast, muscle injections reduced pain, depression, and anxiety (p<0.001), but these changes were not statistically different between lidocaine and saline (p>0.05). Lidocaine injections increased mechanical pain thresholds of CFS patients (p=0.04) but did not affect their heat hyperalgesia.

Importantly, mood changes or lidocaine serum levels did not significantly predict fatigue reductions.

Conclusion

These results demonstrate that lidocaine injections reduce clinical fatigue of CFS patients significantly more than placebo, suggesting an important role of peripheral tissues for chronic fatigue. Future investigations will be necessary to evaluate the clinical benefits of such interventions.

In the media:

Health day: How chronic fatigue syndrome wears patients out by Mary Elizabeth Dallas, 27 July 2017

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Special issue of the Journal of Health Psychology on PACE trial: the making of a medical scandal

Posted on 08/01/2017 by wames

Special issue on the PACE Trial, by David F Marks in The Journal of Health Psychology Vol 22 issue 9 2017 [published online 31 July 2017]

Download as pdf

Abstract:

We are proud that this issue marks a special contribution by the Journal of Health Psychology to the literature concerning interventions to manage adaptation to chronic health problems. The PACE Trial debate reveals deeply embedded differences between critics and investigators. It reveals an unwillingness of the co-principal investigators of the PACE trial to engage in authentic discussion and debate. It leads one to question the wisdom of such a large investment from the public purse (£5million) on what is a textbook example of a poorly done trial.

Concept

The Journal of Health Psychology received a submission in the form of a critical review of one of the largest psychotherapy trials ever done, the PACE Trial. PACE was a trial of therapies for patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS), a trial that has been associated with a great deal of controversy (Geraghty, 2016). Following publication of the critical paper by Keith Geraghty (2016), the PACE Trial investigators responded with an Open Peer Commentary paper (White et al., 2017). The review and response were sent to more than 40 experts on both sides of the debate for commentaries.

The resulting collection is rich and varied in the perspectives it offers from a neglected point of view. Many of the commentators should be applauded for their courage, resilience and ‘insider’ understanding of experience with ME/CFS.

The Editorial Board wants to go on record that the PACE Trial investigators and their supporters were given numerous opportunities to participate, even extending the possibility of appeals and re-reviews when they would not normally be offered. That they failed to respond appropriately is disappointing.

What transpired
Commentaries were invited from an equal number of individuals on both sides of the debate (about 20 from each side of the debate). Many more submissions arrived from the PACE Trial critics than from the pro-PACE side of the debate. All submissions were peer reviewed and judged on merit.

The PACE Trial investigators’ defence of the trial was in a template format that failed to engage with critics. Before submitting their reply, Professors Peter White, Trudie Chalder and Michael Sharpe wrote to me as co-principal investigators of the PACE trial to seek a retraction of sections of Geraghty’s paper, a declaration of conflicts of interest (COI) by Keith Geraghty on the grounds that he suffers from ME/CFS, and publication of their response without peer review (White et al., 4 November 2016, email to David F Marks). All three requests were refused.

On the question of COI, the PACE authors themselves appear to hold strong allegiances to cognitive behavioural therapy (CBT) and graded exercise therapy (GET) – treatments they developed for ME/CFS. Stark COI have been exposed by the commentaries including the PACE authors themselves who hold a double role as advisers to the UK Government Department of Work and Pensions (DWP), a sponsor of PACE, while at the same time working as advisers to large insurance companies who have gone on record about the potential financial losses from ME/CFS being deemed a long-term physical illness. In a further twist to the debate, undeclared COI of Petrie and Weinman (2017) were alleged by two of the commentators (Agardy, 2017; Lubet, 2017). Professors Weinman and Petrie adamantly deny that their work as advisers to Atlantis Healthcare represents a COI:

We are very clear that there is not a COI that we need to declare. We have had nothing to do with the PACE trial and neither of us work on CFS. Our Atlantis link does not provide any conflicts as Atlantis focuses on supporting patient adherence to medication for various long term conditions, and has not had any involvement with patients with CFS. (Weinman and Petrie, 9 May 2017, email to David F Marks)

After the online publication of several critical Commentaries, Professors White, Sharpe, Chalder and 16 co-authors were offered a further opportunity to respond to their critics in the round but they chose not to do so. They wrote: As always, we would refer interested readers to our original publications and trial website where most, if not all, the issues brought up by commentators are addressed (Chalder and Sharpe, 12 May 2017, email to David F Marks).

