All posts by Cort Johnson

Norwegian Rituximab Chronic Fatigue Syndrome (ME/CFS) Trial Fails

November 26, 2017

Over the past five years or so, Rituximab has been the great hope for the ME/CFS community. The anecdotal stories of dramatic recoveries were beyond enticing. A successful trial could ultimately have led to the first FDA-approved drug for ME/CFS and relief for many, a huge shift in how the disease is viewed, and surely more research funding.

That unfortunately is not to be. At a talk in Norway on Nov 21st, Dr. Mella revealed that the Rituximab trial that many laid their hopes on has failed. We don’t know and won’t know the details of the failure until the paper is published next year, and Drs. Fluge and Mella talk more about the study.  Dr. Mella said they provided the result so that ME/CFS patients won’t try the drug on their own.

The Norwegian trial was never by itself going to lead to FDA approval for Rituximab’s use in ME/CFS. The trial was large and rigorous enough, though, to ensure that, if successful, another trial which could lead to FDA approval would follow. The trial’s rigor had equally negative consequences; it’s hard to imagine in this funding-hampered disease that anyone is going to fund a large Rituximab trial in the future.

Ritxuimab's future in ME/CFS

The main finding of the Norwegian Rituximab trial was negative but Rituximab’s ,may role in ME/CFS may not be at an end.

Rituximab may never be an FDA-approved drug for the general ME/CFS population, but its role with ME/CFS may not be over, and smaller, targeted trials are still a possibility. From the beginning, Fluge and Mella recognized the possibility of a trial failure and had a backup plan in case it failed:

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.

Efforts to find biomarkers that identify the responders will be critical and are already underway. David Patrick of Canada reported on his use of microarrays to try and tease out which ME/CFS patients might respond to Rituximab at the 2016 IACFS/ME Conference. Nancy Klimas suggested that the Rituximab sera could very well hold the key to Rituximab’s future with ME/CFS. If autoantibodies are present in the Rituximab responders’ sera, they could be used to screen patients for future trials.  She questioned whether the autoantibody patterns she’s seen in her studies might be predictive.

Norwegian journalist Jorgen Jelstad pointed out that antibodies are used to identify responders to Rituximab and other immune-suppressing drugs in osteoarthritis. Patients with positive antibody findings get the drugs and patients with negative findings do not.

We know that some people with ME/CFS do respond very well to Rituximab. We’ll know more about them and the next steps Fluge and Mella will take with the drug and their other studies in early 2018.

The Rituximab Saga

The Rituximab saga began in 2004 when two oncologists noticed that Rituximab – a B-cell depleting drug often used in cancer – not only cured one of their patient’s cancer but eliminated their chronic fatigue syndrome (ME/CFS) as well. After two more ME/CFS patients responded similarly, they began their work on ME/CFS in earnest.

Several small case studies or trials ensued, all of which produced excellent results. The first one – called a preliminary case series in 2009 – reported on the three ME/CFS patients who’d improved on Rituximab.  The second – a 2011 double-blinded, placebo-controlled 12 month trial of 30 patients – found Rituximab produced “major or moderate” results in 2/3rds of the participants.

The third, a 2015 open-label (the patients knew they were getting Rituximab) study, which involved giving the participants doses over a longer period of time, achieved similar results.  The SF-36 scores of the major responders – about 50% of the study participants – suggested that they might be back to near normal. Not only did the trial succeed, but the trial suggested that the relapses dogging the patients from the first study could be prevented by continuing to take the drug.

The 152 person, double-blinded, placebo controlled trial that eventually resulted was spread across five hospitals in Norway. The trial had a rocky start with the Norwegian government pulling its support, but ultimately patient advocacy and patient support prevailed. The trial began in 2015 and wrapped up on time in September of this year.

Why the Trial Failed

We won’t know why the trial failed or how many people the drug worked for until the paper is published in the first half of next year but speculation is rampant.

Was “Failure”Always the Most Likely Outcome (?) –  My probably minority opinion is that “failure” may have always been the most likely outcome of the study given the heterogeneity this community displays every day on Forums, Facebook and elsewhere on the internet. It may be too much to ask for many drug trials aimed at the entire ME/CFS community to succeed.

It’s important to note that Rituximab may still have a role to play in ME/CFS – just not as a drug for everyone. The key question now is how many people actually did respond to it.  If a substantial number did, and a biomarker to identify them can be identified, the Rituximab trial will not go down as a failure at all.

Patient Bias? – Inadvertent patient bias – a possibility Fluge and Mella considered as the trial started – is probably the best candidate at this point. It could be that the smaller early studies inadvertently plucked out a more receptive set of patients. Once more patients were added to the mix, the effect disappeared. This is not an uncommon result in large Phase III drug trials:

“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).” Fluge and Mella

Placebo Effect? – Jorgen Jelstad put forth the intriguing idea that a high placebo effect could have doomed the drug. A similar situation appears to have doomed the Synergy trial. The Synergy compound actually did quite well but the placebo effect – possibly due to patients’ excitement about the treatment – was so strong that it was impossible to show clear separation between the effects of the drug and the placebo. Given the excitement around Rituximab, it’s possible that a similar situation has prevailed.

Endpoint – Not Disease? – It’s also possible that ME/CFS is not a single disease, but represents an endpoint or condition that can be reached in any number of different ways. Both Gulf War Illness and Lyme disease, after all, symptomatically appear to be the same as chronic fatigue syndrome but studies suggest that the three diseases are probably quite different biologically.

If different pathways exist to the same symptomatic or even cellular endpoints, then different treatment pathways will be needed. Alzheimer’s is possibly an excellent example of a complex endpoint – not a single disease – which will need a variety of approaches to resolve. Dale Bredesen MD believes that hundreds of millions of dollars and hundreds of prospective drugs have failed to make a significant dent in Alzheimer’s because the disease has been misidentified. Dale Bredesen’s studies suggest that an approach which assesses and treats a wide range of factors may actually work quite well in Alzheimer’s.

See Reversing Alzheimer’s: What Could it Mean for Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia

Drug Trial Failures Not Uncommon in Medicine

The ME/CFS and FM communities have recently, unfortunately, been getting acquainted with the fact that disappointments in drug trials are more common than successes.  Rituximab had two small, but good, Phase II trials and seemed likely to succeed, but surprises in medical research, as Ron Davis has pointed out so many times, are common.

Rituximab subsets

The next step will be determining who did respond to Rituximab and why

Jelstad’s interesting blog “The ME Rituximab Trial is Negative” (translated by Google into English) noted that Rituximab also failed in lupus despite the fact that it seemed hand-made for a B-cell associated disease. In fact, researchers were so shocked at the failure of the first large Rituximab lupus study that they immediately started another one – which subsequently bombed as well.  (Despite all that, Rituximab can still work in lupus and is used in patients who haven’t responded to other treatments. )

Closer to home, two major Phase III fibromyalgia trials, one involving 10,000 patients, failed over the past year. As with ME/CFS and Rituximab, their Phase II trials had produced stellar results. Likewise, Wyller’s Clonidine trial seemed set up to reduce the “arousal” that seems manifest in this disease. Not only did the trial fail, but the drug actually made Wyller’s young ME/CFS patients worse.  Medicine is full of surprises. It’s unrealistic to assume that ME/CFS won’t fall prey to some of them.

The Big Hurt: Second Major Drug Trial for Fibromyalgia Fails

Cautionary Findings?

The result is disappointing but it’s perhaps not entirely surprising.  Rumors from doctors using the drug in the U.S. on ME/CFS suggested the success rates might be lower than hoped for. If I’m reading them right, the immune B-cell studies in ME/CFS which sought to identify the issue Rituximab has addressed haven’t exactly been sterling successes.

Fluge and Mella proposed that long-lived autoantibodies or some other “slow alteration in the immune function governed by B-cells” could be causing ME/CFS.  That idea was buttressed by a study finding increased rates of B-cell lymphoma in elderly ME/CFS patients.

When a German study found significantly reduced levels of muscarinic and B-adrenergic antibodies in Rituximab responders, the way forward seemed clear. Rituximab’s B-cell depleting properties were preventing B-cells from producing autoantibodies that were affecting blood flows and other processes.

The study possibly provided a cautionary note, however, when only 30% of the ME/CFS patients not given Rituximab (n=268) displayed the antibodies – a far smaller percentage than had responded in the early Rituximab trials. If those antibodies were what Rituximab was affecting – which was certainly not clear – many patients simply didn’t have them.

Meanwhile, studies that had focused on the B-cells in ME/CFS didn’t seem encouraging. Several studies prior to the Rituximab finding had not shown consistent B-cell differences between ME/CFS patients and healthy controls.  A more recent found mostly modest alterations in B-cells in ME/CFS patients. Bradley’s conclusion that ME/CFS patients exhibited a “subtle tendency to autoimmunity” didn’t seem to jive with the idea that ME/CFS is a B-cell mediated autoimmune disorder”. Another study which found some B-cell abnormalities was unclear what their functional impact might be.  A 2013 study simply found no differences in the B-cells of ME/CFS patients and controls.

