All posts by Cort Johnson

Dr. Pridgen on Doses, Fixing Broken Bodies and Why the Next Fibromyalgia Trials Will Be Better

If Dr. Pridgen is right, his protocol for treating fibromyalgia could end up turning the medical world’s conception of FM (and perhaps even chronic fatigue syndrome) on its head. The first treatment trial had good results but they didn’t exactly turn the FM world upside down. Geoff Langhorne asked him about that in an interview a couple of months ago and I followed up with my own questions.

A confident Dr. Pridgen explained why the first trials result were good but not earth-shattering and why the next trial results will be better. First some background.

How it Happened

“It was never my intention to be involved in Fibromyalgia” William Pridgen

Pridgen didn’t start out to treat fibromyalgia – he was simply trying to get at what was causing the diarrhea/constipation and abdominal pain in his patients.  Both he and his mother – a virologist – recognized that the pattern he kept seeing –stubborn symptoms which got better with treatment then got worse, and then better and then worse – could reflect a virus getting reactivated, then knocked down, reactivated then knocked down. Throw in the fact that his patients gut problems typically got worse during stressful events and a herpesvirus infection became a viable option.

herpesvirus

The pattern of remission and then relapse, particularly, after stressful situation, suggested herpesviruses.

Pridgen started off giving a couple of his patients a single antiviral herpesvirus drug. The fact that some of the patients did get better encouraged him, but it was not until he combined it with the anti-inflammatory Celexicob (Celebrex) that he really began to see results.

The big surprise was that his patients were reporting relief from a whole panoply of other symptoms. Their fatigue, their headaches, their muscle and joint pains, their sleep problems, their difficulty relaxing – all were improved. By the time twenty or thirty patients had reported this he really began to take notice.

“Holy crud!” in the interview he stated, “I discovered something.”

He switched gears and began offering the drug combo to people with chronic fatigue syndrome and fibromyalgia. He lambasted the idea that fibromyalgia or chronic fatigue syndrome are difficult diagnoses to make. As soon as he knew what these illnesses looked like, he said, anyone working in his office could spot them immediately.

Fixing What’s Broken

Patients tended to sporadically improve early with the full effects showing up after about three months. He wasn’t just treating herpesvirus infections, however. Asserting that these diseases “break things”,  he also worked on their treatment resistant sinusitis, acid reflux, thyroid issues, insomnia, anxiety, and depression.

fixing what's broken

Pridgen asserted it’s necessary to fix what else is broken for his protocol to have full effect.

In fact, his first step was to figure out what was broken and fix it and then put them on the drug combo “. He said “if you’ve done a good job with the first half” then 12 to 14 weeks into the treatment program a “switch” often gets flipped with people feeling a whole lot better.

Geoff then asked a great question – would you characterize this as a cure or a successful treatment?  Pridgen stated that you can’t “cure” or eliminate viruses, but that he did feel that his treatment protocol was getting at the core of the disease. Note, however, that Dr. Pridgen did put that qualifier – “If you’ve done a good job with the first half” – in. It’s important to treat the depression or generalized anxiety disorder, symptomatic gallbladder disease, severe reflux and chronic nonseasonal sinusitis, etc. for his combination treatment to optimally work.

His protocol, he believes, is much more effective at symptom reduction than the drugs currently approved for fibromyalgia. He does not feel those meds get at the core of the disorder: his does.

Herpes Simplex Virus-1

The predominant virus he believes that is causing the pain in fibromyalgia is herpes simplex virus-1 (HSV-1). HSV-1 has been put in the “fever-blister” category; it causes some unpleasant symptoms and nothing more. Pridgen believes that view and the accompanying attitude of benign neglect towards the virus HSV-1 are disappearing.

HSV-1, it turns out, isn’t always so benign, after all. Yes, the initial infection is usually mild. And yes, essentially everyone, including healthy people, is exposed to and carries HSV-1 in their body.

neurons HSV--1

HSV-1 hangs out in the neurons. In susceptible people that could be a problem.

Like the other herpesviruses, however, HSV-1 persists in the body hanging out in the neurons. After the initial infection, HSV-1 is able, in some people, to become reactivated, travel up the axon of the neuron to the nerve centers – waiting to be reawakened by a stressor.

Studies indicate that  almost any stressor including colds, eczema, menstruation, emotional and physical stress, stomach upset, fatigue or injury can reactivate it. It can cause encephalitis and blindness, and some evidence suggests it’s associated with Alzheimer’s disease.

Vaccines for HSV-2, a close cousin to HSV-1, are being worked on. If HSV-1 does end up being the cause of fibromyalgia, Pridgen believes widespread HSV-2 vaccination could, just as vaccines have put an end to measles, chickenpox, hepatitis and other viral illnesses, help put an end to fibromyalgia. A vaccine, by the way, could also potentially help some people who already have fibromyalgia much like the shingles vaccine helps people with Varicella Zoster reactivation.

The First Trial

“We didn’t get a 60-70% efficacy, because it wasn’t our ideal dose and a lot of patients had other conditions they couldn’t get fixed in a trial like that.”

If you’ve been following the Pridgen story you’ve probably heard of people who’ve tried the Famvir/Celebrex combination who’ve done well and others who haven’t. Pridgen addressed the variability in results in his protocol by asserting that the doses aren’t set and that many of the participants had more than fibromyalgia to deal with.

The trial was less restrictive than most other phase 2 (FDA approved) FM trials where men or people with severe depression weren’t allowed to enroll. He said they pretty much let everybody with FM in.

He also stated that if the patients failed to commit to fixing the secondary problems they didn’t do as well. The FDA also required only one dose be used in the trial – and that dose was not their “favorite” one.

Fifty-three percent of the patients in the trial had at least a thirty percent reduction in pain. That’s a good but not great figure, but Pridgen noted that almost forty percent had at least a fifty percent reduction in pain – and that’s a very good figure for FM. Already their stats, he stated, may prove to be better than the three FDA approved drugs for FM – and he hasn’t been able to use the dose he ultimately intends to market. He stated that some of the world class experts on IMC’s scientific advisory board have said they had “never seen pain data like this” for FM before.

The Next Trials

The next phase three trials, though, will be slightly more selective as the fibromyalgia patients will not have as many “extra conditions”.

It’s going to take time to raise the money and then do two phase III trials – which can be run side by side. While there may be one dose that works best for the most people, Pridgen asserted that no dose is perfect for this variable population and they’ll probably do a dose-ranging study to get at the variability.

They’re trying to get FDA to fast-track the next trials. My guess is that patient enrollment will not be a problem; they expected it to take nine months to enroll the last study and they did it in three.

When asked how the phase three trials are coming Pridgen stated, “We’re moving as fast as we can….This is not an easy process.”

Confident

“I feel very confident that the next two trials will be far more impressive”.

Dr. Pridgen appears to be utterly confident he’s on the right track. He said he’s seen a 1,000 plus FM patients and an equal number of chronic fatigue patients.

recovery from fibromyalgia

Prigen asserts many people have gotten well using his protocol.

“If a patient does what we tell them to do and they jump through the appropriate hoops it’s unbelievable what happens to these people – they do so much better” Skip Pridgen

When the Blue Ribbon Project came to Tuscaloosa, it was the only place, he said, they saw people getting better.

He said he’s seen “countless” patients get well and go on with their lives, including very ill patients.  “I’ve had some tremendously ill patients who get their life back….get back to working again.”

They come from all over. He gets the protocol started and then refers them back to their physicians. His Canadian and Australian  patients have a good chance of continuing with the protocol because their physicians are more open minded, but the Brits often run into a wall so unless they can cross the Atlantic, presently they are receiving little support from their own medical profession.

Dr. Pridgen Talks

When do you expect the study to be published?

Dr. Carol Duffy is feverishly working on the manuscript and should be submitting it for publication this summer, hopefully in one of the premier pain journals.

How did you, a surgeon, end up treating people with gut problems?

Many general surgeons perform endoscopies in their practice of medicine.

How did you get the idea to combine the antiviral with an anti-inflammatory?

I was merely giving them a NSAID for their joint pains, and serendipitously noticed the two drugs when combined had unexpected benefits. I’d never heard of anti-inflammatories used to hit viruses before. Virologists have known for two decades, though, that NSAID had antiviral properties.

You presented a very different model of fibromyalgia at the Rheumatology Conference than rheumatologist are used to. I don’t know if anyone has looked at fibromyalgia as a herpesvirus disorder let alone treated people with antivirals. What kind of reception did your talk receive?

Lot’s of questions, none too difficult to answer and generally it was well received even if the attendance was not ideal.

neurons

Pridgen and Duffy believe three sites in the body may be particularly affected in fibromyalgia: the gut, the vagus nerve and the sinus area

I know someone who couldn’t tolerate the Famvir but did very well on Celebrex for six months when everything fell apart again.

There are other options, and if his physician had reached out to me, I would have given the physician everything they needed to help that patient.

What can you say about the gut tissue biopsy results?

The preliminary data was presented a little over a year ago at an international virology meeting, and for patients who have FM 100% of those patients have HSV-1 data in their biopsies and 80% have a protein that is found only in cells that are actively infected with HSV-1.

If HSV-1 is found in the guts of FM patients is it your guess that it’s probably reactivating elsewhere?

The vagus nerve is the nerve that controls the gut and the virus lives in its ganglion. We postulate that there are two other major sites, the sinuses, and the urinary bladder, that are also likely sites of chronic reactivation.

If it’s active in the gut would you expect to see an increased incidence of cold sores in FM?

Approximately 30% of the population suffers from cold sores. If you go to the innovativemedconcepts.com site you will be able to watch a couple of video’s that explain this better.

big fibromyalgia studies are next for Pridgen

Has Pridgen cracked at least part of fibromyalgia? Time will tell. The big studies are next…

You tried several different combinations of drugs and Famvir turned out to be the antiviral of choice for the fibromyalgia patients in your study. Do you have any idea why Famvir was more effective than the other drugs?

(Dr. Pridgen said that’s a trade secret for now.)

In your experience are people who improve dramatically able to get off the drugs and maintain their improvement for a considerable amount of time?

Absolutely not! The moment they stop the meds the next time they are severely stressed the condition returns. You can’t stop diabetes, hypertension, and cholesterol medications and you can’t stop these.

What is the timeline for the phase III study or studies?

Plans are underway for the near future.

 

CDC Tanks Toolkit In Response to Institute of Medicine Report

April 21, 2015

The reverberations from the IOM Report continue. In their first official response to the 300 plus page IOM Report (Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness) the CDC stated it was archiving both its brochure on ME/CFS: “Recognition and Management of CFS: A Resource Guide for Health Care Professionals“and it’s much maligned Toolkit.

An anachronism from the day it was published, the 17 page, large-type Toolkit looked like a cartoon copy of how to identify and treat ME/CFS next to the 42 page, densely detailed IACFS/ME Primer released in 2012.  It was a Toolkit with decidedly few tools.

CDC toolkit gone

An anachronism from the day it was published, the Toolkit was finally knocked out by the IOM report

The limited recommendations in the Toolkit, and before that on the CDC website, have been a source of frustrations for patients and knowledgeable medical providers for many years. It’s been exhibit one for patients wishing to portray the CDC as being out of touch.

The Toolkit stated that a team of doctors and mental health professionals and physical therapists were best suited to treat ME/CFS. It emphasized therapies that addressed coping, symptoms and activity management.

Several assertions in the Toolkit that came out of the CDC’s randomly sampled population studies using the Empirical Definition  people were controversial. They included statements that people ME/CFS are more likely to be obese, experience insulin resistance and have metabolic syndrome.

To its credit, the Toolkit did note the need for lower doses of medication, asserted that antidepressants were effective only for those with clinical depression and, while promoting exercise, provided substantial warnings about it.

Cognitive behavioral therapy (CBT), graded exercise therapy (GET) and sleep, however, were the only treatments covered in any kind of depth.  While the Toolkit stated exercise programs should not increase patients symptoms, it also suggested that exercise therapy would ultimately enable people with ME/CFS to “go about their daily life(s)”.

toolkit buried

The Toolkit has been buried deep in the CDC’s website.

In contrast to the Primer which identified what are now accepted as core symptoms of the disorder, the Toolkit stuck with symptoms associated with the 20 year old Fukuda definition. The Toolkit identified seven co-morbid condition – several of which are questionable; the Primer – 48. The Toolkit identified ten illnesses that can mimic ME/CFS; the Primer – 55.

The Toolkit provided no specific recommendations on drug treatments; the Primer provided 49 recommendations. The Toolkit provided no recommendations for managing pain; the primer provided recommendations on both non-drug and drug approaches to pain. The Toolkit provided no recommendations on cognitive issues, orthostatic intolerance, gut problems, etc. The list goes on and on.

The Toolkit has influenced the treatment recommendations on many major medical websites. Now, in response to the IOM Report, it’s essentially gone. You can find an archived version of it on the website, but the CDC is clearly not standing by the Toolkit anymore.

It’s abrupt removal suggests major changes are in store. With the IOM report proposing new diagnostic protocols that was expected. It couldn’t have happened too soon.

Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome

April 3, 2015

“Our results indicate a markedly disturbed immune signature in the CSF of ME/CFS subjects that is consistent with immune activation in the CNS.”

Dr. Mady Hornig, Director of Translation Research, Columbia University

The Hornig/Lipkin lab at Columbia University is involved in numerous ME/CFS studies

Columbia University just published groundbreaking results of the first spinal fluid study to compare ME/CFS with Multiple Sclerosis and healthy controls. For almost his entire career treating CFS patients, Dr. Daniel Peterson has been working toward this day.