After peer review, authors were invited to revise their manuscripts in response to reviewer feedback and many made multiple drafts. The outcome is a set of robust papers that should stand the test of time and offer significant new light on what went wrong with the PACE Trial that has been of such high significance for the nature of treatment protocols. It is disappointing that what has been the more dominant other side refused to participate.

Unfortunately, across the pro-PACE group of authors there was a consistent pattern of resistance to the debate. After receiving critical reviews, the pro-PACE authors chose to make only cosmetic changes or not to revise their manuscripts in any way whatsoever. They appeared unwilling to enter into the spirit of scientific debate. They acted with a sense of entitlement not to have to respond to criticism. Two pro-PACE authors even showed disdain for ME/CFS patients, stating: We have no wish to get into debates with patients. In another instance, three pro-PACE authors attempted to subvert the journal’s policy on COI by recommending reviewers who were strongly conflicted, forcing rejection of their paper.

The dearth of pro-PACE manuscripts to start off with (five submissions), the poor quality, the intransigence of authors to revise and the unavoidable rejection of three pro-PACE manuscripts led to an imbalance in papers between the two sides. However, this editor was loathe to compromise standards by publishing unsound pieces in spite of the pressure to go ahead and publish from people who should know better.

What next?
We are proud that this issue marks a special contribution by the Journal of Health Psychology to the literature concerning interventions to manage adaptation to chronic health problems. The PACE Trial debate reveals deeply embedded differences between critics and investigators. It also reveals an unwillingness of the co-principal investigators of the PACE trial to engage in discussion and debate. It leads one to question the wisdom of such a large investment from the public purse (£5 million) on what is a textbook example of a poorly done trial.

ME/CFS research has been poorly served by the PACE Trial and a fresh new approach to treatment is clearly warranted. On the basis of this Special Issue, readers can make up their own minds about the scientific merits and demerits of the PACE Trial. It is to be hoped that the debate will provide a more rational basis for evidence-based improvements to the care pathway for hundreds of thousands of patients.

David F Marks
Editor
editorjhp@gmail.com

References
Agardy S (2017) Chronic fatigue syndrome patients have no reason to accept the PACE trial results: Response to Keith J Petrie and John Weinman. Journal of Health Psychology 22(9): 1206–1208.  Abstract

Geraghty KJ (2016) ‘PACE-Gate’: When clinical trial evidence meets open data access. Journal of Health Psychology 22(9): 1106–1112.

Lubet S (2017) Defense of the PACE trial is based on argumentation fallacies. Journal of Health Psychology 22(9): 1201–1205.  Abstract

Petrie K, Weinman J (2017) The PACE trial: It’s time to broaden perceptions and move on. Journal of Health Psychology 22(9): 1198–1200. Abstract

White PD, Chalder T, Sharpe M, . (2017) Response to the editorial by Dr Geraghty. Journal of Health Psychology 22(9): 1113–1117.  Abstract

Press release, by David F Marks, 29 July 2017: The PACE trial: the making of a medical scandal [published on Prof Coyne’s blog]

The PACE trial debate illustrates what can happen when researchers become entrenched in a particular point of view, and fail to engage in constructive exchange with critics and stakeholders. It reveals an unwillingness of the Co-Principal Investigators of the trial to engage in authentic discussion and debate. It leads one to question the wisdom of such a large investment from the public purse (£5million) on what is a textbook example of a poorly done trial.

Quick thoughts blog post, Prof James C Coyne, 31 Jul 2017: What to look for in the Special Issue of Journal of Health Psychology concerning the PACE trial

 

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