Finally, researchers have had trouble figuring out what Rituximab was doing when it did work. Lunde’s 2016 study of ME/CFS patients receiving Rituximab found no difference in several immune measures (serum BAFF, T-Lymphocytes, T-cell activation) and just slight (but significant) reductions in immunoglobulin levels.

There’s certainly more to know about B-cells in ME/CFS – the Solve ME/CFS Initiative’s (SMCI) is funding a small study of B-cell energetics – but if B-cells are causing ME/CFS, they haven’t been giving up their secrets easily.

Enormous Impact

While the Rituximab trial failed in its main objective – to provide a drug for ME/CFS patients – there’s no denying that its impact has been enormous. Two highly creative researchers, Oystein Fluge and Olav Mella, have entered the field and say they intend to remain. Their wide-ranging efforts have and are touching on everything from autoantibodies to blood vessel functioning to metabolomics to exercise.

They and the Norwegian ME/CFS community put together the largest non-CBT/GET trial ever in ME/CFS, produced one of the largest biobanks, and created collaborations with researchers in Europe and the U.S.  It proved that ME/CFS patients and their supporters from across the world will respond (Dr. Maria Gerpe reported that over 90 days, 5000 donors from more than 49 different countries contributed to the study). The Rituximab saga has provided a jolt of energy across the entire ME/CFS community.

fluge_mella_research_team

Fluge and Mella and their supporters did the seemingly impossible: put on a large and expensive ME/CFS drug trial in a small country

Plus, the trial was not just about Rituximab. Several other studies baked into the study will add to our understanding of ME/CFS. A study examining endothelial function and skin microcirculation should tell us about blood flow issues – very possibly a key issue in ME/CFS. Their two- day exercise test should validate the highly unusual decline seen in the ability of ME/CFS patients to produce energy after exercise. Their gastrointestinal functioning test should, likewise, tell us about gut functioning in this disease.

Plus, Fluge and Mella are continuing with their cyclophosphamide trial. Cyclophosphamide has some real advantages over Rituximab. While Rituximab selectively targets B-cells, a more broadly based immune drug like cyclophosphamide may be more effective than Rituximab and has the decided benefit of being much, much cheaper.  The drug is being tested in several hospitals across Norway.

Fluge and Mella have also published studies indicating breakdowns in energy production and the effects of cytokines on ME/CFS. Jorgen Jelstad pointed out that Katrina Lien’s multi-center Norwegian study is examining lactic acid production in ME/CFS.  RItuximab’s early success prompted researchers to examine B-cells and autoantibodies more closely.  Maureen Hanson is working with Norwegian researchers to assess the effectiveness of fecal transplants. None of this work would have been possible if Rituximab had not come to the fore.

The Rituximab saga showed that there’s no need to look to the U.S. for potential breakthroughs in this disease.  Activists in smaller countries should be encouraged. Norway put the U.S. to shame in its ability to put together and fund the largest non-behavioral ME/CFS treatment trial ever. The Rituximab saga has shown that an active community and dedicated researchers in small countries can make a major impact on this disease.

We’ll know more about the next steps with Rituximab and Fluge and Mella’s work in 2018.

The Clinical Trials Picture

The loss of Rituximab puts renewed focus on Hemispherx Biopharma’s Ampligen – the other major drug possibility for ME/CFS.

Nancy Klimas at the Institute for Neuro-immune studies feels she has treatments to test now.  Klimas has been chafing against federal restrictions that make it difficult to get ME/CFS clinical trials funded for years now. Neither the Research Centers grant nor, advocates take note, the Program Announcements for the ME/CFS SEP grant review panel, allow for the submission of clinical trial proposals. That means Dr. Klimas has go to rheumatology review panels to try and get her ME/CFS clinical trials funded.

Dr. Klimas reports that she’s received private funding for a phase I exploratory trial for women to start in Jan/Feb of next year and has raised half the money needed for a men’s study to hopefully begin shortly after that. (More on those later.)

Other Reports on the Rituximab Finding

Put simply, clinical trials of treatments for ME/CFS are the missing link and the next mandate, and experience suggest we consider designing them around disease subsets.

 

Is Chronic Lyme Disease – Not Lyme Disease At All?

Is Chronic Lyme Disease (CLD) actually Lyme disease? That’s one of the questions asked during the Simmaron Research Foundation’s Patient Day in September.

It was a full room in beautiful Incline Village sitting on the northern shore of Lake Tahoe in Nevada. Emily Taylor of SMCI came up from LA, Gunnar took time off from medical school. Maureen Hanson and Mady Hornig flew over from the East Coast; Dr. Konstance Knox from the Midwest. The locals included Anita Patton, Courtney Miller, Eric Johnson, and, of course, there was Dr. Peterson.

chronic lyme disease

Why some people remain ill after being treated for Lyme disease is a vexing question

Why some people who have been treated for Lyme disease remain ill is a knotty question, and it has pertinence for chronic fatigue syndrome (ME/CFS). Both in Lyme disease and chronic fatigue syndrome (ME/CFS) many people become and then remain ill after an infection.  Why that happens is a mystery.

Some people think that chronic Lyme disease is simply another subset of chronic fatigue syndrome; that the Borrelia burgdorfii infection which ticked off chronic Lyme disease is no different from the herpesvirus or enteroviral or  other infection that just happened to send ME/CFS patients’ systems into a tailspin. The idea is that it’s not the infection, it’s the fact that an infection occurred.  That’s what the Dubbo and other studies which have shown that ME/CFS can be triggered by a large of number of pathogens suggest.

Others believe that the Borrelia infection is still there, deeply hidden, but grinding away in the chronically ill.

No one knows, but the idea that different pathogens are causing similar issues in ME/CFS and Lyme is belied by a study which found significantly different proteins in the cerebral spinal fluid of ME/CFS and Lyme disease.

Dr. Konstance Knox believes the two diseases may, in fact, be very different. In her Simmaron Patient Day presentation, she suggests a pathogen may be present in chronically ill Lyme disease patients but not the Borrelia bacteria; she believes that a tick-borne virus called the Powassan Deer Tick virus, which at its worst is fully as dangerous as Borrelia or more, may be doing its work.

 The Powassan Deer Tick Virus

The Powassan Tick-borne virus was first isolated from a person from Powassan, Canada in 1958.  (Powassan, like Lyme, Connecticut, is another small town that just happened to get stuck with the name of a disease.) The Powassan virus is a Flavivirus related to such nasties as Zika, Dengue, West Nile Virus, and tick-borne encephalitis virus (TBEV). All these viruses can cause brain swelling (encephalitis).

The scariest thing about the  Powassan virus is how quickly it can be transmitted. Because the Borrelia bacteria that causes Lyme is carried in the stomach of a tick, the tick has to feed for quite a while before the bacteria actually makes into humans. Because the Powassan virus, on the other hand, is carried in the saliva of the deer tick, it takes a mere 15 minutes or so for it to jump from a feeding tick into your bloodstream. A Powassan infected tick can jump on, feed for a bit – transmit the virus – and then jump off, without you ever knowing it.  Since ticks are so small and POWV transmission so rapid, few patients with Powassan encephalitis recall their tick bites.

Powassan virus symptoms - CDC

Most cases of Powassan virus infection are mild but at its worst a Powassan virus infection rivals Lyme disease in its severity

Most people infected with Powassan Virus (POWV) experience flu-like symptoms such as headache, sore throat, drowsiness and disorientation.  If the infection spreads to the brain, the virus can cause everything from lethargy, high fevers, vomiting, respiratory problems and difficulty speaking to paralysis, seizures, coma and even death.

Powassan-triggered encephalitis is accompanied by the infiltration of lymphocytes and monocytes into the brain and the widespread destruction of neurons in the motor areas of the brainstem (affecting movement), the cerebellum, basal ganglia (potentially affecting movement again) and the thalamus. MRI’s pick up only non-specific abnormalities and thus are not diagnostic but suggest that brainstem may be particularly effected.

Studies on Powassan infections are rare but some suggest that no less than fifty percent of Powassan survivors may be left with permanent neurological problems including partial paralysis, headaches, memory impairment and/or paralysis of the eye muscles.

A 2015 paper presenting eight verified cases of neuroinvasive Powassan virus infection in New England bore this out. Two of the patients died, four fairly quickly recovered and two exhibited from medium to long-term problems.  One 21 year old man who entered the hospital with vomiting, fever and confusion was given methylprednisolone and IVIG. He improved over time and left the hospital alert, oriented, and “speaking in short sentences”. He was unable to return to work for seven months.  Fifteen months later, a 52 year old man still had persistent headaches as well as problems with motor functioning and coordination.