Simmaron Research, founded by Dr. Peterson, was a key collaborator in this study, along with Konstance Knox Ph.D. of Coppe Healthcare. Drs. Peterson and Knox provided the spinal fluid samples, and Simmaron’s Research Manager Gunnar Gottschalk did clinical coordination. Drs. Mady Hornig (lead author) and Ian Lipkin (senior author), who run Columbia’s Center for Infection and Immunity, designed the study and led the sample and data analyses. Many thanks are due all the collaborators and especially  the Chronic Fatigue Initiative and Evans Foundation for funding this novel work.

Molecular Psychiatry. 2015 Mar 31. doi: 10.1038/mp.2015.29. [Epub ahead of print]Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Hornig M1, Gottschalk G2, Peterson DL2, Knox KK3, Schultz AF4, Eddy ML4, Che X4, Lipkin WI5.

Cerebral spinal fluid is a colorless fluid that surrounds and cushions the brain and spine. Constantly being produced and absorbed it is fully replaced about four times a day. It provides immunological protection and removes metabolic wastes from the brain.

Lumbar punctures such as those used in this study are primarily used to diagnose neurological disorders.

cerebral spinal fluid

Cerebral spinal fluid protects and removes metabolic wastes from the brain

In several ways, this study distinguished itself from other spinal fluid studies in chronic fatigue syndrome. It examined a more comprehensive cytokine panel (n=51), did more sophisticated statistical analyses (logistic regression/network analysis) and included a multiple sclerosis group as a control. With ninety-one subjects, it was a large sample size for a spinal fluid study (32 ME/CFS patients, 40 MS patients, 19 controls) and it was suitably complex.

Highly Significant Results

Major differences were found. With all the central nervous system problems present in MS, we expect MS would be different from healthy controls. The levels of over half of the cytokines tested (26/51) in the MS group vs the controls were significantly different. An almost equal degree of difference, however, also occurred in the ME/CFS group. Almost half the immune factors tested (23/51) were significantly different in the ME/CFS patients relative to the healthy controls.

Highly significant differences in immune factor levels (p<.0003 or less) were found in 13 cytokines in MS group vs healthy controls, in 4 cytokines in ME/CFS vs healthy controls, and in 8 cytokines comparing ME/CFS to MS.

Immune Exhaustion

reduced immune factors in chronic fatigue syndrome

Most immune molecules were lower in both the ME/CFS and MS patients

The immune system is a complex place. Cytokines have a role in both producing and controlling inflammation. Some evidence points to ME/CFS being an inflammatory disorder, and there’s no doubt that multiple sclerosis is an inflammatory disorder. Interestingly, the cytokine levels in the MS  patients spinal fluid were even lower than those in the ME/CFS patients.

In general both MS patients and ME/CFS trended in the same direction – mostly reduced cytokine levels relative to the controls – but the immune dysregulation was very different. With twenty-three immune factors differing between the ME/CFS and MS patients, a case could be made that the ME/CFS and MS groups differed the most immunologically. The researchers stated ME/CFS patients demonstrated a “markedly greater degree of CNS immune activation” than the MS group.

People in the current study had had chronic fatigue syndrome for about seven years. The relatively low cytokine levels found parallel those found in the longer duration patients in the large blood cytokine study the Columbia researchers recently completed.

“I think what we’re seeing is an immune system exhaustion over time,” Dr. Hornig speculated in HealthDay.

Chemokines, Infections and CNS Damage

Scientists at Columbia … identified a unique pattern of immune molecules in the cerebrospinal fluid of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that provides insights into the basis for cognitive dysfunction—frequently described by patients as “brain fog”

Chemokines are of special interest in neuroinflammation because these very small proteins regulate immune cell entry into the brain. When an infection occurs, they draw immune cells into the brain by increasing the permeability of the brain blood barrier. The microglia and astrocytes are the primary chemokine producers in the brain.

Infection or demyelination possible in ME/CFS

High CXCL10 levels have been associated with infection or demyelination

Two chemokines (CCL11 and CXCL10) were increased in both the MS and ME/CFS groups with much higher levels of both found in the MS group.

CXCL10 clears the way for the entry of natural killer cells and T lymphocytes into the brain. It is often prominently expressed in the CNS in response to viral infection.

As always the immune system walks a fine line. Too little chemokine expression and a deadly infection can take root. Too much chemokine expression and brain damage and seizures can result. While CXCL10 plays an important role in combating viral infections, excessive CXCL10 levels can cause neuron die off and trigger a immune-mediated demyelinating disease.

Demyelination is a major problem in MS but is only a possibility at this point in ME/CFS. A small recent Stanford study suggested myelin abnormalities along with white matter atrophy may be present in ME/CFS. .

Not surprisingly, CXLC10 clearly has an impact on symptoms. Neutralizing CXCL10 even during a persistent infection can greatly reduce symptom severity.

Allergic Response, Eotaxin and Brain Fog

“These immune findings may contribute to symptoms in both the peripheral parts of the body and the brain, from muscle weakness to brain fog.” Dr. Mady Hornig

IL1ra is supposed to tamp down an allergic response as well. The network analysis in this study suggests that it’s not working so well in ME/CFS patients. The inverse relationship between IL1ra and CSF2 (GMCSF) levels in the ME/CFS patients, indeed, suggested an allergic response was underway. Reduced CSF2 levels were found in a prior ME/CFS spinal fluid study as well.

Then there is eotaxin (CCLII). Eotaxin recruits white blood cells called eosinophils that are involved in producing an allergic response in the brain. The logistic regression suggested increased levels of eotaxin (and decreased levels of IL1b) are highly associated with “ME/CFS caseness”.

eotaxin chronic fatigue syndrome

Eotaxin has been associated with cognitive declines and reduced neuron growth in mice.

Eotaxin is not a chemokine one particularly wants to have around. Increased eotaxin levels have been associated with impaired learning, memory deficits and reduced neuron production in mice as they age. Introducing eotaxin into the CNS of young mice reduces neuron production. (At the last IACFS/ME Conference, the CDC reported reduced telomere length – another possible sign of increased aging – was present in ME/CFS.)

“…we now identify systemic immune-related factors (eotaxin) as potentially critical contributors to the susceptibility of the aging brain to cognitive impairments”. Villeda et. al. 2011 – From a mouse study published in Nature

One doesn’t think of allergy in terms of the central nervous system, but the authors reported that allergic processes could be indicative of a central nervous system infection. The chemokines upregulated in the ME/CFS patient’s spinal fluid have been associated with microglial activation and central nervous system infections.As the publication notes, “Persistent secretion of cytokines by activated microglia, brain immune cells of macrophage-monocyte lineage, may contribute to this pattern.”

Networks Awry

“The inverse relationship we found between IL1ra and CSF2 in the CSF of cases using a network analysis approach suggests that neuroimmune responses may be shifted toward allergic or Th2 (autoimmune) patterns in the CNS of individuals with ME/CFS.”

The Hornig/Lipkin team also found evidence of disturbed “networking” in ME/CFS; i.e. immune cells communicating strangely. IL-1ra is an interleukin that prevents cells with IL-1 receptors from producing the powerful pro-inflammatory cytokines IL-1A or IL-1B. It stops that part of the immune response in its tracks, but the network analysis suggested it wasn’t doing that in ME/CFS.

Summing Up

  1.  The fact that the alterations in the immune factors in the ME/CFS were almost as extreme as in multiple sclerosis – a disorder characterized by severe central nervous system dysfunction –  suggests a major pathology is present in the central nervous systems of ME/CFS patients.
  2. The low cytokine levels suggest that some sort of immune exhaustion –  caused by an infection or by immune upregulation – is present in ME/CFS.  These findings parallel those of the recent Hornig/Lipkin study suggesting that  immune up regulation early in the disorder may lead to immune burnout later on.
  3. Several of the immune factors in the ME/CFS patients spinal fluid suggest an allergic type of reaction may be occurring in their CNS. A similar finding is also found in some central nervous system infections; i.e. an infection could be driving this process.
  4. The immune factor most identified with the ME/CFS patients has been associated with cognitive declines, aging and reduced neuron production.

Moving Forward

“Diagnosis of ME/CFS is now based on clinical criteria. Our findings offer the hope of objective diagnostic tests for disease as well as the potential for therapies that correct the imbalance in cytokine levels seen in people with ME/CFS at different stages of their disease,” adds W. Ian Lipkin, MD, John Snow Professor of Epidemiology and director of the Center for Infection and Immunity.

Daniel Peterson

Dr. Daniel Peterson

Early on, MS didn’t have biomarkers or diagnostic tests, and it had skeptics like CFS does. Later it was diagnosed by specific proteins in spinal fluid. Now there are FDA-approved treatments.

ME/CFS patients often have central nervous system symptoms, like cognitive dysfunction, balance problems, and nerve and pain issues. Those symptoms convinced Dr. Peterson many years ago that spinal fluid may hold the key to understanding the disease. His perseverance helped make this study possible.

Columbia University’s press release stated:

“There is precedent for use of human monoclonal antibodies that regulate the immune response in a wide range of disorders from rheumatoid arthritis to multiple sclerosis. However, the researchers note, additional work will be needed to assess the safety and efficacy of this approach.”

We need more research to translate these unprecedented findings into diagnostics and treatments.

Simmaron Research | Give | Donate | Scientifically Redefining ME/CFS

Major Study Suggests Early Immune Activation May Drive Chronic Fatigue Syndrome

“This study delivers what has eluded us for so long: unequivocal evidence of immunological dysfunction in ME/CFS and diagnostic biomarkers for disease” W. Ian Lipkin

big me-cfs study

Big study – big results

Distinct plasma immune signatures in ME/CFS are present early in the illness. Hornig. M. Monotoya, J, Levine, S., Felsenstein, D., Bateman, L, Gottshalk, G….Likpin. L. Sci Adv 27 Feb. 2015.

It’s a major study indeed – the first, I believe, to come out of the Hutchins Foundation’s Chronic Fatigue Initiative and the media is picking it up quickly. The Hutchins Foundation doesn’t mess around. They’re putting $10 million into researching chronic fatigue syndrome. They do big rigorous studies with top researchers.

This study with its carefully selected patients from across the country was loaded with ME/CFS expertise. Besides Mady Hornig and Ian Lipkin of Columbia, Dr. Montoya, Dr. Peterson, Dr. Klimas, Dr. Bateman, Dr. Levine and Dr. Komaroff were listed as co-authors.

The Simmaron Research Foundation and Dr. Peterson provided samples for this study. One of  Simmaron goals is to provide samples and data from well-characterized patients to major researchers and institutions.

It’s Biological

“These immune signatures represent the first robust physical evidence that ME/CFS is a biological illness as opposed to a psychological disorder, and the first evidence that the disease has distinct stages.” Columbia University Press Release

Once again we see claims made that finally, finally we have proof that ME/CFS is a biological illness. (The head of the CDC said something similar regarding their study about ten years ago at a National Press Club event.) This time the claim is a bit different, however. This time they have not just evidence but “robust” evidence that ME/CFS is a biological illness.

If the study size is any indicator of robustness – and in a well-designed study it is – their evidence is robust, indeed.

It’s So Big!

This wasn’t just a big study – it was a huge study containing almost 650 patients and healthy controls (298 ME/CFS patients and 348 healthy controls).  (A similarly large study is underway at Stanford).

All the patients met both the Fukuda and Canadian Consensus Criteria.

The study wasn’t just big in size – the 51 immune factors it measured meant it was deep as well, and  leptin was one of the immune factors measured.

Different But Not Substantive

The study started off on a bit of a downer. Differences in immune factors between the ME/CFS patients and the healthy controls were present, but not “substantive”.

Note, however, almost all the immune factors are lowered – not increased –  in the chronic fatigue syndrome patients. We’ll come to a reason for that later.

  •  Pro-inflammatory – IL171A (p<.0043), CXLC10 (p<.04), TNF-B (p<.0028), Il-6 (p<.04), sFasL (p<.01)
  •  Anti-inflammatory – Il-10 (p<.024), CSF1 (p<.025)

The one immune factor moderately  increased in ME/CFS was leptin (p<.03).

That didn’t mean many in the group hadn’t experienced profound immune alterations, though. They had – earlier…

Hit and Run

“The immunopathology of ME/CFS is not static” the authors.

Further analyses uncovered something the authors freely admitted surprised them. The ME/CFS patient’s immune measures didn’t differ by triggering factor or age or even by sex – they differed by time.

chronic fatigue syndrome early immune findings

The key factor for the immune system – was time

Alterations in over half the immune measures found (combined with some very, very low probability factors that the results weren’t correct)  (p< >0002-.0008) indicated that “substantive” differences in immune functioning had existed at one point in time.  The short duration patients showed signs of intense immune activation not found in the other groups.

Both the pro and anti-inflammatory sides of the immune system were on high alert early on in ME/CFS.

Immune Differences Between Short-term ME/CFS patients and Healthy Controls:

  • • Increased levels in ME/CFS: IL1A, IL1B, IL-6, IL-12, IL-17a, Il-17f, IL-8, TNF-a, sFasL, TRAIL, IFN-y, CCL2, TGFa, CSF, resistin, CCL-11, CSF2, IL1RA, IL-13.
    • Reduced Levels in ME/CFS – PDGFBB, CD40L

Cytokine results have been spotty in ME/CFS and that’s been a problem.   A few up or down regulated cytokines just don’t raise many eyebrows in the research world. They’re looking for evidence of broad immune alteration – and here it is. I don’t think anybody has seen this kind of sweeping immune activation in ME/CFS before.

Viral Fighter Stands Out

A logistic regression suggested that IFN-y played a particularly significant role in the immune system activation. Produced mostly by natural killer and cytotoxic T-cells – two cells with similar problems in ME/CFS – IFN-y is both an immune stimulator and pathogen inhibitor. (Microglia are big IFN-y producers in the central nervous system).

The IFN-y findings suggest either a pathogen attack or an autoimmune shift may be triggering the immune upregulation seen early in the disease.

infection chronic fatigue syndrome

Bug alert! The early immune findings were consonant with a pathogen attack.

High IFN-y levels are associated with Th2 dominance in the immune system and an increased risk of autoimmune processes. Post-viral fatigue has been associated with high IFN-y levels, and alterations in the IFN-y gene have been associated with increased fatigue following infection as well.

IFN-y also showed up in Broderick’s small study examining 16 cytokine levels in adolescents in the first two years after coming down with infectious mononucleosis. Four cytokines IL-8, Il-23, IL-5 and IL-2 were significantly altered or nearly significantly altered.

IFN-y levels were not increased but a computer model suggested it and four other cytokines constituted an immune signature that differentiated people who came down with ME/FS after IM and those who recovered.

Mady Hornig on the Study

IL-5 levels were significantly decreased in ME/CFS patients but IL-5 did not, interestingly enough, make it into the computer model. Further analysis indicated that IL-5 levels were significantly correlated with Il-23 and IFN-y: two cytokines that did make into the model. These cytokines were essentially analogues for IL-5 in the body.

THE Pathway???

IFN-y also accelerates tryptophan degradation by activating the indoleamine-2,3 deoxygenase enzyme in the kynurenine pathway – Mady Hornig’s favorite pathway. That pathway produces neurotoxic substances that increase production of the excitatory neurotransmitter glutamate that some researchers believe is in play in both fibromyalgia and ME/CFS. Andrew Miller of Emory University has earmarked the kynurenine pathway in ME/CFS.

kynurenine pathway chronic fatigue

Could the kynurenine pathway be it for ME/CFS?

Cognitive problems and mood changes have been associated with up-r egulation of the kynurenine pathway in diseases ranging from Alzheimer’s to depression. In fact, disruption of the one part or other of the kynurenine pathway occurs in many neurological and psychological disorders.

The authors were confident enough to hypothesize that lesions produced by high IFN-y levels early in the disease are producing the cognitive slowing and depression found in ME/CFS. Andrew Lloyd of the Dubbo project has been suggesting for years that high cytokine loads early in the disease process had disrupted brain functioning, but nobody has gotten this specific before. Now Hornig and Lipkin et. al are proposing a specific mechanism for that: IFN-y produced lesions.

“We propose that IFN-y mediated lesions in kynurenine metabolism may culminate in the depression and psychomotor tardiness (slowed information processing) that contribute to disability in some patients with ME/CFS”.

That kynurenine pathway gets more intriguing when we consider that IFN-y activation and tryptophan degradation has been associated with chronic Epstein-Barr virus infection. Epstein-Barr virus is often associated with infectious mononucleosis – a common trigger of ME/CFS.

CD40L

CD40L appears to be another early key immune factor. A clear driver of immune functioning in the healthy controls and longer-term ME/CFS patients, CD40l was found to be reduced and strangely disengaged from the immune system in shorter-term ME/CFS patients.

A B-cell maturation regulator, deficiencies in CD40L are associated with recurrent infections and unexplained cognitive issues and CD40 deficient mice exhibit major immune deficiencies. Citing the Fluge/Mella Rituximab study the authors suggested the collapse of this immune factor   early in this disease could be important.

Nice Fit

One scenario proposed by this study – natural killer and cytotoxic T-cells pumping out IFN-y early in the disease only to collapse later on–appears to fill in some holes that smaller studies would have missed. If this study is representative maybe 20% of the patients in any study have probably had ME/CFS for three years or less. That would mean that the typical low NK dysfunction will show up but the up-regulation early in the disease the authors believe may be contributing to that doesn’t.

Flipping the Switch

That suggests that somewhere around the 3rd year of illness major immune shift occurs. The immune system flips from being hyperactive not to being normal but to being somewhat under active.

Dr. Hornig described a condition of immune system burnout:

“It appears that ME/CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop.”

primed for burnout cfs

Does the immune system get burned out in longer duration ME/CFS patients?

There’s something very right about “immune exhaustion” being associated with this disease The fact that many cytokines  increased in the early stages of ME/CFS are  decreased in the later stages suggests a kind of burnout process is occurring.

Poor natural killer cell functioning in ME/CFS is often described as a type of immune system “burnout” and evidence is emerging of similar cytotoxic T-cell problems as well.

Leptin Again

It’s hard for me parse how leptin showed up in this study. The only immune factor increased in the whole ME/CFS group vs the controls, leptin was highlighted in one network analysis of early duration patients and showed up moderately in two others. The authors noted that it was tightly correlated with most of the immune factors later in the disease but not early.

Another cytokine called PDGFBB appeared to be the main driver of the immune reductions later in the disease.

Hit and Run

That suggests the disease has in some way moved on from the immune system. The authors of the paper didn’t have a great explanation for why people remained ill after their immune system activation had died down or had become decreased. If Younger’s findings pan out perhaps the lone elevated immune marker – leptin – found is enough.

hit and run me/cfs

The findings suggested ME/CFS is a hit and run disease.

A email to Jarred Younger gave a quick answer  and a warning that it was not based on a close reading of the paper. He suggested systemic inflammation may drive ME/CFS early on but sensitized microglia and astrocytes in the central nervous system drive it in its later stages. Because we don’t have good ways to test central nervous system inflammation at that point the disease mostly becomes invisible to testing afterwards.

In fact, the authors tantalizingly noted because ME/CFS appears at least in part to be a central nervous disorder cerebral spinal fluid may very well be a better medium to investigate than peripheral blood. That could suggest we’re due some more important findings in a couple of weeks when the Simmaron Research Foundation/Chronic Fatigue Initiative CSF study is published.

The High Cytokine Longer Duration Patients

The study doesn’t make any mention of longer duration patients ME/CFS patients with high cytokine levels. Anecdotal reports from patients indicate they are definitely out there, but this study – involving many quite ill patients being seen at ME/CFS practitioners – suggests that they probably constitute a relatively small subset of patients.

Conclusion

“We now have evidence confirming what millions of people with this disease already know, that ME/CFS isn’t psychological,” Mady Hornig, MD

This large study presents what appears to be almost novel finding in medicine: distinct before and after stages early in a chronic illness. In the early stages of ME/CFS (first 3 years) a distinct and impressive immune activation is present that is followed by modest immune deactivation.

The early immune activation is highly suggested of an infection or some other immune altering process.

The study may ultimately open up possibilities for treating patients with recent onset but provides no possible treatment options at this point for patients who have been sick longer. The  more modest immune deactivation found later in the disease suggests that the core causes of the disease are either found elsewhere or were not illuminated by the study.

A major question facing researchers now is finding ways to translate this hit and run immune activation or viral infection into long lasting central nervous system problems. Microglia sensitized by chronic immune activation/kynurenine pathway activity is one possible answer.

Ian Lipkin’s statement that they hope to find important answers in their microbiome study suggests he believes a permanently altered microbiome  could provide an answer to that question.

“The question we are trying to address in a parallel microbiome project is what triggers this dysfunction.”Ian Lipkin

The authors statement that cerebral spinal fluid may provide a better medium for understanding this disease could mean we’re in for some interesting findings in a couple of weeks.  The Simmaron Research Foundations rare  and extensive trove of cerebral spinal fluid samples from ME/CFS patients provided the foundation for that study.

Stay tuned!

The Biggest Chronic Fatigue Syndrome Treatment Trial Begins: Fluge/Mella On Rituximab

Doctor’s Fluge and Mella shocked the ME/CFS world with their 2009  case series and the 29-person 2011 study which found that about 2/3rds  of ME/CFS patients had a significant and positive response to the chemotherapy  and autoimmune drug Rituximab. With some patients achieving near miraculous recoveries, the results from Norway had the ME/CFS world buzzing.

rituximab-chronic-fatigue

The big question is – what percentage of ME/CFS patients will respond?

As encouraging as the results were, however, they were but a prelude to the big study ahead – the one that will definitively tell us how effective Rituximab is in this disorder.

As they begin the study, the doctors appear to be both cautious and optimistic. There’s no doubt now that Rituximab doesn’t significantly help some people with ME/CFS – the question is how many and how much – and that’s what this 152 person, multi-center study will tell us

Multi-dimensional in scope, it’s actually four studies in one – some of which are almost as exciting as the trial itself – that  could tell us much about ME/CFS. This very long study started up in the last quarter of last year – a bit later than expected. As  it did I asked the doctors some questions.

(Check  out the study on the ClinicalTrials.gov database).

How is the Rituximab (RituxME) study going? 

The RituxME study has just started recruiting patients. We plan to include 152 patients, in five centers in Norway. There will be 1:1 randomization between rituximab and placebo.

We will give the first two infusions two weeks apart (500 mg/m2, max 1000 mg, or placebo) followed by maintenance infusions 500 mg fixed dose (or placebo), at 3, 6, 9 and 12 months. The placebo solution with saline and some added albumin will look identical to the Rituximab solution. The study will be double-blinded and placebo-controlled.

The follow-up will be for 24 months, and the code for intervention will be revealed after the last included patient has been to 24 months visit and the database is locked.

measuring activity levels - me/cfs

Many measurements will be done – including activity levels.

Patients from 18-65 who have ME/CFS according to Canadian criteria (2003), age 18-65 ME/CFS for at least 2 years up to 15 years can be included.  People with severe, moderate/severe, moderate, mild/moderate and mild ME/CFS may be included.  If they have “mild” ME/CFS they need to have had the disease for at least 5 years. People with very severe ME/CFS (completely bedridden with need for help for all tasks) will not be included.

Self-reported symptom scores will be recorded every second week, and SF-36 questionnaires every third months. Activity levels will be assessed for seven consecutive days using the Sensewear armband at baseline, and repeated at the17-21 month follow-up.

Do you plan to publish the results of the open-phase trial? If not can you say anything about the results? (This was an open label (patients knew what they were taking) study with 29 patients using rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished). This trial continued patients on Rituximab (a maintenance dose) for much longer, in a effort to reduce the relapses seen in some patients after they went off Rituximab.)

We have used the experience from our open-label phase-II study using rituximab maintenance. This study ended in February 2014, but due to all the work with the new study we have not had time to complete the manuscript. However, we are now completing the manuscript, and hope to submit soon.

We included 29 patients in the open-label phase-II study (KTS-2-2010). In this study there was no placebo group, and that will of course be the main criticism of the study. The reason for doing an open-label study was to gain experience on dose-response relationships in order to better design the randomized phase-III study. We also wanted to give patients who had taken the placebo in our first randomized study (Plos One 2011, KTS-1-2008) an opportunity to take part in a study without being randomized again (that was in agreement with the ethical committee approving the KTS-1-2008 study).

One patient had an allergic reaction at the first infusion and did not get further intervention, leaving 28 patients to receive rituximab maintenance treatment. The patients received two infusion with rituximab two weeks apart,  followed by maintenance rituximab infusions after 3, 6, 10 and 15 months (7 patients received further infusions according to an approved amendment in the study).

We will not give details on the results here, even though the study has been presented at some meetings the last year. For now we can state the response rate was quite similar to the first KTS-1-2008 study, and that the response durations seem to be much prolonged (as compared to the Plos One study) when giving rituximab maintenance treatment.

Rituximab-chronic-fatigue

Fluge and Mella’s data indicated that maintenance doses of Rituximab worked: i.e. they largely kept patients from relapsing

To us, the most important issue now is to do a proper phase-III study which will determine if the results of the first trial can be trusted. It is important to understand that our first phase-II study (Plos One, 2011) – the first to evaluate the treatment principle of B-cell depletion in ME/CFS – had several limitations.

We do not know how much selection bias was present in our first two studies. If the putative immunological disease that we have seen is commonly found in the broad groups of ME/CFS patients that fulfill the Canadian criteria, we have a chance to get a significant result in favor of rituximab in the ongoing study.

However, if our selection bias in the first studies is large (i.e. if we selected out patients that are not representative of ME/CFS patients as a whole) the new study might very well turn out negative (i.e. no difference to placebo). Should that happen we would then focus our efforts on figuring out how to select the subgroup that has an   immunological, rituximab-responsive disease.

The Substudies

Blood vessel, exercise and gastrointestinal substudies occurring alongside the major study could tell us much about ME/CFS as well. Some of the substudies are, to my mind, almost as interesting as the Rituximab study itself. I asked Dr. Fluge about them. 

For the RituxME study, we will perform three substudies. (We originally planned to use these in the main study, with some parameters as secondary endpoints, but because all centers could not perform the analyses they were designed as substudies.)

All three substudies will be performed at baseline and repeated at the 17-21 months follow-up, which is the time interval our previous experience suggests that the therapeutic effect of rituximab maintenance to be most evident.

Endothelial Functioning Substudy

Our substudy of endothelial function (Bergen Notodden) in 72 patients will use flow-mediated dilation to test large blood vessel endothelial functioning.  We will also test microvascular endothelial function in Bergin using skin laser-doppler measurements.

blood vessels chronic fatigue

Is a problem in the blood vessels triggering the sympathetic nervous system activation found in ME/CFS?

We believe that endothelial function is important in ME/CFS. Even though many symptoms can be ascribed to the central nervous system we are not convinced that ME/CFS is primarily a central nervous system disorder. We believe the sympathetic nervous activation seen in ME/CFS may be (partly) secondary to an underlying (peripheral) pathology.

It is important to get an understanding of which symptoms that are caused by the primary pathology, and those which may be ascribed to secondary (compensatory) mechanisms.  We are working to elucidate whether endothelial dysfunction, and subsequent inadequate fine-tuned autoregulation of blood flow to meet the demands of tissues, may be an important feature of ME/CFS.