Because surveillance of the Powassan virus has been poor, it’s difficult to estimate its true incidence in humans.  Luckily, far more ticks carry the Borrelia bacteria (20-50% of ticks in endemic areas) than carry the Powassan virus (1-10%). Unluckily, the Powassan virus appears to be spreading.

After Powassan virus caused the sudden death of a Massachusetts woman, a tick surveillance program found from 0-16% of ticks in a given area carried the virus. A Canadian survey suggested that 3% of residents of Ontario province in Canada had been exposed to the virus. These surveys suggest far more people have been exposed to the virus than suspected. Most undoubtedly experienced symptoms similar to those of a mild cold.  Others who were more seriously affected probably never got tested for Powassan.

Much of what we know about the Powassan virus comes from study of a closely related virus in the Europe and Asia called Tick-borne encephalitis virus which causes thousands of neurological illnesses every year.  Studies on the Powassan were almost non-existent until around 2011 when the research started picking up. Powassan virus is considered a “rare but severe neuroinvasive disease“.

Could Chronic Lyme Disease Caused by the Powassan Virus?

Dr. Konstance Knox,       Coppe Lab

Simmaron Scientific Board member and collaborator, Konnie Knox has been leading a recent surge in research publications on the Powassan virus. Her recent survey of the Ixoides scapularis ticks known to carry Lyme disease and Powassan virus in Wisconsin found that 5% carried the Powassan virus. Rather ominously half of the ticks carrying Lyme disease also carried the Powassan virus.

With Lyme disease fairly common in Wisconsin (@ 187 cases/100,000)  Knox’s finding strongly suggested that Powassan infections were being under-reported in Wisconsin.  (If Knox’s findings are validated, then Powassan virus infections probably occur on the order of at 90 cases per 100,000 in Wisconsin, or as much as 5400 cases per year.)

Next, Knox tested 95 patients seen at a clinic for possible Lyme disease over four months in 2015 in northern Wisconsin.  Lyme disease,  POWV, West Nile virus (WNV), Tick-borne encephalitis virus, V, yellow fever virus, dengue viruses 1–4, and Japanese encephalitis virus were tested for.

Powassan virus Lyme disease

Could chronic Lyme disease actually be a Powassan virus infection?

Serologic evidence of POWV infection was present in 10% of the patients and confirmed in 3% of them by other testing.  Almost half of the patients with an acute Borrelia infection were infected with the Powassan virus. When the patients with a validated Powassan infection were tested, 87% were also found to be infected with Lyme disease. None, fortunately, had signs of a neuroinvasive disease.

The fact that 10% of Lyme patients come down with Chronic Lyme Disease and, Knox’s findings suggest that about 10% of patients with Lyme disease may also be infected with the Powassan Virus, is of course, more than intriguing.

Could chronic Lyme disease or ME/CFS patients be suffering from a unusual, untreated infection? Knox’s present research into ME/CFS patients could help answer that question. Knox will be testing several hundred ME/CFS patients for evidence of Lyme Disease, Powassan virus, and other tick and insect-borne diseases.

Lyme Disease Or ?

  • Konstance Knox who owns a diagnostic laboratory, noted that Lyme testing has improved and that good Lyme testing is not impossible. (She liked the CDC protocol which calls for a two-step testing process.)  She’s confident in the results from her lab which uses machine testing rather than subjective human testing to assess the test results.

She noted that one of the biggest problems with Lyme diagnosis is getting tested too early. Because it takes about four weeks for the Lyme immune factors to show up in the blood, the tests aren’t accurate until you’ve been infected for about a month.

The Lyme diagnosis question, of course, is a big one.  Get it wrong, as the story of one ME/CFS patient in the audience indicated, and you could be in for years of expensive treatments which leave you worse off.  After a diagnosis based on neurological and non-specific symptoms, a CD 57 test, and a negative Western blot test from Igenex, this patient had been on and off antibiotics for about five years. Talking to her later she said she’d improved tremendously on antibiotics at times, but the treatment ultimately failed and left her worse off than ever. (She suspected that the anti-inflammatory effects of the antibiotics had temporarily helped.)

She would be in the chronic Lyme disease category except for the fact that she never have had Lyme disease in the first place. In fact, her symptoms didn’t really fit. She’d marveled at other “Lyme patients” who were able to exercise. Despite the fact that she’d visited a clinic that treated complex, chronic diseases, she didn’t know that her main symptom – post-exertional malaise – was the defining characteristic of ME/CFS until she visited an ME/CFS clinic last year.

Knox suggested that a lot of putative “Lyme” patients may not be Lyme patients at all. She’s found, for instance, a very low incidence of Lyme disease in Dr. Peterson’s patients, many of whom probably hail from the Western United States. She did, however, find evidence of a tick borne virus in about 11% of a 200 patient sample.

Conclusion

People who still suffer from the symptoms of Lyme disease after being appropriately treated for it are a medical mystery.  Some doctors believe the Lyme bacteria is still present. Others believe that the Lyme infection may have triggered an ME/CFS-like condition. Simmaron Research Foundation Board member and collaborator, Dr. Konstance Knox, believes some people with chronic Lyme disease may be suffering from an unidentified Powassan virus infection transmitted by the same tick.

Powassan virus is a poorly studied virus that can be quickly transmitted by ticks. While most people probably pass off the virus quickly, a neuroinvasive infection can cause serious symptoms including paralysis, stroke, coma and even death.

Dr. Konstance Knox’s studies suggest that Powassan virus is often present in ticks harboring the Borrelia bacteria that causes Lyme disease, and that about 10% of Lyme disease patients have been exposed to the virus. That’s an intriguing finding given that about 10% of Lyme patients come down with chronic Lyme disease.

Dr. Knox is currently studying the incidence of the Lyme disease bacteria, Powassan virus and other insect vectors in Dr. Peterson’s chronic fatigue syndrome (ME/CFS) patients. Stay tuned…

 

A Entire State Goes “M.E.” in Congressional Breakthrough

September 13, 2017

Nevada Goes “M.E.”

An entire state goes “ME”. That’s never happened before. Courtney Miller of Simmaron, Emily Taylor of the Solve ME/CFS Initiative, MEAction and the USAWG worked together to enroll the entire Nevada Congressional delegation to put its total support behind increased funding for ME/CFS.

This is notable not just because it’s never been done before, but because for years patients in Northern Nevada sought help from Congressman Amodei and Senator Heller with little success. This is the story of persistence and success. Hopefully we’ll be seeing more of this as the attitude towards chronic fatigue syndrome (ME/CFS) shifts.

Courtney and Bob Miller have been advocating for ME/CFS for many years, but when Emily came up with the rather audacious plan to get the entire state delegation on board, they were energized.

Persistence Works

After the elections in Nevada, Courtney Miller and a group of patients recommitted to taking a sustained approach. Not willing to let the decisions of the past stop them, Courtney met the staff of the Congressman and her Senators after the Women’s March in Washington. At that point Amodei got interested in ways to improve the federal agencies’ response to the disease.

Then in a Spring Town Hall meeting Courtney got up to the microphone and publicly asked Sen. Catherine Cortez Masto for her support. With that Sen. Catherine Cortez Masto’s staff got involved and she joined the effort.

Next during the first Lobby Day in ten years (thanks to SolveME/CFS and MEAction) some patients from Nevada met with Cong. Amodei himself and the Senators. Emily, Sonya, Courtney and others created a draft delegation letter (see attachment). In June Courtney returned to DC and visited the office of every member of the NV delegation. This time the response was enthusiastic; Congressman Amodei agreed to sponsor the letter and set a deadline.

Finally, last week Emily from Solve ME/CFS Initiative and Courtney hit the phones, Anita – the go to person for patients in Incline Village – urged Nevada patients to send emails, and Emily set up a Solve ME/CFS Nevada action alert so that more Nevadans could urge their reps to sign on. (The SMCI has an automated and easy way to contact our reps.) By Friday, the entire Nevada delegation agreed to push Director Collins for more funding.

The State Delegation Game

The game now is to get entire state delegations to sign on. Obviously it’s going to be harder with bigger states (although in conversation Emily mentioned the “big apple”). Besides everything else, getting everyone in a state delegation on board is a great game to play. It sends a powerful message when an entire delegation comes together like that.

I asked Emily what was next.

Who’s next? Now that Nevada has proven it can be done, who’s next? If you want to your state to be the next to go all “ME” email Emily Taylor at ETaylor@solvecfs.org and let her know.