A study from Dundee in 2011 showed endothelial dysfunction to be present in ME/CFS. Our pilot studies in a group of ME/CFS patients suggest it is as well.

In the substudy to RituxME, we ask if we can reproduce the endothelial dysfunction in a larger cohort of ME/CFS patients? Is there a relation between endothelial dysfunction and disease severity? Is there a relation between endothelial function and a later clinical response (in the rituximab group)? In patients that improve after B-cell depletion therapy (Rituximab) is there a relation between improvement in self-reported symptoms or in physical activity levels, and changes in endothelial function?

We have written a manuscript on our thoughts and hypotheses including the relation between immune response, endothelial function, and the possible effector system for symptom maintenance in ME/CFS. However, we still believe that we need more data to underpin out thoughts and have therefore not submitted the paper yet.

[Dysfunction of the endothelial cells lining the blood vessels in the circulatory system has been a subject of interest in ME/CFS since MERUK’s pioneering efforts in the early 2,000’s. These cells  – present everywhere from largest arteries to the small capillaries – control how dilated or narrowed the blood vessels are, affect inflammation, control blood clotting and more.  Each of these factors have been implicated in ME/CFS at one time or the other. In 2012 Newton et al.  reported both small and large blood vessel dysfunction was present in ME/CFS.

The finding last year that  autoantibodies to the adrenergic receptors found on endothelial cells are present in postural orthostatic tachycardia syndrome (POTS) suggested an autoimmune process was knocking out one group of POTS patients. Now Fluge/Mella appear to be proposing that a similar autoimmune process is messing up the blood vessels and producing the sympathetic nervous system activation in ME/CFS. If that’s so Rituximab’s efficacy could lie in its ability to restore proper blood flows (and presumably blood volume) to ME/CFS patients allowing them to exercise, think, digest, etc. as healthy people do.  This is a hypothesis that is pregnant with possibilities.

Fibromyalgia patients should note that Rice has found evidence of small blood vessel dysfunction in the hands that may also be impeding normal blood flows throughout the body. – Cort. ]

 Exercise Substudy

The cardiopulmonary exercise tests for two following days will be performed at baseline and repeated in the 17-21 months follow-up. We will do this substudy in Bergen, Notodden and Oslo, but only for patients with mild and moderate disease (not severe), The total number may be 50, perhaps more.

exercise chronic fatigue syndrome

The ultimate test of Rituximab’s effectiveness – an aerobic exercise test.

We want to see (in a double-blind fashion) if the performance (VO2max, VO2 at anaerobic threshold, workload at max and at anaerobic threshold) of patients who respond to Rituximab will improve on day two of the exercise test.

It may be a disadvantage that we exclude patients with a high symptom burden from this substudy, but we did not want to put patients with moderate/severe or severe ME/CFS through such physical exertion because they may worsen for many following weeks. They will also start the intervention (Rituximab or placebo) three weeks after these tests  – maybe too soon for some moderate/severe or severely ill patients to fully recover.

Gastrointestinal Functioning Substudy

The substudy on gastrointestinal function will only performed in Bergen, and only for patients with GI symptoms resembling functional dyspepsia or irritable bowel disease. Approximately 15-20 patients will be included.

Gastroenterologists in Bergen will evaluate the patients using several self-reported forms, and with a soup meal followed by ultrasound assessment, and also with endoscopy and biopsies from those willing to participate in this (in fact, most of those we have evaluated are willing to do the endoscopy!). The GI studies will be performed at baseline and repeated after 17-21 months.

Genetics Study

Dr’s Fluge and Mella will  also be looking at the genetics of ME/CFS patients and their families. Dr. Fluge wrote

genetics-chronic-fatigue

The list goes on…Fluge and Mella are also looking at genetics

To further elucidate possible clues, we are also working on exom-sequencing of families with many affected individuals among first- and second-degree relatives, sequencing all coding parts of the genome (with flanking introns) both from affected and healthy family members. We test candidate genes with targeted sequencing in all patients included in our studies. We hope to be able to link the genetic and clinical data, to underpin the hypotheses.

An Autoimmune Disorder?

I asked Dr. Fluge why they thought the patients responding to Rituximab may have an autoimmune  disorder?

Why we think this is a variant of an autoimmune disease? First, we have not shown that ME/CFS is an autoimmune disease. However, we believe that in a subgroup of patients an autoimmune pathogenesis involving B-lymphocytes and possible immunoglobulins (autoantibodies) makes sense.

The arguments are as follows:

  • The observed pattern of responses and relapses after rituximab treatment, with a lag time of several/many months from initial and rapid B-cell depletion until start of clinical responses. Such patterns are also seen in established autoimmune diseases after rituximab treatment, such as Wegener’s granulomatosis and rheumatoid arthritis.
  • A high proportion of women with ME/CFS
  • Our studies suggest a high occurrence of autoimmune diseases exists among relatives of ME/CFS patients (could also be a marker for a selected population in our studies?)
  • A moderate, but highly significant risk of B-cell lymphomas in elderly ME/CFS patients, shown in a large case-control study from National Cancer Institute in 2012. To me, this is an important study, showing that patients may have a chronically activated B-cell system.
  • Emerging data from a few other poorly understood diseases (POTS, Chronic Regional Pain Syndrome, CRPS) which have some common characteristics and possibly to some extent may overlap with ME/CFS, in which research groups have detected (functional) autoantibodies.

Long Lag Time Also Suggests Autoimmunity

Epstein-barr chronic fatigue

The different responses Fluge/Mella’s ME/CFS patients and their chronically activated EBV patients have had to Rituximab suggest to them autommunity, not EBV reactivation, is ocurring.

The long lag time from rapid initial B-cell depletion to start of the clinical response (2-8 months) is why we do not think elimination of EBV or CMV is the principle mechanism for symptom relief in our patients. In my work as a lymphoma oncologist, I have treated a few patients with chronic EBV infection, with moderate lymphadenopathy, night sweats and general symptoms for several years, and with no clear clinical benefit from valganciclovir.

In one patient, the B-cells in bone marrow and in lymph nodes were packed with EBV and she had a high EBV titer in her peripheral blood. When given rituximab, her symptoms waned in a few days after start of treatment – very different from what we see when treating ME/CFS patients.

Two Cautionary Notes

Dr. Fluge wanted to make two cautionary notes: 

caution rituximab chronic fatigue

Caution! Rituximab use in severely ill patients is not recommended…

Very severely ill ME/CFS patients – We are also conducting a study (KTS-3-2010), which includes very severely ME/CFS patients. Only four very severely ill ME/CFS patients have been at our hospital, and it is very difficult to give them the care they need in a very busy oncology ward. For these for patients, although rituximab has influenced their disease in a slightly positive manner for two, none of the four could be characterized as responders. We do not encourage treatment of patients with very severe ME/CFS with rituximab outside clinical trials!

In fact, until further scientific data and evidence are available, all patients receiving rituximab for ME/CFS should be treated within clinical trials.

Etanercept - We started a clinical open-label phase-II study on weekly subcutaneous etanercept (a TNF-alpha inhibitor). Only four patients were included, and we decided to stop the trial because two patients had a clear worsening of ME/CFS symptoms, while two were unchanged (no response). Ideally, we should have included additional patients to gain experience for a more solid conclusion; we however decided to stop the trial.

New Open Phase-II Trial

After observing a few pilot patients for one year, we have decided to begin another open-label phase-II study in Spring 2015 on another immunomodulatory drug, in three sets of ME/CFS patients:  ME/CFS patients who have not treated before with rituximab, in nonresponders to rituximab treatment, and in patients with a clear response to rituximab but with evidence of gradual relapse the last year. This study has been approved by the Ethical Committee, and will occur at a single center study in Bergen (Haukeland University Hospital)

Conclusion

In conclusion, we hope our efforts will help to increase our knowledge of ME/CFS, and that the results of the new randomized study will provide some important answers to aid further research, either by us or others in the research community. We need a better understanding of the disease with regards the genetic predisposition, the immune disturbances and the endothelial dysfunction present and the effector systems for symptom maintenance in order to develop rational treatments for this devastating and misunderstood disease.

 

 

 

 

 

 

 

 

 

 

 

 

P2P Report Urgently Calls for Major Increases ME/CFS Research: Tightening Needed

January 19, 2015

“We hope our work has dignified ME/CFS and those affected, while providing expert guidance to the NIH and the broader research community.” – P2P Executive Draft Summary

pathways-to-prevention

ME/CFS is the third disorder to go through the P2P program

The Pathways to Prevention Program (P2P) is an NIH program begun in 2012 that is tasked with identifying research gaps, methodological weaknesses and suggesting research needs for disorders that cause major health problems but are not being addressed well by the medical field.  The limited published data and few randomized controlled trials in these disorders of “broad public health importance” have made it difficult to produce systematic reviews.

That chronic fatigue syndrome is only the third disorder or condition — after polycystic ovary syndrome and opioids and chronic pain — to go through the P2P process, suggests the NIH may be increasing its commitment to this disorder.

The Panel was tasked with (1) identifying research gaps, (2) determining methodological limitations, and (3) providing future research recommendations regarding diagnosis and treatment.

Panelists “Get” Community Needs

In the first part of the P2P Draft Report it was gratifying indeed to see a panel of outsiders – none of whom had any connection to chronic fatigue syndrome (ME/CFS) – “get” the major issues facing the chronic fatigue syndrome community.  In retrospect perhaps it’s not so surprising; people who take the time to get to know the ME/CFS community and the problems it faces have become allies in the past.

big-leap

Major gaps in every area were identified…Will the panel recommendations help to surmount them?

The first part of the report  identified numerous gaps that are keeping the field from progressing. In the second part they provide a long list of recommendations that would, if acted upon, result in significant and long-sought progress in this field. The panelists appear to have thrown virtually everything they can think of at this disorder which has so many needs.

The lack of specific funding recommendations or time or numerical targets, however, left me wondering if panel understands the kind of cultural shift that has to occur at the NIH before ME/CFS gets its due. The panel is up against a culture of dismissal that has even been willing to ignore its own studies showing that high prevalence rates, disability rates, high economic losses, and enormous unmet needs are present.

The NIH, we know, will very likely do everything it can to ignore, distort, wave off, and pretend to comply with the P2P report’s recommendations.  Jennie Spotila and Mary Dimmock have pointed out the federal government can be very good at taking the least possible action to fulfill minor recommendations while ignoring or not acting on major recommendations. Does the panel, for instance, recognize

  • head-in-sand

    The P2P is up against an embedded culture of neglect and dismissal at the NIH

    that this million-person disorder has been in the bottom five percent of NIH funding for decades?

  • that adjusted for inflation the NIH is spending about what it did on ME/CFS twenty years ago -when it was considered a small, niche disorder?
  • that disorders of ME/CFS’s prevalence, effects, and economic losses typically receive twenty times as much funding?
  • that most major cities in the U.S. do not have one expert ME/CFS practitioner?
  • that the NIH’s response to that dearth of ME/CFS experts has been to turn down requests for Centers of Excellence year after year? That over a decade of requests has not produced one COE?
  • that similar disorders such as fibromyalgia, which also affect large numbers of people (often women) and produce severe economic losses, but do not usually kill, are in a similar situation?

The panel recognizes help is needed in every aspect of this field and the P2P report is going to help – there’s no doubt about that – the only question at this point is how much. With that in mind, I propose ways to tighten up some recommendations and add some others. I believe the Panel must be as specific as possible and not allow wiggle room.

First the gap is presented, then the recommendation, and then ways to tighten it up. I look forward to hearing suggestions from others.

January 16th is the last day to submit comments using this email address:  prevention@mail.nih.gov. They ask that each comment reference the line number of the report it’s referring to. 

The P2P Panel’s Recommendations to Fill Gaps in ME/CFS Research and Treatment

“Innovative biomedical research is urgently needed to identify risk and therapeutic targets, and for translation efforts.“ – P2P Draft Report

GAP: A Definition Needed to Provide the Foundation for Research and Clinical Trials

The panel endorsed a large-scale effort to finally find a suitable definition for ME/CFS that included creating a team of stakeholders, creating a research network, and examining commonalities with other disorders.

team-building

A team of stakeholders should agree on a definition

Create Team of Stakeholders – The panel recommends creating a team of stakeholders (patients, clinicians, researchers, and federal officials) that will come to consensus on a definition now, even if it’s an imperfect one.

That’s almost been done; the Canadian Consensus and International Consensus Criteria involved patients, clinicians, and researchers, but not federal officials.  The advocacy letter requesting that the NIH adopt the Canadian Consensus Criteria (CCC) indicated also that a large number of stakeholders agree that the CCC should be adopted, but also did not include federal officials.

A National and International Research Network should be developed to clarify the definition and “advance the field”.  This is an important part because no suitable research definitions are present at the moment. The CCC and ICC are fine clinical definitions, but studies suggest they may result in selection of a high percentage of ME/CFS patients who also have psychiatric disorders and allow a significant percentage (15-20%) of healthy people to be identified as having ME/CFS.  A better research definition can be developed.

leaking-pipe

Tightening the recommendations is recommended.

Tightening

  • NIH shall develop a National Research Network consisting of 3-5 centers in the US each with a dedicated research budget of $5 – 10 million and make efforts to enroll other countries in producing similar centers. A funded grant opportunity (Request For Applications (RFA)) should be issued within one year to produce the outcome measures and studies needed create a validated research definition. (See research section for more.)

Identify Commonalities and Co-morbidities with Other Disorders – Produce a Conference to Highlight Them -   the panel recommended that Gulf War Syndrome, Lyme disease, fibromyalgia, multiple sclerosis, and Parkinson’s disease be studied alongside ME/CFS to discover commonalities and differences. A conference to enable discussion and interaction between researchers studying these disorders should occur.

Tightening

  • An NIH sponsored conference to examine commonalities and differences among ME/CFS, Gulf War Syndrome, Lyme disease, fibromyalgia, multiple sclerosis, and Parkinson’s disease and others should take place within one year.
  • The conference should lay the foundation for a $5 million RFA to further explore commonalities and differences in these disorders.

GAP – New Knowledge is Needed

Bench to Bedside ME/CFS Research is Recommended.

Bench to bedside or translational research is what Centers of Excellence do: they research (bench) and treat patients (bedside) in the same facility, yet the panelists don’t specifically recommend them — although they do recommend something that appears to be similar (See Collaborative Centers recommendation below.)

Tightening

  • Five Centers of Excellence should be established within two years, and five more within five years. (See Network  of Collaborative Centers below.)

GAP: Many Research Needs Are Present

“Determining the most important physiologic measures and pathophysiology, as well as genome-wide association studies (GWAS) and phenotyping, is essential for stratifying patients.”

test-tubes-blood

Many research needs were identified

The P2P panel recommends that a broad and deep effort employing the latest technology be mounted to understand the pathophysiological mechanisms at play in ME/CFS. Specifically they recommended priority be given to efforts to:

  • Develop biomarkers using genomic, epigenomic, proteomic, and metabolomic strategies.
  • Identify subsets using physiologic markers and genome-wide association studies (GWAS).
  • Use fMRI and other imaging studies to understand the neurological problems in ME/CFS.
  • Use cutting–edge technologies such as high throughput sequencing and neuroimaging to investigate the effects the gut microbiome has on ME/CFS.
  • Identify who is at high risk of getting ME/CFS, chart the geographical distribution of the disorder, and illuminate health care disparities (who has access to good medical care and who does not).
  • Develop algorithms to determine who is at high risk of coming down with ME/CFS after an infection.
  • Put the data from large “-omics” (genomics, proteomics, metabolomics, etc.) studies in publicly accessible databases that enable researchers to use data mining techniques to understand the  molecular mechanisms present, to do pathways analyses, and to aid drug companies in drug discovery/drug repurposing.
  • Identify immunological mechanisms and pathways (cytokines, inflammation, NK cell dysfunction) that contribute to the progression of the disease.
  • Use twin studies to identify differences in gene expression.
  • Investigate the effects (if any) of homeopathy, non-pharmacologic, complementary, and alternative medicine treatments. Studies addressing biopsychosocial parameters (including the mind-body connection), function, and QOL should be encouraged.

A National Biobank – A national registry/repository should be created to house the results of these studies and to help researchers better understand the pathogenesis, prognosis, and biomarkers present  in ME/CFS.

upwards

A key recommendation: spending on ME/CFS research be brought in line with that found in other disorders if similar size, prevalence and economic costs

Issue : The panel’s recommendation that a broad range of pathophysiological targets be explored is very helpful. Their unwillingness, however, to recommend specific federal spending targets, or specific grant programs (RFAs) could allow the federal government to fund one or a couple of studies from each section and say they met the recommendations.

The NIH is currently funding, for instance, at least one neuroimaging study, a gene expression after exercise study, a natural killer cell study and a microbiome study. Funding one or two studies in an area every four to five years means more of the glacial pace of progress that has characterized this field for decades. This is not the rate of progress that patients, the panel earlier noted, want and deserve, and it’s not the outcome that the P2P panel, judging from its otherwise very helpful report, wants to see.

Tightening

  • The NIH bring pathophysiological research funding for ME/CFS into line with that provided for disorders of similar size, economic losses, and disability rates (excluding comorbid disorders such as fibromyalgia, interstitial cystitis, etc. which receive low funding) within five years.
  • The NIH should produce a series of $5 million RFAs over the next three years to address critical questions regarding the role the immune, autonomic, and central nervous systems and metabolism play in ME/CFS.

GAP: Inadequate Methods and Measures to Assess Treatments and Identify Subgroups

tools

A Working Group should identify the right tools to assess ME/CFS

Throughout the report the panel referred to inadequate outcome and other measures. The NIH has been saying this for years, but without doing anything about it.  Now they get their chance.

Establish Methodological Working Group – to oversee the development of these measures, plus:

  • Online tracking tools should be utilized.
  • Immobile patients should be included.
  • A community-based research approach should be used to increase patient involvement in determining priorities for research and patient care.
  • Assess psychiatric comorbidities to assist with measurement of quality of life.
  • Long-term longitudinal studies already underway should include ME/CFS.

GAP: Provider Education Lacking

Few physicians understand how to treat or even to recognize chronic fatigue syndrome.

  • Use  accreditation and licensing programs to produce ME/CFS curriculum.
  • Use Health Resources and Services Administration (HRSA) to facilitate training.

Tightening

  • Create accredition program to license ME/CFS practitioners.

 GAP: Finding New Funding

The panel’s statement that a “relatively small number of researchers” are present in the field vastly overstates the number of researchers studying ME/CFS relative to other disorders and suggests the panel may not have quite gotten to the depth of the NIH’s neglect.

In the Finding New Funding Resources section a number of good, but at times somewhat vague, recommendations are given to address funding needs. The recommendation to create collaborative research centers is a highlight.

Create a Network of Collaborative Centers

research-network

A collaborative research network should be created to move the field forward.

The centers should determine diagnostic and prognostic biomarkers, do epidemiology (e.g., health care utilization), determine functional status and disability, create patient-centered QOL outcomes, and determine the cost-effectiveness of treatments and the role of comorbidities in clinical and real-life settings.

This promising recommendation with its research and treatment components sounds very similar to COE’s. Unless the panel is more explicit, though, the NIH could create two small, overburdened centers and say “job done”.

Tightening

  • Recommending that the NIH fund five COEs, each with a $5 million budget (?) over the next two years, and five more over the subsequent five years would go a long way toward enhancing research and improving access to medical care in  major cities.

Others

  • NIH institutions need to partner together to advance the research and develop new scientists for ME/CFS.
  • More investigator-initiated studies (grant applications) are needed. (How many more? And how? By producing RFAs?)
  • Career development pathways for ME/CFS researchers should be developed.
  • Small grants should target younger investigators to get them into the ME/CFS field.

The ME/CFS field desperately needs new researchers and younger researchers and career development pathways. That would be superb… but what it really needs – and what would solve most of these problems – is dedicated funding for research and, so far as I can tell, that means grant opportunities that come loaded with money; i.e. RFAs. While the spirit of the report suggests funded grant opportunities or RFA’s would be necessary to carry out the panel’s recommendations, the panel has not specifically recommended them.

Tightening

  • Patients, ME/CFS experts, and federal officials will work together to set a target for the number of investigator-initiated studies needed to bring research funding into line with the disorder’s effects and come up with ways to meet that target, including RFAs.
  • The NIH will produce a series of $5 million dollar RFAs over the next three years to address critical questions regarding the role the immune, autonomic, and central nervous systems and metabolism play in ME/CFS.
  • Smaller grants targeting young investigators should be produced every year for the next five years. At the end of five years the effectiveness of the small grant project should be assessed.

Adding Working Group Members

failure

Adding more working group members to a group that does not work will not help

Issue – This statement, “Opportunities exist within HHS to engage new ME/CFS working group members, to create efficiency, and to co-fund research that will promote diversity in the pipeline, eliminate disparities, and enhance the quality of the science,” reflects the panel’s understandable ignorance of the structural problems facing ME/CFS at the NIH.

The Working Group is at the top of the list of factors that have stifled – not advanced – opportunities for ME/CFS.  If the last fifteen years has shown anything, it has shown that relying on the Institutes to do anything meaningful under the aegis of the Working Group is a pipe dream.

With the buck not stopping at any of the institutes in the Working group, it’s easy to see why all have essentially washed their hands of it. Adding more members (NIMHD or NCI) to the already long list of Working Group members would, unfortunately, change nothing.

Tightening

  • Recommend that a commission of patient advocates, ME/CFS experts, and federal officials assess the effectiveness of the Working Group in supporting ME/CFS research,  identify structural factors that are impeding funding for ME/CFS, and provide recommendations for change.

GAP: More Clinical Trials Needed

  • Create a website for patient and clinician educational materials and clinical trials.
  • Utilize the NIH Clinical Center for clinical trials.
  • Explore opportunities to fast-track new therapies.

Multimodal treatment – The panel should take note of the enormous numerical disparity between behaviorally-oriented treatment trials and all other kinds of trials found in ME/CFS. The fact that CBT and GET have been the focus of some thirty clinical trials while no other treatment modality has, to my knowledge, received more than one, indicates the powerful  hold that behavioral studies, many of them UK and European government funded,  have had in the clinical trial arena.

While the panel stated that neither CBT nor GET should be considered a primary treatment, it might reflect that, given the history of bias in this disorder, that recommending multimodal clinical trials could be interpreted as recommending a biopsychosocial approach to treatment – an approach that has failed, after many efforts, to get at the cause of ME/CFS.  With so many other compelling research needs present, putting more money into that approach would be counterproductive.

Tightening

  • Multimodal – The panel should make explicit its recommendation regarding multimodal trials to ensure such trials involve drugs and other such treatments that affect pathophysiology.
  • FDA –  New pathways for drug development need to be developed that take into account the barriers found in large, poorly studied heterogeneous disorders that get little interest from drug companies such as ME/CFS.. A panel of patient advocates, ME/CFS physicians and experts, federal officials, and drug company officials should identify those barriers and provide recommendations to surmount them.

Patient Participation Emphasized

“Patients must be at the center of the research efforts, and their engagement is critical” – P2P Draft Report

The panelist made explicit one feature that applies to most of it’s the recommendations: patient involvement is necessary.

Conclusions

funding

Following the P2P reports recommendations would require the federal government to spend money – much more money on ME/CFS…Will they?

In their conclusions, the panel added more recommendations, among them that the Oxford definition be retired. In the interim, they recommended multimodal therapies be employed until a cause and primary therapies are developed. They recommend that federal departments, advocacy groups, and industry work together in public-private partnerships to help advance research for ME/CFS. Federal agencies (e.g., AHRQ, the U.S. Department of Veterans Affairs [VA]) and professional societies should work together to create quality metrics and a standard of care.

Were the federal government to follow the spirit and letter of the P2P draft summary recommendations they would need to — for the first time –spend some real money on ME/CFS. That would probably require re-organizing the way the program is currently maintained and funded. ME/CFS has little chance of advancing significantly under its current structure, and a re-evaluation of the program’s funding mechanisms should be a natural outcome of a report that has exposed so many needs after almost thirty years of research.

The P2P recommendations are not perfect. I believe they need to be significantly tightened up, and numerical targets, in particular, be attached to them. It’s puzzling in particular to me, given the lack of research funding, that the panel did not explicitly call for RFAs.

The panel is essentially recommending, however, that the federal government finally get serious enough about the ME/CFS field to provide it the benefits that other major disorders enjoy: sufficient research funding, collaborative networks, Centers of Excellence, RFAs, validated outcome measures, and a place in the medical curriculum. That would include educating doctors,and enrolling young new researchers in ME/CFS career paths. It’s a potential game-changer.

Now it’s up to us to support the federal government in carrying out the recommendations their own panel has produced.

P2P Panel Surprises – Points Out Vast Needs For Chronic Fatigue Syndrome: Pt I

December 29, 2014

The goal of the Pathways to Prevention (P2P) program is to… identify research gaps in a scientific area, identify methodological and scientific weaknesses.., suggest research needs, and move the field forward through an unbiased, evidence-based assessment of a complex public health issue. The National Institutes of Health

In a surprise the P2P panel “got” the major issues facing ME/CFS

The expectations for the Pathways to Prevention report were, to put it mildly, low. The report’s reliance on four outside experts none of whom, by design, had any experience with chronic fatigue syndrome raised fears. Fifty-one percent of respondents in a Health Rising poll felt outside experts probably shouldn’t be reviewing ME/CFS. Sixty-nine percent had low trust that outside experts could be objective, and seventy-nine percent had low trust that the outsiders could get major issues right.

After all the worries over whether the Pathways to Progress (P2P) panel – none of whom had any expertise in this disorder – could possibly “get” chronic fatigue syndrome and, in fact, might set it back for decades, just the opposite happened: the P2P panel actually “got” ME/CFS, and they produced a report which, if implemented, would push it forward significantly.

Coming from independent, outside experts and relying in part on another independent review (AHRQ report), the 19 page draft reports findings – that ME/CFS has been understudied, that patients have borne the consequences of that neglect, and that a vast increase in the commitment to understand and treat this disorder is needed – should have all the more impact. In the end, the data, as Dr. Bateman suggested it would, won out, and Bob Miller’s sense – he was the patient advocate in the early stages of the process – that the panel was listening and working hard ended up being correct.. A review of the first half of the report follows. A review of the critical recommendations section is next.

Medical Community Fails Chronic Fatigue Syndrome Population

The report begins by citing the high rates of disability and economic costs, and then lays the extraordinary burdens people with ME/CFS face directly at feet of a medical community that has essentially failed in its core commitments to assist and provide care. “ME/CFS is an area where the research and medical community has frustrated its constituents by failing to assess and treat the disease and by allowing patients to be stigmatized.”

Medical Community Neglect Leaves ME/CFS Community with Heavy Burdens

Over the last 20 years, minimal progress has been made to improve the state of the science for patients with ME/CFS, and the public and provider community is frustrated. P2P Report

The report evocatively protrayed the burdens the ME/CFS community faces

The panelists “got” to a surprising degree the heavy burdens ME/CFS patients have borne by confronting an often uncaring medical system. It excoriated a medical system that often treats people with ME/CFS with “disdain, suspicion, and disrespect” and considers them “lazy, deconditioned, and disability-seeking”. These outdated and untrue themes, the P2P asserted, have hampered scientific progress and have led patients to be treated inappropriately with psychiatric drugs that have not helped and at times caused harm.