Is Poor Sleep Pummeling the Immune System in ME/CFS and Fibromyalgia? A Vicious Circle Examined

August 29, 2017

Most people with chronic fatigues syndrome (ME/CFS) and fibromyalgia (FM) know the consequences of poor sleep – the fatigue and pain, the difficulty concentrating, the irritability and more. Sleep is when our body rejuvenates itself; no sleep – no rejuvenation. Given how important sleep is to our health, it’s no surprise that poor sleep is the first symptom many ME/CFS and FM doctors focus on in.

insomnia fibromyalgia

Poor sleep is often the first symptoms ME/CFS/FM practitioners focus on

The effects of poor sleep go beyond just feeling bad, though. It turns out that poor sleep can have significant effects on our immune system – effects, interestingly, which are similar to what’s been found in the immune systems of people with ME/CFS and FM. There’s no evidence yet that ME/CFS and FM are sleep disorders – that the problems ME/CFS and FM patients face are caused by poor sleep – but depriving the body of sleep can cause one immunologically, at least, look like someone with these diseases.

Why Sleep Is Important for Health: A Psychoneuroimmunology Perspective
Michael R. Irwin. Annu Rev Psychol . 2015 January 3; 66: 143–172. doi:10.1146/annurev-psych-010213-115205.

Irwin begins his review on sleep and immunology by noting the “explosion” in our understanding of the role sleep plays in health over the past decade. First, Irwin demolishes the idea that sleep studies are effective in diagnosing insomnia or sleep disturbances other than sleep apnea. Far more effective than a one or two-night sleep study is a home based sleep actigraph “study” which estimates sleep patterns and circadian rhythms over time and is coupled with a sleep diary.

In fact, Irwin points out that the diagnosis of insomnia in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is based solely on patient reports of difficulties going to sleep, maintaining sleep, having non-restorative sleep (common in ME/CFS) and problems with daytime functioning (fatigue, falling asleep, need to nap). (Problems with daytime functioning are actually required for an insomnia diagnosis).

Several effective sleep questionnaires exist including the Insomnia Severity Index, which assesses sleep quality, fatigue, psychological symptoms, and quality of life and the Pittsburgh Sleep Quality Index, a 19-item self-report questionnaire that evaluates seven clinically derived domains of sleep difficulties (i.e., quality, latency, duration, habitual efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction).

Assess Your Sleep Quality

The Immune System and Sleep

The immune system is vast and incredibly complex and has it’s own extensive set of regulatory factors, but it itself is regulated by two other systems, the HPA axis and the sympathetic nervous system. Both are involved in the stress response and both are effected in ME/CFS and FM. One – the HPA axis – is blunted in ME/CFS while the other – the sympathetic nervous system – is over-activated.

Poor sleep, it turns out activates both system. The HPA axis is generally thought to be blunted not activated in the morning in ME/CFS patients but the sympathetic nervous system (SNS), on the other hand, is whirring away at night (when it should be relaxing) in both FM and ME/CFS. (Having our “fight or flight” system acting up at night is probably not the best recipe for sleep.) ‘

sleep HRV

One study likened sleeping in fibromaylgia to a stress test (!)

Sympathetic nervous system activation, in fact, was the only factor in one Australian study which explained the poor sleep in ME/CFS. The authors of a recent FM/autonomic nervous system study went so far as to suggest that going to sleep with FM was equivalent to undergoing a stress test (!). Heart rates, muscle sympathetic nervous activation, and other evidence of an activated sympathetic nervous system response made sleep anything but restful for FM patients. In fact, the authors proposed sleep problems could be a heart of fibromyalgia.

Many questions have involved the roles pathogens play in ME/CFS and FM. That’s intriguing given the almost universally poor sleep found in the disorders and role recent studies indicate that sleep plays priming the immune systems pump to fight off invaders. During sleep pathogen fighting immune cells move to the lymph nodes where they search for evidence of pathogens. If pathogens are present those immune cells mount a furious (and metabolically expensive) immune response.

Metabolism is a big issue in ME/CFS right now but guess what? Poor sleep also appears to interfere with producing the metabolic reserves our immune cells need to fight off infections.

We often think of inflammation in negative terms but the pro-inflammatory cytokines our immune cells produce are necessary to fight off invaders. Reductions of a key pro-inflammatory cytokine called IL-6 during poor sleep hampers our immune system’s ability to destroy pathogens.

Getting your circadian rhythms (sleep and wake times) out of whack isn’t doing you any good either. Having insomnia or altered sleep patterns (very late bedtimes) appears to cause deficits in two hormones (growth hormone (GH) and prolactin) produced during early sleep which enhance T-cell activity and promote pathogen defense. That suggests that anyone with an altered circadian rhythm (i.e. late bedtimes) might want to do their best to get to bed earlier.

While pro-inflammatory cytokine production at night primes the immune system to fight off pathogens, the day time is a different story. Chronic sleep deprivation is associated increased daytime levels of several immune and endothelial factors ((IL-6, TNF) and endothelial markers (E-selectin, sICAM-1) that are associated with chronic inflammation.

One study found IL-6 levels actually became flipped in sleep deprived people; they were low at night (thereby hampering their pathogen fighting ability) and high during the day (adding to inflammation).

pathogens sleep

Pathogens love it when you get a night of poor sleep

The situation may be even worse if a sleep deprived person is fighting off an infection.  One study found skyrocketing levels of damaging pro-inflammatory cytokines when sleep deprived people were given a toxin (LPS) associated with infections. Those damaging cytokines did not show up in healthy people. That suggested that besides the infection they probably weren’t doing too well at fighting off, sleep-deprived people now had inflammation to deal with.

As it often happens, women seem to have gotten the short end of the stick with immune issues and it’s no different with sleep. Women appear to be more susceptible than men to inflammation that occurs as the result of poor sleep; it’s women, not men, who show elevations of pro-inflammatory cytokines the day after getting less than eight hours of sleep. (Men show elevations of pro-inflammatory cytokines after getting less than six hours of sleep).

Many people with ME/CFS/FM get too little sleep but sleeping more than normal, it turns out, is not such a great idea either. People sleeping much longer than normal tend to show the same kinds of elevations of pro-inflammatory cytokines as do people who get too little sleep.

The C-reactive Protein Sleep, ME/CFS and Fibromyalgia Connection

CRP is associated with a variety of inflammatory states resulting from infection, cancer and stress. Increased levels of the inflammatory marker, C-reactive protein (CRP), are increasingly being associated with sleep disturbance.

The CRP – sleep connection is intriguing given Jarred Younger’s preliminary finding of increased C-reactive protein (CRP) levels in a subset of ME/CFS patients, and a recent finding in increased CRP in FM.

See Early Results Suggest Two Radically Different Immune Subsets Present in Chronic Fatigue Syndrome (ME/CFS)

Those findings might not be so surprising. Ten days or so of partial sleep deprivation in healthy controls caused “robust” increases in CRP levels. In fact, the CRP-poor sleep connection is so robust that simply scoring above five on the Pittsburg Sleep Quality Index (PSQI >5) strongly suggests that your CRP levels are elevated. A huge nurses study (n=10,908) found that non-restorative sleep – probably the most common sleep issue in ME/CFS/FM – was associated with increased CRP levels even in these healthy individuals.

The early or innate immune response has long been thought to play a special role in ME/CFS. This immune response involving NK cells, neutrophils, macrophages, dendritic cells and others constitutes the immune system’s first defense against pathogens. Immune cells involved in the early immune response called monocytes/macrophages also play a key role in producing chronic inflammation.

NK cell activity hits a low during sleep but then begins to rise. That the rise is blunted in people with poor sleep probably comes as no surprise to NK cell challenged ME/CFS patients.

ME/CFS isn’t the only disease associated with NK cell problems; depression is as well and having poor sleep increases your risk of being depressed twofold. Plus, for reasons that are not understood, poor sleep appears to trigger stress and depression initiated reductions in NK cell activity; i.e. if you’re having poor sleep and are under considerable stress or are depressed – it’s likely that your NK cells are punking out when it’s time to defend the body from invaders.

We know that having a chronic illness increases ones chances of becoming depressed markedly, but so does poor sleep. In fact, Irwin reports that having insomnia for over a year increases your risk of becoming depressed 14-fold. That finding is leading some of the more progressive psychologists to focus on preventing or ameliorating sleep problems.

Sleep disturbance also induces a shift toward a type-2 immune response often seen in ME/CFS and in allergic and autoimmune diseases. Just one poor night’s sleep the night before a person is given a vaccine is enough markedly reduce the effectiveness of that vaccine. A study showing just how frighteningly malleable the immune system can be to stressors such as poor sleep found that a 50% reduction in the effectiveness of an influenza vaccine persisted over a year. Even after three doses of the vaccine and a booster shot were given adults getting fewer than six hours of sleep a night still received less protection from a hepatitis B vaccination than normal.

The common cold, of course, is no joke to some people with chronic fatigue syndrome (ME/CFS) and FM when it lingers and lingers. Studies suggest that poor and fragmented sleep – which is, of course, common in ME/CFS/FM – significantly increases one’s susceptibility to the common cold. If you’re catching a lot of colds or if they linger and linger, poor sleep could be one reason why.