The panel cited the heavy emotional burdens caused by “frequent and negative interactions” with the medical community ME/CFS patients must carry. The stigma that surrounds ME/CFS leads to patients being isolated. Financial distress is common. The report’s statement that the lack of available medical options “usually”, not sometimes, but “usually” requires patients to “make extraordinary efforts, at extreme personal costs, to find a physician who will correctly diagnose and treat ME/CFS symptoms” indicates that the panel understood how underserved this population is, and provides a strong foundation for the ME/CFS community to press for federally sponsored Centers of Excellence.

Inability to Resolve Fundamental Issues Thwarts Progress

“ME/CFS results in major disability for a large proportion of the people affected. Limited knowledge and research funding creates an additional burden for patients and health care providers.”

Fundamental issues thwart the field from getting better results

The report will assert again and again that the failure to resolve fundamental issues has thwarted efforts to understand and treat this disorder. The inability of the research community to develop “consistent, specific, and sensitive” diagnostic tests and criteria (a definition) has, they stated, hampered all downstream research on pathogenesis and treatment, thereby causing harm”.

Citing small sample sizes, problems with the instruments used to evaluate patients, problems defining ME/CFS patients versus others, the report agreed with the AHRQ draft report’s findings that significant methodological problems have thwarted understanding of this disorder. [One sometimes wonders what the field has done right :). In the end, though, it’s not the researchers so much as basic elements they’re missing – validated endpoints, well-funded studies, a clear and concise definition – as well as some things they haven’t been doing (specificity, sensitivity, including other disease groups) that are getting in the way of their efforts bearing real fruit. These critiques may be painful, but they do provide valuable guidelines – and they provide issues the ME/CFS community can use to advocate for increased support.]

ME/CFS “In”

Addressing the “wastebasket” theme held by many researchers and doctors, the panel simply and powerfully stated, “ME/CFS exists” and referred to it as a “distinct pathologic entity” the causes of which remain unknown.

Oxford Definition – Out

Echoing a P2P panelist’s statement during the recent P2P Workshop that the Oxford criteria should be retired, the panel stated that the flawed Oxford criteria were confounding the science by allowing people with other disorders to participate in “CFS” studies.

Inadequate Research Funding Noted

ME/CFS is an area where the research and medical community has frustrated its constituents, by failing to assess and treat the disease and by allowing patients to be stigmatized. P2P report
The report’s highlighting of “the lack of well-controlled, multifaceted studies using large, diverse samples, and the limited research dollars directed at ME/CFS from both the public and private sectors” should prove invaluable in advocates’ quest to finally get an sufficient federal response to ME/CFS.

Disorder Faces Unique Challenges

ME/CFS faces challenges other disorders do not face

Remarking on the “unique challenges to ME/CFS” the panel appeared to understand, as well, that they were dealing with a disorder that faces challenges that few other disorders do. When asked how to foster innovative research to produce treatments they noted that twenty years of research has produced scant progress leaving patients frustrated.

ME/CFS is Not a Psychological Disorder

Patients want … a meaningful recovery (not just incremental improvement) P2P Report
Importantly, they asserted that, while psychological repercussions often follow ME/CFS, it is not a psychological disorder. ME/CFS overlaps with many other disorders including fibromyalgia, major depressive disorder, and a variety of chronic pain or inflammatory conditions. [Finally, inflammatory disorders are included as a co-morbid condition.] Fatigue is an essential component, but does not nearly begin to “capture the essence of this complex condition.” The panel got the constellation of important symptoms right: fatigue, post-exertional malaise, neurocognitive deficit, and pain. The panel did not [and could not in my opinion given the lack of studies in this area] endorse a single definition for ME/CFS, but their statement that a “clear case definition with validated diagnostic tools is required” will enhance efforts to get the NIH to fund studies to produce a statistically determined research definition that will propel this field forward. Their statement that it is “critical” to include homebound (“non-ambulatory”) patients in studies will, hopefully, spark efforts in that area as well.

CBT/GET Downplayed

CBT and GET….are not a primary treatment strategy. P2P Report
The Panel took the very moderate findings from the AHRQ draft regarding CBT/GET and moderated them even more, stating, in what will be music to many ears, that because neither therapy shows improvement in quality of life, they should not be considered “ a primary treatment strategy”. (The CDC Toolkit, in the P2P panel’s eyes, now contains no primary treatment strategies.)

Doctor’s Lack Basic Understanding

Most doctors lack basic knowledge of the disorder

Doctors lack understanding of basic management skills (pacing, realistic goals, basic rights, understanding of emotions, exercise, relaxation) that can be helpful. Too strenuous exercise programs in the past have turned some patients off to milder, more appropriate exercise regimens (they mentioned stretching) that can be helpful.

Laundry List of To Do’s

The laundry list of “to-do’s” for ME/CFS is long indeed and feature basic research elements this field has not yet produced or hasn’t had the money to utilize. Standard and validated tools and measures are missing, studies are too small to identify subgroups, endpoints need to be clarified, and clinically meaningful symptoms are not being assessed. In perhaps a critique of the European emphasis on behavioral studies, they noted that the biological factors causing and promoting ME/CFS are often neglected in research studies.

Promising Avenues for Future Research Cited

In contrast to the AHRQ’s report that simply wiped out most ME/CFS research findings because of methodological problems, the P2P draft report asserted that “strong evidence” indicatesthat the potent avenues for future research include the immune system, metabolism (exercise), the mitochondria, neurotransmitter signaling, and the microbiome [but not the autonomic nervous system?]. Their call for large, multi-center studies with diverse groups of patients (to replace the small studies typically done now) can only help advocates’ efforts to increase funding. Research priorities should focus on finding biomarkers and developing treatment options. Key research needs include:

Determining the pathogenesis of ME/CFS, in particular the role herpesviruses and other viruses play in triggering the disorder is critical. Encouragingly, the authors plucked out the role infectious mononucleosis (IM) plays in adolescents. (This should be included to include the role IM during adolescence plays in adults coming down with ME/CFS later.) They also highlighted

  • Understanding that the genetic predisposition present.
  • Is ME/CFS a spectrum disorder?
  • Are different pathways responsible for different symptoms?

Conclusion

“We noted … the limited research dollars directed at ME/CFS from both the public and private sectors. P2p Report”

In a surprise, the panel of outside experts – none of whom had any experience with ME/CFS – mostly “got it” about ME/CFS. Any report will have shortcomings and this one will as well, but the list of ways the panel got it right is impressive. The report suggests that, given enough time and information, outside experts can be trusted to understand.

ME/CFS faces many challenges. Next up – the Panel’s recommendations…

Halfway through the Pathways to Prevention report, it’s identified many barriers to progress and has provided the ME/CFS community ample opportunities to press the federal government for change. The panel is in agreement on many longstanding issues that advocates have asserted plague ME/CFS, including paltry public and private research funding, lack of knowledgeable doctors, poor patient care, and a stigmatization of ME/CFS the medical community has fostered and allowed to continue.

The report downplays the significance of CBT/GET treatments, states the Oxford Definition is causing more harm than good, and, in agreement with the AHRQ report, provides a list of basic issues that need to be resolved. The future research section missed some points (such as the autonomic nervous system) and may have over-emphasized others, but it always focused on pathophysiology.

The report got the major issues right. We’ll see how they do in the all important Future Directions and Recommendations section next.

Study Suggests Hormones, Autoimmunity and/or Viruses at Work in ME/CFS

December 15, 2014

Age Patterns Provide Pointer

A Norwegian study of ME/CFS patient records that found two age peaks in Chronic Fatigue Syndrome, one starting from ages 10-19, the other from 30-39, could tell us something about the disorder.

Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008–2012   Inger Johanne Bakken1*, Kari Tveito2, Nina Gunnes1, Sara Ghaderi1, Camilla Stoltenberg1,3, Lill Trogstad1, Siri Eldevik Håberg1 and Per Magnus1 Bakken et al. BMC Medicine 2014, 12:167

mountain

ME/CFS can occur almost any time but two distinct age-related peaks showed up in a Norwegian study …What does it mean?

It wasn’t as if people of other ages didn’t come down with Chronic Fatigue Syndrome – many people in other age groups did – but the numbers of ME/CFS cases spiked in these age groups.

The least likely times to come down with ME/CFS were at the two ends of the age spectrum: from 5-9 and after the age of 55.

Just 121 cases were reported from ages 5-9, but after the age of nine the incidence of ME/CFS spiked up sharply with almost 700 cases reported from ages 10-14 and 15-19. From 20-29 it dropped about 30% with about 500 cases reported, and then zoomed up again to about 700 cases from ages 30-39. From ages 40-44, 45-49, 50-54 declined until at ages 55+ the incidence was very low indeed.

That’s in contrast to many disorders which get more prevalent as we age.

As in other surveys, young female and adult women in their most productive years were much more likely (75%) to come down with ME/CFS than men.

What does it all mean?

Females Dominate

The high rate of females with ME/CFS combined with the unusual pattern of incidence points a finger directly at female hormones.   Three periods of major hormonal fluctuations occur in women; during puberty, during pregnancy and during menopause. Spikes in ME/CFS incidence occurred during two of these; puberty and when women often get pregnant, but not during menopause.

Sex Hormones, ME/CFS and IBS

make-female

As expected females dominated

A CDC study indicating women with ME/CFS have greatly increased rates of gynecological disorders also suggested that sex hormones could play a major role in the disorder. Despite the female predominance in ME/CFS and FM sex hormones have not been well studied in either disorder, but they have been better studied in another female dominated disorder  that often co-occurrswith ME/CFS and Fibromyalgia – irritable bowel syndrome.

The same pattern of disease development over time is found in IBS. The incidence of IBS peaks in women from their teens to about their mid-forties and then declines over time. By the time women reach their seventies their incidence of IBS drops to that found in men.

Estrogen

Estrogen is the major female  hormone produced. Its many effects on the body and its widely varying production had made it difficult to  study, but Broderick’s ME/CFS model suggests that estrogen triggered dysregulation of the HPA axis may play a key role the development of Chronic Fatigue Syndrome in females.

That’s Low Estrogen – If estrogen plays a role it’s probably low not high estrogen levels that are the problem. Estrogen effects neurotransmitter production and activity and electrical excitability, and has a neuroprotective effect on central nervous system functioning.

estrogen

Estrogen has many effects on the body. It surely plays a role somewhere – but where?

Pain Connection – Some evidence suggests low estrogen level may play a role in chronic pain.  The greater degree of emotional arousal women with IBS display in response to pain could reflect reduced estrogen levels. The association of high estrogen levels with increased opioid receptors suggests higher estrogen levels may reduce pain.

Gut Connection – Female hormones not only influence gut motility – a key feature of IBS – but also gut secretions, gut contractions, immune functioning and pain sensitivity. The fact that about a third of women with IBS issues have them only during menstruation again suggests reduced sex hormone levels could play a role.  Reduced hormone levels during menstruation have been linked to abdominal pain and bloating.

Overall, the evidence suggests that estrogen probably plays a protective role in IBS, multiple sclerosis, pain disorders and possibly chronic fatigue syndrome.  However, the lower incidence of ME/CFS during menopause – when estrogen levels tend to be low – suggests that more than estrogen is  involved.

A Positive Role for Male Hormones

In contrast to women, age appears to play little role in the development of IBS in men:  they experience no significant changes in IBS incidence throughout their lifespan.

menstrual

IBS symptom flares in the premenstrual period implicate estrogen

Male hormones often get a bad rap :) but the lower rates of incidence and the lack of a discernible pattern of incidence in men suggests they may have a protective function. Broderick’s modeling studies suggest that male hormones such as testosterone are protective in ME/CFS and some evidence suggests the same may be true in IBS.

Testosterone also appears to have pain reducing properties that provide protection against the development of pain disorders.  Low testosterone levels in men, for instance, have been associated with increased sensitivity to rectal pain.  Some men with ME/CFS have find testosterone supplementation helpful.

Hormones, or the lack of them, may very well be a contributing  factor to getting ME/CFS, but the spikes in incidence also point a finger at two other factors: viruses and autoimmune disorders.

The Viral Connection – Epstein Barr Virus

Spike in Adolescence  – The increasingly late exposure to the Epstein-Barr virus found in the Western world could contribute to the spike in ME/CFS prevalence in adolescence.

Exposure to EBV in infancy, when cytotoxic T-cell levels are at their highest, is usually hardly noticed, but a first exposure to EBV in adolescence often results in a severe illness such as infectious mononucleosis/glandular fever  –  which appears to trigger ME/CFS in about ten percent  of patients.

gone-viral

The earlier age peak could, in part, reflect late EBV exposure

Spike in Middle Adulthood – Attributing the spike in ME/CFS prevalence in from 30-39 to EBV activation is a bit more difficult. Pregnancy in combination with the stress of child rearing could help explain it, however.

EBV reactivation in response to stress is well documented, but EBV reactivation also commonly occurs during pregnancy. One study found EBV reactivation in 35% of pregnant women by the second trimester and reactivation rates may be as high as 50% in pregnant women experiencing depression or high rates of stress.

Dramatic changes in estrogen,  progesterone and interestingly enough, cortisol – given Broderick’s model of ME/CFS – also occur during pregnancy.

Pregnancy is  also  associated with an increased risk of autoimmune disorders and the incidence of  MS increases in the first six  months after pregnancy.

Reductions in symptoms that often also occur in existing cases of ME/CFS and multiple sclerosis during pregnancy are believed to reflect spikes in estrogen.  (Anti-inflammatory cytokines that spike during pregnancy could play a role as well.)  Coming up shortly we’ll explore an estrogen targeting drug for MS that could possibly spell good news for people with ME/CFS and FM.

Set to Up to Fail? - Studies indicating that infectious mononucleosis increases the risk of coming down with multiple sclerosis later in life two-threefold raises the question whether a similar pattern might exist in chronic fatigue syndrome. Could a severe case of mononucleosis as a teenager set you up for getting ME/CFS several decades later?

Autoimmune Disorders

A similar age-related  incidence pattern is also found in some autoimmune disorders. Lupus is most commonly diagnosed between the ages of 15-35. Multiple sclerosis (MS) is most commonly diagnosed in people between the ages of 20 and 50 years.  Sjogren’s  Syndrome typically begins in the same “middle adult” years  that ME/CFS spikes are seen in.

Conclusion 

complex-issue

The age peaks may reflect a complex array of factors that coincide during certain periods to raise incidence levels.

The age spikes  found in this study  suggests chronic  fatigue syndrome shares  features with several other disorders.  Similar patterns of incidence in IBS, multiple  sclerosis, lupus and Sjogren’s Syndrome, and high rates of female predominance also occur in some autoimmune disorders (systemic lupus erythematosus (SLE; females:males – 9[ratio]1), autoimmune thyroid disease (8[ratio]1), scleroderma (5[ratio]1), rheumatoid arthritis (4[ratio]1) and multiple sclerosis (3[ratio]1)).

Determining what the spikes mean will  take time and much in the very complex interactions involving hormones and the immune system. The evidence suggests that a constellation of factors, perhaps involving hormones, immune activation, central nervous system excitation, and in some cases viruses play a role in producing ME/CFS.  This study highlights “danger points” when women may be particularly vulnerable.

The reduced incidence of ME/CFS and autoimmune and pain disorders in men, on the other hand, may reflect the protective effects male hormones provide.

Next Up – a possible breakthrough multiple sclerosis drug that affects estrogen activity. Could it have potential for ME/CFS?

Drug Combo in Pridgen Antiviral Fibromyalgia Trial Identified – Some Results Available

A lengthy article originating on the University of Alabama website and an  abstract presented to the American College of Rheumatology Conference indicates that the two drugs Dr. William “Skip” Pridgen and virologist Carol Duffy PhD used in their Fibromyalgia antiviral trial were Famciclovir, better known as Famvir and Celexicob, best known as Celebrex.

The report also indicates that  Duffy found only herpes simplex – 1 viruses (HSV-1) in the gastrointestinal tissues of the FM patients. Neither of these drugs nor this type of herpes virus have been commonly used or associated with chronic fatigue syndrome.

HSV-1

Duffy found only herpes simplex-1 viruses in the gut tissues of FM patients

We also learned Pridgen discovered the two drug combo similar to the way Fluge/Mella uncovered Rituximab in chronic fatigue syndrome – by observation. Suspecting that herpes viruses might be to blame for the gastrointestinal issues in his patients, Pridgen started them off on Famvir.  The drug helped but symptoms remained.

After Pridgen noticed much greater improvement in the symptoms of the patients also put on Celebrex for their arthritis he combined the two drugs – for everyone.

In the University of Alabama article, Duffy reported the improvement on the two drug combo was immense.

““The patients who took both drugs, however, came back and said everything was better. Their fibromyalgia was gone. Their chronic fatigue was gone. Their headaches were gone. All of these things had cleared up. When the first few patients approached him, he thought it was a fluke, but as more and more and more patients said the same thing, he knew it couldn’t be a coincidence.”

The Triad

That drug combo never been used in herpes virus infected patients before, but it made sense to Duffy. She knew that some herpes viruses  increase the production of COX-2, a pro- inflammatory enzyme. While Famvir stopped the herpes viruses from replicating, Celebrex weakened the viruses, making them “unstable”.  Since Celebrex also has some antiviral properties, the drug combo hit the virus in three ways.

Famvir

Famvir

Famvir – rarely mentioned in ME/CFS – was the antiviral of choice for Pridgen

Valtrex, Valcyte and Vistide are often used to treat herpesvirus infections in chronic fatigue syndrome but Famvir is rarely mentioned. (Dr. Dantini appears to use Famvir frequently to treat his ME/CFS/FM patients.)

One of the reasons may be that Famvir is mostly used to treat herpes virus infections such as herpes simplex virus, herpes simplex virus 2 (genital herpes) and herpes labialis that have not been typically associated with ME/CFS.

The Newcomer – Herpes Simplex

Duffy scoured the gastrointestinal tissues of 45 patients for a virus. In the end it wasn’t EBV, cytomegalovirus or HHV-6 that showed up, but herpes simplex virus-1 (HSV-1) – the very virus she’s been studying in her lab.  (That’s a little scary, but a technique called immunoblotting was used to ensure contamination had not occurred.)

Herpes simplex virus is best known for its ability to cause cold sores and genital herpes, but according to a Wikipedia article can also cause  herpetic whitlowherpes gladiatorumocular herpes, cerebral herpes infection encephalitisMollaret’s meningitisneonatal herpes, and possibly Bell’s palsy.

HSV-1

The group believes HSV-1 could be affecting many different tissues in FM and other disorders

HSV-1 can infect various organs in the body including the peripheral and central nervous systems, upper respiratory tract, and gastrointestinal tract. It may play a major role in Alzheimer’s. It’s able to deplete mitochondrial DNA. One article suggests herpes simplex virus may be better adapted to take advantage of poorly functioning natural killer cells than any other herpes virus.

The group believes HSV-1 may be responsible for fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome and perhaps other disorders. A video on the Innovative Med Concepts website indicates the virus can attack the facial, gastrointestinal and pelvic regions and that it ultimately takes up residence in the vagus nerve.

It took Pridgen and Duffy about a year to raise the $4 million dollars for the 100 person plus phase II trial to assess the drug combo’s efficacy and safety.  Along the way they enrolled a member of the drug team that brought Savella to market in FM, and a past president of Pfizer in their effort at Innovative Med Concepts.  Noted FM researcher Daniel Clauw joined their advisory board.

Conference Abstract Provides Results

An abstract presented at the ACR conference yesterday suggested the drug combo produced strong improvement in some measures and not as strong improvement in others. The changes in pain using the revised Fibromyalgia Impact Form appeared impressive (p< 001) as did changes in function and symptoms (p<.004) and overall impact (p<.003). Fatigue was significantly improved but less so (p<.02).

stop-pain

Changes in pain were impressive. Fatigue was improved but not as much

However, only 33% of patients (vs 19% of those not on it) met the criteria for a secondary measure called the  Global Impression of Change Scale which asked about changes in a person’s activity, limitation, symptoms, emotions and quality of life. It‘s not clear how to parse the more impressive results in some of the tests with less impressive results in the last one.

The drug combination was judged very safe with more adverse events found in the placebo group than in the patients taking the drug.

Improving Efficacy Efforts Underway

If the trial wasn’t a complete win it nevertheless produced significant improvements in a notoriously difficult to treat illness.  Since fibromyalgia, like chronic fatigue syndrome, is believed to be a quite heterogeneous illness asking any drug or drug combo to be effective in everyone is unrealistic.

Phase III Trial Will Tell the Tale

tablets

Finding the optimum dose will be a key aim of the big trial

Designed to  assess basic aspects of efficacy and safety, Phase II trials are not the last word in efficacy. As the Pridgen/Duffey team proceeds to the Phase III trial  they’re exploring several ways to bump up efficacy. Duffy is working on diagnostic tests to identify which FM patients are most likely to benefit from the combo, and is doing toxicology tests to determine if higher doses are feasible. The optimum doses of the drug combo will also be determined in the Phase III trial. Expect efficacy rates to rise.

Big Trial Ahead

Next up is the big third phase trial – a jaw dropping $50-100 million trial the FDA needs in order to approve the drug combo for the treatment of fibromyalgia.

No one is satisfied with the state of fibromyalgia treatment – and few have looked to the immune system or to pathogens. If the results of this trial are not breathtaking – they are still very good –  and will hopefully improve as the therapy becomes better targeted.  They should begin to prompt a revaluation of what’s going on FM.

The publication of the study is probably just around the corner….

Going Grassroots: Dr. Unger on the CDC’s Chronic Fatigue Syndrome Multisite Studies

November 8, 2014

The CDC’s Chronic Fatigue Syndrome Multisite Studies

The CDC multisite studies will hopefully change the way physicians think about Chronic Fatigue Syndrome, identify subsets, open up treatment options, provide outcome measures for clinical trials, validate the significance of post-exertional malaise and basically help legitimize ME/CFS.  That’s a lot to ask, but then again these are large studies,  the likes of which we’ve never seen before.

high-stakes

With the CDC focusing most of their resources on the study, the stakes are high.

The stakes are pretty high for Dr. Unger’s CFS team. They  haven’t exactly  been lighting  up the research world with their ME/CFS publications. The last one – on a patient registry – was published over a year ago and publications were pretty spotty  before that. The last really interesting CDC study was a gynecologic study published in 2011.  One ME/CFS expert bluntly  told me “Don’t expect breakthroughs from  the CDC – that’s not what they do”.

Dr. Unger has stated the CDC’s CFS team is devoting most of their energy  to the multicenter studies. If major insights don’t come out of them quite a few people are going to be surprised and disappointed.  They should start appearing in the not too distant future.

To get ready for that, first-we check out an ME/CFS Alert  interview with someone who was smack dab in the middle of all the moving pieces –  former Simmaron research assistant Gunnar Gottschalk – and then present an  interview with  Dr. Unger of the CDC about the studies and other matters.

Gunnar Gottschalk on on the Simmaron Research Foundation and  the CDC’s Multisite ME/CFS  Study

 

 

Background – The Open Medicine Institute Opens the Door

Dr. Kogelnik with his double PhD in medicine and computer science is doing his best to usher the ME/CFS field into a new age. Kogelnik believes lots of data is going to be needed to understand Chronic Fatigue Syndrome. In order to get it he struck a deal with a network of top ME/CFS physicians.  He would give them electronic data bases and show them how to use them and they would provide him with numerically identified data (no names) he could use to assist his  research.

medical-records

Hundreds of hours were spent putting decades of medical records into the database

Everybody won.  With their almost 40,000 charts the Simmaron Research Foundation and Sierra Internal Medicine (Dr. Peterson’s practice) had been almost drowning in immune data. It took hundreds of hours to get the data processed, but whereas accessing that data before required a chart by chart review now it simply requires telling the computer to search for, say, NK cell functioning test results.  The updated approach laid the foundation for Dr. Peterson and the Simmaron Research Foundation to participate in research studies with top  researchers. It also opened the door for the multisite studies.

When some money got freed up at the end of the year Dr. Unger asked for proposals.  Kogelnik jumped at the chance and submitted a grant for a multisite study examining patients at ME/CFS expert’s practices across the country. Unger snatched up Kogelnik’s proposal and added more sites and the multisite study, now the main focus of the CDC’s ME/CFS research group, was born.

The Sites

  • Dr Lucinda Bateman (Fatigue Consultation Clinic, UT)
  • Dr. Nancy Klimas (Center for Neuro Immune Medicine, FL)
  • Dr Andreas Kogelnik (Open Medicine Clinic, CA)
  • Dr Charles Lapp (Hunter-Hopkins Center, NC)
  • Dr. Benjamin Natelson (Pain and Fatigue Study Center, NY)
  • Dr Daniel Peterson (Sierra Internal Medicine Associates, NV)
  • Dr Richard Podell (Richard Podell Clinic, NJ)
klimas-nsu

Dr. Klimas’ Institute For Neuroimmune Medicine in Miami is one of the nine centers involved

Gunnar stated the motto behind the study was getting the CDC on the ground grass-roots style and take close look at ME/CFS patients.  The multisite study is going to give the CDC, he said, a sense of what this illness really is. What are the primary symptoms? Do you have a history of viral infection or autoimmune disorder? What illnesses run in the family? How sick are these patients? How long have they been sick? What do they test positive for? (What do they test negative for?)

For the first time the medical world and the CDC is going to view Chronic Fatigue Syndrome patients, not through the filter of the CDC’s Toolkit or the dumbed down sites on the Mayo Clinic or WebMD, but through the eyes of expert practitioners trying to help them.

Standardized Approach Aids Subset Search 

The doctors came together with the CDC to produce a standardized intake form which included newer, simpler ways of measuring fatigue and other symptoms.

(The group clearly was not satisfied with the current symptom assessment tools used in ME/CFS. The AHRQ panel was not particularly satisfied with them either and reported that no validated tools exist for ME/CFS. That’s a big problem. Somehow you have to find a way to measure fatigue, even if it’s only to determine that a biomarker is actually a biomarker.)

Standardized testing will  greatly enhance the  search for subsets

Standardized testing will greatly enhance the search for subsets

They also agreed to a standardized testing protocol. Before the study these practitioners used different tests to assess the health of their patients. They still do their own tests, but now all patients in the study get a core set of tests. Dr. Peterson’s patients,for instance, will get a comprehensive immune workup that includes everything from NK cell numbers and function and IgG subclasses to clonal T-cell rearrangements, but they’ll also get a standard set of tests.

This group, then, did two things right off the bat the AHRQ panel was calling for; they developed (hopefully) better symptom assessment tests and agreed to a standardized testing protocol.

If subsets don’t pop out after all this everyone is going to be surprised.  Besides characterizing the patients in every way possible (symptoms, disease history, medication use, treatment outcomes, test results) the study may help develop outcome measures for clinical trials. Developing “outcome measures” – standardized tests drug companies could rely on to determine if their products were making a difference in ME/CFS – would be a big deal.