What To Do?

OK – so poor sleep places a big hurt on our immune system’s effectiveness. What to do about it?  No studies, unfortunately, have examined the effect of sleep drugs on immune factors so we’re not going to go there.

stress reduction ME/CFS fibromyalgia

A little stress reduction could play dividends…

Several studies have, however, assessed the efficacy of stress reduction therapies. Dr. Irwin notes reports that practices such as cognitive behavioral therapy, Tai Chia and yoga which tamp down sympathetic nervous system hyper-arousal can help improve immune functioning. Tai chi has even been found to improve vaccine effectiveness and reduce inflammation.

Other studies point to the ability of mindfulness based meditations and/or yoga to reduce the cytokine levels and pro-inflammatory gene expression caused by poor sleep.  One remarkable study showed a 50% reduction in CRP levels in insomnia patients after a year of cognitive behavioral therapy.

Poor sleep, then, doesn’t just make you feel tired and irritable; it takes a pretty good whack at your immune system, as well.  Getting better sleep through better sleep hygiene, supplements (melatonin), calming botanicals (valerian root, L-theanine, passifloraMelissa, Scutellaria, etc.), stress reduction techniques (meditation, mindfulness, meditation), and sleep medications might just give your immune system a boost.

Major Stanford Study Indicates Chronic Fatigue Syndrome (ME/CFS) is Inflammatory Disorder

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

There’s nothing like a high-profile study from a major university. For one thing it can get you publication in one of the most prestigious journals around. The  journal the Montoya/Mark Davis study was published in, The Proceedings of the National Academy of the Sciences, is the official publication of the National Academy of Sciences. Its website gets about 21 million hits a month; this study is going to get around.

Dr. Jose Montoya, the leader of the Stanford Myalgic Encephalomyelitis/Chronic Fatigue (ME/CFS) Initiative  has been talking about this study for years. Now that it’s finally here, it’s making an impact with many media outlets picking it up.

The results were positive and that was good news indeed. This was one study we really didn’t want to fail.

Too Big To Fail?

Cytokine signature associated with disease severity in chronic fatigue syndrome patients Jose G. Montoya, Tyson H. Holmes, Jill N. Anderson, Holden T. Maecker, Yael Rosenberg-Hasson, Ian J. Valencia, Lily Chu, Jarred W. Younger, Cristina M. Tato, and Mark M. Davis.  Proc Natl Acad Sci U S A. 2017 Jul 31. pii: 201710519. doi: 10.1073/pnas.1710519114. [Epub ahead of print)

The study examined the levels of a very large number of cytokines (n=51) in the blood of a very large number of patients and healthy controls (ME/CFS=186; healthy controls= 388). Age, sex, race and something called “nonspecific binding” were accounted for.

missing the mark

This was one study we really didn’t want to fail

One of the biggest ME/CFS immune studies ever undertaken, done at a top University, this was a study that we dearly didn’t want to fail. This is the kind of study likely to be labeled “definitive”. It was on scale with the Columbia cytokine study, where co-authors Ian Lipkin and Mady Hornig analyzed 51 cytokines in 298 patients and 348 healthy controls.  If the results of these two hallmark studies were discordant, it would have had negative consequences to any immune interpretation of this disease.

Smaller cytokine studies in ME/CFS have a history of inconsistency, making the similarities in these two studies important.

Results

The first news was not good. The levels of only two cytokines, TGF-Î (elevated) and resistin (lowered) were different in the patients compared with controls.  Displaying an unusual level of consistency for ME/CFS, TGF-B has now been found elevated in about six out of the ten studies it’s been tested in.

TGF-B has not received a lot of attention possibly because researchers are not sure what it means. An anti-inflammatory cytokine that can have pro-inflammatory properties, the authors noted that TGF-B is elevated in a number of dissimilar conditions (cancer, liver disease, inflammatory bowel diseases among others). The authors suggested TGF-B may have pro-inflammatory properties in ME/CFS; instead of tamping down inflammation, they proposed it may be “may be a major factor in promoting relentless inflammation.”

Big Finding

“Remarkably, 17 cytokines were associated with severity in ME/CFS patients.” The study authors

Dr. Montoya got the money for the study and conceived it, and Mark Davis advised him on it, was the senior author of the paper, and tested the samples in his lab.

Davis has won a slew of prizes (The Paul Ehrlich Prize, The Gairdner Foundation Prize, The King Faisal Prize, the General Motors Alfred P. Sloan Prize) and is on the Open Medicine Foundation’s Scientific Board. He’s a big deal in the immune world.

bulls-eye

Montoya and Davis hit the bulls-eye when they threw severity into the mix

I talked to Davis a couple of days after the study’s publication.  I asked him about the main results; those 17 cytokines that predicted severity – was that a lot?  It’s an important question. A couple of cytokines popping out might mean that the immune system is involved but is not a major player – time to look someplace else.  A lot of cytokines showing up, on the other hand, suggests the immune system may very well be it in ME/CFS – time to dig deeper.

Was 17 cytokines a lot? Even in the staid language of scientific journals the surprise at the size of the effect came through: “Remarkably”, the paper said, “17 cytokines were associated with severity in ME/CFS patients.”

When I asked Davis if it was really a lot, I heard him take a deep breath:  “it’s a lot – really a lot” – he said. Getting a third of the immune factors to show up suggests massive immune involvement. Davis – who is involved in constructing immune signatures for different diseases and health – said everything he’s seen about this disease suggests autoimmunity.  That’s a particularly meaningful statement  from such a well-known immunologist. He’s getting to know ME/CFS pretty well: Montoya’s study is the biggest study his public lab has run.

(Mark Davis has two labs – his private research lab and a larger, more public lab he set up to run many more samples at a time. That lab, which got a big federal grant, was designed to bring the same kind of rigor he uses in his private lab to bigger studies.  Researchers like Dr. Montoya can bring their samples to the lab and have the lab test them. That’s what happened in this study)

A Different Kind of Disease?

Mark Davis thinks ME/CFS is probably an autoimmune disease. You don’t see the kind of overt cytokine increases in ME/CFS that are seen in autoimmune diseases like rheumatoid arthritis  and lupus.  This study, in fact, suggested that cytokines were not increased in the patient group as a whole relative to healthy controls.

Adding severity to the mix, however, suggested that cytokines were heavily involved in this disease. Mark Davis said he’d never seen a disease with mostly normal cytokine levels but which presented such clear indications that cytokines affected symptoms.  He suggested that other diseases like Alzheimer’s might display similar patterns if researchers started looking for them.

In an interview with Miriam Tucker, Dr. Montoya echoed the unusual nature of the disease: he simply called the immune activation in ME/CFS – as he has for some time now – a different kind of inflammation.

“Inflammation is much more complicated than two imperfect old measures [sed rate and C-reactive protein]. We’re showing an inflammation that has not been seen before.” Jose Montoya

Three Options?

But what could be causing this bizarre pattern?  Higher cytokine levels could certainly explain the more severe fatigue in some ME/CFS patients, but how do the low or normal cytokine levels explain the fatigue in the more moderately fatigued patients? They do have ME/CFS after all; even if they are less ill than the severely ill, they are still enormously fatigued but their cytokine levels aren’t elevated at all. In fact the cytokine levels are lower than normal in some of them. Three options have been suggested.

(1) Loss of Immune Control In the Severely Ill

One possibility the paper presented is that the healthier patients with lower levels of pro-inflammatory cytokines are able to control them to some extent. Their immune systems are grinding away but they’re keeping – probably at some cost – the pro-inflammatory elements under control. The control mechanisms of the sicker patients, though, have collapsed – they’re bearing the burden of unremitting cytokine activity.

(2) A Localized Infection

In conversation Mark Davis suggested that a localized infection could also be causing the immune system to react – not with the huge increases in cytokines seen in systemic inflammatory or autoimmune diseases but with small, harder to detect ones.  He’s not the first to suggest that. A couple of years ago Michael Van Elzakker proposed exactly that scenario for ME/CFS.

Different

ME/CFS may be a different kind of inflammatory disorder

Van Elzakker proposed that localized infections – probably involving the vagus nerve – were causing small, hard to detect elevations of cytokines. Meanwhile the infections were playing havoc with the vagus nerve’s ability to communicate sensory and immune information to the brain.

I asked Van Elzakker about the study.  He believes the cytokines this study picked up in ME/CFS are probably spillovers from an infection or injury. He cited Robert Dantzer, an important figure in sickness behavior research and pyschoneuroimmunology, who in a (2014) Trends in Neurosciences review, The Neuroimmune Basis of Fatigue agreed that with regard to fatigue:

 “The measurement of circulating concentrations of cytokines represents the main limitation of the present studies on fatigue and inflammation. Given that cytokines are autocrine and paracrine communication factors, their circulating levels have little functional value and represent mostly spillover from the site of cytokine production and action.

Given how profoundly limited many people with ME/CFS are – Van Elzakker believes these localized infections probably exist in the neuroimmune nerves such as the vagus or trigeminal nerves.

(3) Context  – Is Context King?

There’s another possibility. Gordon Broderick’s modeling work in chronic fatigue syndrome (ME/CFS) suggests that context may be king in the immune system.   During a recent phone call Broderick described the co-expression study he did that found a changed immune landscape in ME/CFS.  Cytokines such as IL-1b, 2, 4, IFN-γ, TNF-α  and IL-10 had larger than expected impacts in ME/CFS patients relative to healthy controls while other cytokines had less impact.

If Broderick’s right, none of the cytokines found in Montoya’s study need to be elevated to have a significant effect – they simply have to be embedded in a dysregulated immune network.

Leptin is Back

This is the second time leptin has shown up in a Stanford study, and the researchers suggested that it might be the keeping the chronic inflammatory state in ME/CFS intact. It turns out that adipokines – cytokines secreted by fat cells – like leptin may be able to trigger neuroinflammation. They’re also found in higher levels in women and may be a particularly important trigger in female dominated inflammatory diseases such as multiple sclerosis.

 Duration

In contrast to the Lipkin/Hornig and another study, this study found little evidence of increased cytokine levels earlier in the disease or decreased levels later in the disease. The small numbers of short duration patients (n=30) in the study, however, could have prevented any findings from reaching statistical significance. Interestingly, the study did not find that disease duration was correlated with severity; i.e. patients who had been ill longer were not necessarily worse off.

 Diagnostic Test?

Mark Davis suggested the findings might prove the basis for a diagnostic test but in conversation indicated we’re far from one right now. Much more study is needed.

The diagnostic test problem is greater in the low to moderately ill patients who have similar cytokine levels to healthy controls. How to devise a test to distinguish them from the healthy controls with similar cytokine levels is the big question.

Montoya reported that his team was working on a five-cytokine panel that would require a doctor first classifying each patient by severity. If Montoya can devise specific cytokine signatures for each level of severity, a test might be feasible, but it’s clearly going to be a complex undertaking.

Big Study (Too Big?)

Montoya rather courageously put a lot money into an area of research – cytokine analyses – that have had their problems in ME/CFS. As the Lipkin/Hornig study and this study showed, when it comes to immune studies size is definitely better.

While it is possible that this study had more controls than needed, at least Montoya didn’t err on the other side – too few patients; that might have been fatal to this study. Mark Davis thought that given all the noise in the data, that a smaller study might not have found much.

 Don’t Think Too Much: the Zen of ME/CFS

In a kind of Zen-like statement Mark Davis cautioned about “thinking too much” about this disease at this point.  Davis wasn’t suggesting not inquiring about the disease, but not coming to conclusions about it.  We’re not there yet. We’re more in a space of creative inquiry than anything else.

tea-house-mt-fuji

Mark Davis warned against coming to conclusions; more views of ME/CFS is what we really need

Things got even more zen-like when Davis referred to a famous series of paintings called Thirty-six views of Mt. Fuji to underscore where we are with ME/CFS right now. The celebrated series by Japanese artist Hokusai shows Mt Fuji from different perspectives including from at dawn, from a window in a house, from behind a huge wave, etc., etc.

To Davis, ME/CFS is like Mt Fuji; we need to look at it from a lot more angles to fully understand it. The most important thing we can do now is to test, test, test and let the data guide us.

This study may demonstrate that more than anything. It, after all, had four highly unusual results – very little evidence of immune dysregulation compared to healthy controls; massive evidence (17 cytokines!) on the other hand, that the immune system is effecting severity, a substantial number (on the other, other hand) of individuals with low or low-normal cytokine levels, and finally two cytokines with abnormal levels which didn’t have anything to do with severity at all.

This study, then, boosted interest in the immune system in ME/CFS, while raising a lot of questions about it at the same time. A lot of work – a lot of exploratory work –  remains to be done to figure this puzzle box of a disease out.

In fact, exploration is largely carrying the day in ME/CFS research. Montoya got hundreds of samples, tested them as widely as possible, analyzed them a bit and then stood back. Ditto with the Ian Lipkin/Mady Hornig immune study,  the metabolomics studies from Armstrong and Naviaux, (Naviaux, however, has a hypothesis), Ron Davis and the Open Medicine Foundation with their severe ME/CFS Big Data study, and Avindra Nath and his deep Intramural NIH study.  They’re all exploring.

Mark Davis’ talk at Open Medicine Symposium on Saturday should be a good one.  NINDS Director Dr. Koroshetz talked up Davis’s exciting findings in the recent NIH Telebriefing, and Ron Davis thinks they may be even more significant than this paper. If you’re at the Symposium you can ask him about his work or Mt Fuji or just say hello and thanks.

Treatment

This study is a major legitimizer and a big spur for more immune studies – particularly big immune studies. One thing it doesn’t present are clear treatment options. When I asked Mark Davis about treatment options, he was unwilling to commit to any line of treatment based on the results. He agreed that basing treatment options off of this study would be like shooting fish in a barrel.

That doesn’t mean the study won’t help on the treatment end. The severity results, after all, scream inflammation. That suggests anti-inflammatories might very well help. Ron Davis noted that many immune affecting drugs are under development right now which might be useful for ME/CFS in the future. We simply need more study to assess which targets might be best.

If Gordon Broderick’s right, though, it may take more than knowing a cytokine’s levels to find the right target. Broderick’s working on complicated models that incorporate the effects hormone levels, in particular sex hormone levels, have on immune factors in ME/CFS.  Broderick believes he’ll be able to devise a treatment approach that pushes the immune system one way and then another in order to nudge it back to a stable and healthy state.

Fatigue or Functioning?

While the multi-dimensional fatigue index used to assess fatigue has been validated as a good measure of fatigue across many diseases, one wonders if a functionality scale might have worked better. Fatigue is what ME/CFS is known for, but it’s real impact is on functioning. It’s possible to be very fatigued and still work, or to be pacing effectively – and not doing much work – and be less fatigued.

The MFI worked well in this study and past ME/CFS studies have used it, but one wonders if a scale that tracks functionality – how much activity one is actually doing – might have been more effective at tracking severity.

 Slow Progress

Montoya has been given much (reportedly $8 million donation in 2008) and promised much, but the ME/CFS work has been slow. He’s a toxoplasmosis expert, possibly the top expert in the country, and he’s been pouring out toxoplasma studies – fourteen since 2015 – but the work in ME/CFS has gone much slower.  Since 2009 he’s been the senior or lead author on just four ME/CFS studies – two of which involved the valganciclovir trial and predated the opening of his ME/CFS center.

This latest study was the most important one – it will undoubtedly help the field – but one hopes that with this monster study out of the way Montoya will be able to move faster on his other ones. His current research projects page lists ten studies. Two involve the Zinns who, unable to publish their work at Stanford, exited to work with Lenny Jason. Those studies are surely not extant.

The eight others, though, involve brain imaging, neuroendocrine, gene expression, cardiovascular, immune and pathogen studies. In a telephone conversation Mark Davis referred to some scintillating results he and Montoya are working on using the immune data Montoya gathered.  Let’s hope we’ll see those results and more from Montoya’s Chronic Fatigue Initiative in the not too distant future.

Conclusion

lighthouse

This study, as did the Lipkin/Hornig study, suggested you have to approach ME/CFS differently than other diseases to be successful.

One of the things that emerged from this study is that ME/CFS really, really is different and woe to any researcher who assumes that it’s not. The regular rules of the road do not apply – you can’t just measure cytokine levels and expect to get anything. You have to dig deeper, and what this study and the large Lipkin/Hornig study before it demonstrated was that if you do dig deeper, you might stumble on something extraordinary.

The study’s excellent pedigree – it’s size, the lab it took place in and the journal it was published in – guarantees it will get noticed and that’s a good thing. The most important aspect of the study may be the legitimization it confers on the illness. Hopefully the study will introduce new researchers intrigued by what could be a new type of inflammatory disorder to the field.  While more work is needed, the study also points to possible future effective treatment options. Lastly, the study indicates, as did the Lipkin/Hornig study, that bigger really is much, much better in ME/CFS research. Hopefully funders will take a cue from these large studies, and support the bigger and more definitive studies this disease needs to move forward.

 

 

 

 

 

 

 

 

 

 

 

 

The Big Fishing Expedition: Report From the NIH Intramural Study on ME/CFS

A Big, Deep Fishing ExpeditionNIH jpeg

“We’re throwing every known sophisticated technology at these patients.”