The CDC will also continue to follow up the patients over time to determine how the disease proceeds.

Expansion – the Second Phase of the Multisite Study

The first phase of the multisite study has been finished and we’re awaiting publication of the results.  The CDC study was already very large – 75 patients at each of the 8 sites – and in the second phase, if I have it right, it gets much larger (150 persons at each site.) If those numbers are correct this is easily the biggest ME/CFS study ever undertaken.

Pediatric patients, healthy controls and people with similar illnesses are being added to the second phase of the study and biological data will be collected specifically for the study for the first time.

That biological data includes salivary cortisol awakening levels, gene expression and lactate levels before and after a 1-day exercise test and ‘exercise capacity’.  The blood will be banked to aid future research efforts.

Interlude: The Simmaron Research Foundation’s BioBank Multiple Sclerosis Study

Gunnar spoke about the Simmaron Research Foundation’s BioBank. The BioBank doesn’t get mentioned a lot, but with 6,000 specimens it’s one of the largest in existence and with samples dating back   decades it’s certainly the oldest. The jewel in its crown are its unusually large number of the spinal fluid samples – something Dr. Mady Hornig has called ‘a treasure’.

The Simmaron Research Foundation contracted with the Chronic Fatigue Initiative to analyze 60 of those samples and compare them to  people with multiple sclerosis and healthy controls.  That study got more interesting when a recent study found very low levels of a neuronal repair agent called BDNF in both multiple sclerosis and ME/CFS patients.

A Talk with Dr. Unger

 “Publishing this information is a priority”

unger-cdc

Dr. Unger put her stamp on the CDC’s ME/CFS program with the multisite project

You’ve done a lot of outreach including visiting the clinics involved in the multi-site study. Can you say one thing that surprised you or stuck in your mind from your visits to the different clinics?

It was really a pleasure visiting the clinics and meeting those who care for CFS patients and work so hard on making sure the study is a success.  While the style of each clinic varied, I was impressed by the care taken to make the waiting and examination rooms accommodate the special needs of CFS patients.  In each clinic, the staff provided positive energy and empathy for their patients and it was clear how important these intangible items are to the patients.   The experience emphasizes the need for us to work towards the time when all CFS patients will have access to the level of care provided in these clinics.

Preliminary information on the CDC multi-site studies for CFS was provided at an FDA meeting a year and a half ago, but no studies have been published and no presentations on the studies were given at the IACFS/ME conference. Can you tell us roughly when the studies will start to be published. What subjects will the published studies be on?

At the time when abstracts for IACFS/ME were due, the interim analysis presented at the FDA meeting was publicly  available and therefore not appropriate to submit as new information. We were in the process of finalizing and verifying (sometimes called “cleaning”) the final dataset for the baseline year of enrollment into the multi-site study.

We are now conducting analyses on these data and will write the papers and submit them to peer reviewed journals as soon as we can.  The first paper will describe the characteristics of patients and their illness as measured by the questionnaires they completed.  All patients enrolled in the baseline study will be included.

Subsequent papers will describe additional features, such as medication use and medical history.  The total time to write, clear, submit and have the articles peer reviewed is difficult to estimate. Publishing this information is a priority, and we will move this process along as quickly as possible.

Treatment and Testing

“The long-term goal is to identify biologically meaningful subgroups so that the design of treatment trials could be refined, both in terms of those enrolled and outcomes measured”

Are you examining treatment effects in the second part of the study?

physician

Treatment efficacy will be highlighted in the second phase of the multisite studies

As patients return to the clinics, we are collecting follow-up information about the characteristics of their illness.  We plan on doing this over several years to get an idea of whether/how their illness changes with time.  This information, often referred to as “disease course,” will reflect both treatment effects and the natural history of the illness.  We are collecting information on medications and therapy, so a correlation between disease course and treatment could be made.

However, information from this observational study (i.e., a study that collects data without introducing a specific intervention) will provide only indirect evidence of treatment effects.

[This excellent news indicates that the second part of the study will, for the first time ever, report not just on the wide variety of treatments used by ME/CFS experts, but on their efficacy.  The report will lack the weight of an interventional study but documenting the efficacy of the wide range of treatment approaches – from antivirals to beta blockers to blood volume enhancers – should  open eyes in the medical community.]

Could this part of the study be used to broaden physician understanding of the appropriate diagnostic tests for Chronic Fatigue Syndrome? Do you expect that the CDC might, based on the data collected, update their recommendations for diagnostic testing in the Toolkit? 

Summarizing the tests used by our clinicians is only one step in understanding the best diagnostic practices for CFS.  We hope that this will form the basis for dialogue between clinicians about the rationale for each test and how they use the test results to improve treatment.  This study information, along with other evidence-based research, may enable updates to future CFS educational materials.

“One of our goals is to use data from this multi-site study to help refine sub-groups of CFS”

I see that lab test data is being gathered for the multi-site study. Does that mean we can expect a study at some point indicating what percentage of people with Chronic  Fatigue Syndrome at these clinics test positive for, say, IgG subclass deficiencies or orthostatic intolerance or even reduced aerobic capacity (understanding that not all practitioners test for them)?

medical-testing

A records review will determine what types of tests and their results ME/CFS experts use to assess their patients health

We have included a record review of testing in order to provide information on the different kinds of tests that CFS expert clinicians find helpful in managing CFS patients.  Because testing is not uniform (not all clinicians order the same tests for their patients) and not random (testing is guided by the individual patient’s symptoms), test results from record review will not be a good estimate of the percentage of CFS patients with test abnormalities.  Tests that are being done as part of the study, such as a measure of orthostatic intolerance that is part of the physical examination or wakening cortisol response, should be available for most patients and will be reported.

In an earlier interview you stated that “The study is expected to provide data to support new initiatives throughout the CFS research community.” What kind of new initiatives do you expect the study might support?

One of our goals is to use data from this multi-site study to help refine sub-groups of CFS and provide information on reliability of measures of illness.  Findings from this study will require validation by others.  Similarly, the validity of patient subgroups suggested by other studies could be tested in our data.

The long-term goal is to identify biologically meaningful subgroups so that the design of treatment trials could be refined, both in terms of those enrolled and outcomes measured.  In addition, the biorepository we are building will be linked to carefully curated patient data.  This could be used by researchers to refine or validate promising biomarkers or disease hypotheses.

The Exercise Study

 “PEM is just one of the factors that could be used to stratify patients”

There is fatigue and there is post-exertional malaise. For myself the inability to do even mild exercise without experiencing significant symptoms is the outstanding aspect of ME/CFS. Everything else is kind of nebulous; the fatigue, the body pains, the cognitive problems – but ask me to exercise and everything gets much worse very quickly. It’s hard for me and others to imagine, therefore, that PEM is not the most biologically significant symptom in this illness, but some people who meet the CFS criteria are significantly fatigued but don’t appear to experience PEM. I have two questions

(1) Don’t we run the risk that we are mixing apples and oranges – and thus doing injustice to both – by not separating these two groups in research studies? 

(2) Will the multi-site study help us understand these two groups better?  

Patient heterogeneity is a problem for research studies.  PEM is just one of the factors that could be used to stratify patients.  Type of onset (acute versus gradual), severity of individual symptoms, and cognitive measures are some other examples.  Information from the multi-site study will hopefully start the process of identifying biologically meaningful subgroups.  When we have good ways to look at all the components of the illness, studies can then be designed to look at subgroups.

apples-oranges-cfs

Are we mixing apples and oranges by not requiring PEM to be present? Dr. Unger suggested other ways to differentiate people with ME/CFS

[Commentary: Dr. Unger has not been convinced in the past that post-exertional malaise is a defining characteristic of ME/CFS or  “ME” and she clearly is not now. The idea that PEM is one factor among many has been the CDC’s stance for some time.

The fact that Dr. Unger is using an exercise test of all things to reveal the biological breakdowns present in this disorder indicates that she recognizes how important a role exertion plays in this illness, but she believes that stratifying patients according to disease onset, cognition or symptoms severity might produce  as biologically meaningful subsets.

That’s questionable. Because many different processes undoubtedly contribute to symptom severity in ME/CFS, focusing on that seems unlikely point a finger at a specific disease process. Nor have differences in cognition (working memory problems vs say information processing speed) ever been suggested as being possible differentiating factors in ME/CFS. Disease onset is a more likely candidate but most studies that have examined disease onset have not found it to be a significant factor.

The Light ME/CFS multiple sclerosis study suggested that the PEM induced fatigue and  pain is different physiologically from the “lassitude” type of  fatigue in MS. If PEM is a more or less unique contributor to fatigue in ME/CFS  it would provide an important tool to differentiate ME/CFS from other disorders. It’s clear that “fatigue” is too crude of a concept to denote  what’s happening  in  ME/CFS.

Dr. Unger ‘s assertion that when we have ‘good ways to look at all components’ of ME/CFS then we should look for subgroups  was echoed, to some extent, by the AHRQ  in their report to the P2P panel.  That we still, after thirty years, don’t have the tools to properly assess the symptom presentation in ME/CFS is nauseating, but simply reflects the lack of federal support for this field.  The NIH’s willingness to point out the flaws in ME/CFS research has never, unfortunately, coincided with a willingness to spend any money to fix them.]

One report suggested the CDC was gathering data on lactic acid accumulation during exercise. Is this so?

We are measuring lactate during the exercise test that is being conducted at several of the clinical sites as part of the combined cognition-exercise protocol.  Lactate is measured at the start of exercise and periodically throughout the test (including peak exercise intensity) and during exercise recovery.

This information will be used along with other measures taken during the test (gas exchange data) to assist with determination of the exercise capacity of participants.

exerccise-test-cfs

Will the CDC’s one-day exercise test suggest aerobic capacity is higher than it really is in ME/CFS?

[One of concerns regarding  using the one-day aerobic exercise test  to measure ‘exercise capacity’  is that studies indicate that a two-day exercise test in ME/CFS is required to pick  significant  decrements in aerobic exercise capacity.  The one-day test then, is a poor and misleading measure of exercise capacity in ME/CFS.  The CDC’s use of the one-day test has lead to fears that the negative results will overshadow the two-day exercise studies that indicate ‘exercise capacity’ is, indeed blunted in ME/CFS.

It’s not clear what Dr. Unger meant when she said the 1-day test will assist with determining the  ‘exercise capacity’ (probably VO2 max, etc. and lactate) of ME/CFS patients. The lactate measurements taken during the test may demonstrate decrements in exercise capacity but past studies suggest aerobic capacity – the ability to generate energy – will largely appear normal in her group.

If  the study results  mirror  what Dane Cook  in his Solve ME/CFS study are finding, however, the one-day test will reveal significant drops in cognitive functioning after exercise.]

In that interview you also stated “We believe that the data collected in our study will help identify the best options for either measuring post-exertional malaise or for identifying measures that correlate with this characteristic.” Could you expand on that a bit?  What data might come out of the study that could help measure the extent of PEM present?

We are asking participants in the exercise and cognition study to complete simple self-reported scales of physical fatigue, mental fatigue (or mental fog), muscle aches, joint aches, headache, muscle weakness and light headedness. In addition, we are asking participants to complete online cognitive tests after they return home.  We hope that changes in these measures across multiple time points before, during, and after testing will provide insights to the extent of PEM.

[It’s a bit mystifying that Dr. Unger did not include lactate or gene expression in her answer since she is measuring them in response to and after exercise as well, but perhaps the question was not phrased well. Differing gene expression results or lactate levels in ME/CFS patients and controls could surely help  measure the extent of PEM present in ME/CFS. ]

Do you see any possibility that we might identify some diagnostic factors that could predict the presence of PEM without having ME/CFS patients get on a bicycle? 

It is not clear whether there are diagnostic factors that correlate with PEM, but we will be evaluating all measures collected as part of the study.  Ideally, we would like to have an alternative to formal exercise testing.

Will the gene expression part of the study target the same genes that the Lights identified during their exercise studies? Will you be banking the blood collected during and after the exercise test so that it can be assessed again when future research suggests it might be appropriate to do that?

We will have one blood sample collected before and one after exercise testing.  RNA from whole blood can be tested for multiple genes including those identified in the Lights’ studies.  The samples will be available to test different hypotheses.)

Other CDC ME/CFS Research

“A review of the literature on CFS suggests that CFS shares some features with accelerated aging …”

What was the rationale for the telomere length study? How does that fit in with past/future CDC research?

telomere

Reduced telomere lengths puts ME/CFS in the same conversation as aging, cancer, heart disease and infection

Your question about telomere length probably refers to information that Dr. Rajeevan presented at the 2014 IACFS/ME meeting.  We conducted an analysis of telomere in archived samples from our population-based study of CFS.  This was prompted because of the association of telomere length with aging, cancer, heart disease, infection and stress.  A review of the literature on CFS suggests that CFS shares some features with accelerated aging and post-infective fatigue.

Around the time that the laboratory had finished testing telomere length, we also completed the testing to identify genes that had different methylation patterns in CFS cases compared to non-fatigued controls.  Samples in the methylation analysis were also part of the population study.  The exploratory methylation testing identified several genes that differed in methylation, but only one gene that also showed a difference in expression.   That gene was TERT (telomerase reverse transcriptase), an enzyme that is involved in maintaining telomeres.  These observations need to be confirmed in other populations.

Many factors that occur with CFS could contribute to both methylation and telomere length, so the findings are not clear.  They do suggest that some of the same biologic factors that are seen in a variety of chronic conditions are also seen in CFS.

Resources

  • Beth Unger on the CDC’s multi-center study on YouTube
  • CFSAC committee meeting – Spring 2013 –  The Multi-site Study Pt II – YouTube