Avindra Nath, MD – Lead Investigator of NIH Intramural Study on Chronic Fatigue Syndrome

The NIH’s Intramural Study on ME/CFS now underway is almost certainly the most comprehensive chronic fatigue syndrome (ME/CFS) study ever done. In fact, it may be one of the more multi-faceted studies done in any disease. It’s breadth is astonishing. Besides the blood, urine, fecal matter and saliva gathered, participants will spend a night in a metabolic chamber, get their brains scanned, have their their immune systems transplanted into mice, and their neurons grown in a petri dish. After years of patient advocacy – at least in this one study – ME/CFS has abruptly transitioned from being one of the poorest studied diseases of all to getting an array of cutting-edge technologies thrown at it.

NIH intramural study net me/CFS

The NIH is casting a wide, wide net in its intramural ME/CFS study

Featuring top researchers at the NIH’s big research hospital its results are guaranteed to get noticed. This one study won’t solve ME/CFS – no one study can do that –  but it could and really should provide dramatic new insights into it, and, most importantly, provide the foundation for years and years of study into it.  Nath, for instance, recently suggested the study could produce the bio-signature we’ve been seeking for years.

The study is basically a huge fishing expedition, an anomaly for an institution known for its strict adherence to hypothesis testing. The NIH is looking (and building data) just about everywhere in patients.

We probably have NIH Director Francis Collins to thank for that. Collins has more control and discretion over the intramural site than any other part of the NIH and it shows. Collins got this study started before the NIH allocated money for the research centers. He wanted and got Avindra Nath – a highly prestigious researcher specializing in neuro-infectious diseases – to lead it and he got the NIH to bring out its fishing poles and fish.

Round One: The NIH’s “Deep Phenotyping Exercise”

Not only is the breadth of the study unusual, but the rigor with which it’s being run is unmatched. The first part of the study (participants come in for two rounds of testing) is partially being done to ensure that only one kind of patient participates. This is an important point since the ME/CFS disease population is very heterogeneous and mounting studies are identifying distinct subgroups.

In order to capture post-infectious ME/CFS patients, the study requires participants to have a sudden flu-like onset that’s been documented in a doctor’s files.  After taking questionnaire after questionnaire, a complete review of a patient’s medical records are being made by a panel of ME/CFS experts. Dr. Dan Peterson noted that one patient’s file ran to 191 pages (he said read every one). Dr. Peterson, longtime expert ME/CFS clinician and Simmaron Scientific Advisor, is reviewing patient selection for the NIH Intramural study.

Even the ME/CFS doctors reviewing the patient records have been taken aback at times with the strictness of the study. Dr. Peterson relayed one incident where Brian Walitt’s questioning of whether a patient should be included in the study raised eyebrows. (Walitt is the clinical lead investigator. Wallitt promptly dug into the Canadian Consensus Criteria to show the exact criteria the patient didn’t meet.)

Dr. Peterson noted that the reviewers have debated how “sudden” a sudden onset needs to be for someone to be included in the study. Does a patient have to remember the exact date they became ill or is something more general sufficient?

Another interesting twist concerns the rigor with which prospective patients have been tested. ME/CFS doctors that do more testing that others are more likely to find something that could kick a patient out of the study. That same patient coming from an ME/CFS doctor that doesn’t do a lot of testing might get into the study.

The first part of the study is apparently an attempt to level the playing field. Test after test after test is being done during the nine days a) to gather data and b) to ensure that nothing other than ME/CFS (and specified co-morbid diseases) is going on in these patients. At least in these early stages anything that looks off is being investigated. The NIH is calling the visit a “deep phenotyping” exercise.

An ME/CFS Patient Reports: Brian Vastag on Round One of the Intramural Study

It was fitting that Brian Vastag be one of the first ME/CFS patients to go through the first part of the study. He did after all, play a role in getting it started.

Vastag’s  “Dear Dr. Collins: I’m Disabled. Can the N.I.H. Spare a Few Dimes?” piece effectively used Vastag’s personal story to highlight the devastating funding problem and, importantly, provide a way out of the problem that was probably very appealing to Collins. (The dark humor in the piece didn’t hurt either.)

Francis Collins - Brian Vastag

Francis Collins, the Director of the NIH stops by for a visit. Vastag pushed for more ME/CFS funding and asked for ME/CFS to be assigned to a single institute

Vastag used to work for the NIH; in fact, Vastag worked with John Burklow, Francis Collins’ right hand man for communications for years. Vastag also worked with the Journal of American Medical Association (JAMA), and then reported for the Washington Post on science and medical issues. He knows the NIH well and used his personal connection to Collins to lobby for more funding.

He got in the study the old-fashioned way – by emailing the study recruiter.  In the months leading up to his stay, Vastag reported he had several conversations with the lead clinical investigator, Dr. Brian Wallitt, provided his medical records, was fully informed what he was in for and was provided several opportunities to bow out if he chose.

Thus far the reviews of Dr. Walitt from two people (Dr. Peterson, Vastag) participating with him have been positive.  Dr. Peterson said he found him attentive and interested, and Vastag, who said he spent a lot of time with him, found him available and dedicated.

Vastag spent five or six hours relaying his medical history to Dr. Walitt and nine full days in the NIH hospital. The history, he said, was very detailed.

Some people have worried that the ME/CFS patients well enough to participate in the NIH’s intramural aren’t sick enough to get results. Brian Vastag is exhibit number one why that hopefully is not the case.

When Vastag got sick he got really sick. At one point, he was 98% bedbound.  On his eighth or nineth doctor journey, Vastag saw neurologists and got checked out at a multiple sclerosis clinic.  Now he’s probably moderately ill for an ME/CFS patient and has to limit his walking to about 2 blocks a day; e.g. Vastag cant work at all, and he’s functionally very limited.

My guess is that if you can only walk two blocks a day without getting whacked there is something seriously, seriously wrong with you. Ditto with work; if you can’t work without getting hammered you have something seriously wrong with you that should be discoverable.

Having moderately ill people (by ME/CFS standards) participate in a study may not get the sickest patients in the study but it also brings with it the bonus that researchers don’t have to worry about the confounding factors that severe deconditioning brings. If there’s something to find in the testing the NIH is doing it should be found in these patients.

Cutting-Edge Technology

“I can’t believe they are letting us do all this stuff”.

Brian Walitt, MD MPH

The NIH is after all, throwing a lot of new technology at this disease. Vastag was told the intramural researchers have the green light to do a deep exploration of this disease and to let the evidence take them where it will.  They also have carte blanche to add to the study if the need arises.

Nath-Vastag-NIH

Avindra Nath stops by. Vastag said Nath had a great sense of humor. (Photo by Beth Mazur)

The head of Clinical Neurology at the Intramural Center, Avindra (Avi) Nath, heads the study. Nath has co-authored hundreds of journal articles and is on the editorial board of several journals. His main research focus – on the effects of infection on the brain – couldn’t be better suited to ME/CFS.

His latest paper on the cerebral spinal fluid in the survivors of the Ebola epidemic is exactly the kind of post-infectious work he’s been tasked with doing in ME/CFS. His 2016 review of Ebola survivors highlighted the functional declines seen in those who survived the outbreak. The study also noted that joint and muscle pains were “persistent problems” in more than half the 200 plus survivors assessed.

“Tellingly, the survivors reported a functional decline when compared with before the EVD outbreak. In comparison with the household contacts, the survivors were more likely to report a decline in both overall health (70% vs 18%) and ability to work (70% vs 7%).”

Nath told Dr. Peterson, after Peterson’s NIH talk on epidemic presentations of ME/CFS, that the Incline Village outbreak was probably an infectious encephalitis type of outbreak but that the technology at the time wasn’t up to diagnosing it. Nath has also collaborated often with Dr. Ian Lipkin on infectious diseases, and we know Lipkin’s work in ME/CFS is refining our understanding of immunity in the disease. Nath’s 2015 review paper demonstrated that the HIV virus may be able to survive in reservoirs in the brain indefinitely.

Nath will oversee a huge amount of work and do some cutting-edge work of his own. Using a new technique developed in his lab, Nath will knock out the immune systems of transgenic mice and give them the immune systems of ME/CFS patients.  He’ll also turn white blood cells from ME/CFS patients into “brains in a dish” neurons grown in the lab that Nath can then test. This technique, pioneered by Nath for other neurological diseases, can point highlight certain types of cellular problems.

A ton of data is being gathered in the first part of the study.  Besides his half a day of questionnaires, Vastag had standard labs done, provided his spinal fluid, did a sleep study, got 3.4 billion white blood cells drawn for Nath’s experimental studies, had his blood drawn for the Sea horse (mitochondria/energy production) study, had an EMG done to rule out muscle myopathy, did a tilt table test( positive for POTS), an MRI, and gave samples for the metabolomics part of the study. Just about every “tissue” possible, from blood, to urine, to cheek swabs to cerebral spinal fluid was gathered.

Seahorse-Vastag-chronic-fatigue

Rebekah Feng is studying the mitochondria in ME/CFS

Some results may already be showing up.  The Seahorse study results from just three patients were unusual enough that the intramural mitochondrial expert came down to Brian’s room and chatted with him.

Part II of the study will require a week’s stay and include an exercise test on a stationary bicycle, sleeping in a metabolic chamber, cognitive testing, and more blood and other tests.

The study’s only down-side appears to be its size and the time it is taking. Vastag reported that Nath expressed regret that the study was taking so long and told him that he was trying to speed things up. A couple of months ago, Vastag said he was the fourth patient to go through the study. At the NIH Telebriefing Nath said ten people have now gone through the first part of the study and one will start the second part at the end of July. Since the second part of the study was originally slated to begin in fall, it appears that Nath may indeed have speed things up.

Some researchers and doctors have expressed concern about the study’s forty-patient size, but Nath is convinced he can peel off any subsets with the patient group he has to work with.

 

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Even “Minor” Infections Can Cause Chronic Fatigue Syndrome (ME/CFS)

Giardia hasn’t historically ranked high as a potential cause of chronic fatigue syndrome (ME/CFS). Some anecdotal reports suggest that a Giardia outbreak may have occurred prior to the Incline Village ME/CFS outbreak in the 1980’s. More recently, Corinne Blandino’s severe, decades long case of ME/CFS – which originated with an exposure to Giardia at work – demonstrated how devastating a case of Giardia triggered ME/CFS can be.

Giardia long lasting effects

Giardia is thought of as a minor infection – but it can have long lasting effects.

It wasn’t until city in Norway got exposed to Giardia in 2004, however, that Giardia, a protozoa, became one of the pathogens definitively linked with chronic fatigue syndrome (ME/CFS). Large studies (n=1254) examining the aftermath of the outbreak in a public water system in Bergen found that five years later, almost 50% of those originally infected still had symptoms of irritable bowel syndrome and/or chronic fatigue (post-infectious chronic fatigue).

“Other patients suffer a severe, long lasting illness, for which treatment is ineffectual, and even after the parasite has finally been eliminated, some sequelae persist, affecting quality of life and continuing to cause the patient discomfort or pain” (LJ Robertson et al, 2010)

Five percent suffered from fatigue severe enough for them to lose employment or be unable to continue their education. Interestingly, all had taken anti-parasitic drugs and all had apparently cleared the pathogen from their systems.  Five years later, 30% were deemed to have an ME/CFS-like illness and almost 40% had irritable bowel syndrome  (IBS).

“Minor” Infection – Sometimes Serious Results

By all accounts Giardia shouldn’t be doing this. Giardia is not normally considered a serious infection. Most people have some diarrhea and pass the bug quickly – and if they don’t, antibiotics are usually (but not always) effective. Giardia, seemingly, produces the kind of “minor” infection that our medical system doesn’t spend much time on.

The Mayo Clinic reports that Giardia infection (giardiasis) is one of the most common causes of waterborne illness in the United States. The parasites are found in backcountry streams and lakes throughout the U.S., but can also be found in municipal water supplies, swimming pools, whirlpool spas and wells. Giardia infection can be transmitted through food and person-to-person contact.

Research studies are slowly revealing that the effects of even vanquished Giardia infections can be long lasting for some. The Mayo Clinic reports that intestinal problems such as lactose intolerance  may be present long after the parasites are gone. (Even though half a dozen studies have been published on the Bergen outbreak, Mayo fails to note that long term issues with fatigue and pain (or ME/CFS) may result).

The Bergen studies indicate, however, that this rather common infection worldwide can cause long term and even at times debilitating fatigue as well. The takeaway lesson from the Bergen studies is that one doesn’t need to have mono, Ross-River virus or Valley fever or any of several serious infections to get seriously afflicted. As Dr. Chia has been saying about enteroviruses for years, any minor infection has the potential to cause ME/CFS in the right person.

The Galland-Giardia Chronic Fatigue Syndrome (ME/CFS) Connection

The Norwegians wrongly reported that they were the first to associate fatigue with Giardia infections, but they couldn’t be blamed for thinking so. Way back in 1989, an integrative doctor named Dr. Galland suggested that Giardia infections were associated with ME/CFS. That year, Galland reported at a scientific conference that Giardia might be more common in ME/CFS than expected. Using a new test, Galland found active Giardia infection in 46 per cent of his chronic fatigue syndrome (ME/CFS) patients. (Galland noted that many of his patients may have picked up the bug during travel to foreign countries).

In 1990 Galland published a paper “Giardia lamblia infection as a cause of chronic fatigue.” in the Journal of Nutritional Medicine. (The paper never appeared on PubMed, the main English research database, apparently because of the journal it was published in. Citations from present and past journals devoted to ME/CFS have never appeared in PubMed either.)

chronic fatigue - giardia

Galland found the most devastating long term symptom after a Giardi infection was not gut pain but fatigue

Interestingly, given the involvement of a pathogenic gut protazoan, the patients’ gut symptoms were relatively minor; it was their fatigue, muscle pain, muscle weakness, flu-like feelings, sweats and enlarged lymph nodes that stood out. Galland reported that treating the infection alleviated the fatigue in over 80% of his patients and removed the digestive complaints in 90%. In 1998 Galland reported that one outbreak of Giardia, in Placerville, California, “was followed by an epidemic of Chronic Fatigue Syndrome, which swept through the town’s residents”.

Galland found that a longer than usual treatment regimen was often necessary to clear the body of the bug. Instead of the normal five-day treatment, his average treatment regimen lasted three weeks and could extend to eight.  He has also reported treatment successes involving other parasites (Entamoeba hystolytica, Cyrptosporidium) and other diseases such as rheumatoid arthritis.

In 2011, Galland hadn’t let up on the ME/CFS/giardia/intestinal parasite angle, reporting that a woman with severe fatigue and dizziness (but not many gut symptoms) who had tested positive for Giardia slowly recovered under his anti-parasitic protocol. Citing a Johns Hopkins study indicating that 20 percent of healthy controls had antibodies to Giardia, Galland suggested that Giardia infections were much more common, particularly in small town water systems (such as Incline Village?), than previously suspected.

Giardia is probably not a common cause of ME/CFS: Dr. Peterson said he regularly tests for it but rarely finds it – but because it is usually treatable, it’s a test that probably everyone, particularly those who got ill after foreign travel, should get.

The biggest question for the ME/CFS community (and the Lyme community), though, is why, as with other infections, some people who get enough treatment to make the pathogen disappear are still ill.

Back to the Norwegians

Galland may have generated some buzz in integrative medicine circles, but it took the Norwegian researchers to get Giardia and ME/CFS on the map in the research world. Tests revealing increased numbers of cytotoxic (i.e. killer) T-cells indicated an immune system on the alert for a pathogen.  (Similar findings occur in herpesvirus and cytomegalovirus infections, infectious mononucleosis, etc.)

With the Norwegian studies indicating that depression and anxiety weren’t the culprits in the ME/CFS outbreak, several hypotheses popped up:

  • The Sneaky Pathogen theory – The pathogen wasn’t gone at all, it was laying low. Poor immune surveillance was allowing low, undetectable levels of the bug to produce low-grade inflammation that was causing fatigue, abdominal distress and other symptoms.
  • The Hit and Run Gut Attack Theory #1 – Before it was overcome, the water-borne pathogen permanently damaged the lining of the intestines causing problems with gut permeability, hypersensitivity, bacterial overgrowth, immune reactions (fatigue, etc.) and irritable bowel syndrome.
  • The Hit and Run Gut Attack Theory #2 – the pathogen triggered the activation of mast cells in the gut causing fatigue, hypersensitivity, IBS and other symptoms.

The Latest Study

Giardia-specific cellular immune responses in post-giardiasis chronic fatigue syndrome, Kurt Hanevik1, 2Email authorView ORCID ID profile, Einar Kristoffersen1, 3, Kristine Mørch1, 2, Kristin Paulsen Rye1, Steinar Sørnes1, Staffan Svärd4, Øystein Bruserud1 and Nina Langeland1, 2 BMC Immunology 201718:5 DOI: 10.1186/s12865-017-0190-3

The latest Norwegian study attempted to explain the lingering fatigue and other problems by testing immune responses (T-cell proliferation assay, T cell activation and cytokine release analysis) to Giardia in 20 Giardia exposed fatigued individuals, 10 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls.

The study did not find increased immune responses to Giardia (including T-cell activation or cytokine responses) in the post-infectious Giardia group. The still ill Giardia patients did, however, have higher levels of a key immune marker called sCD40L implicated in inflammation and in severe symptom flares in ME/CFS patients after exercise.

giardia question chronic fatigue syndrome

No one knows why 5-10% of the post-giardiasis patients are still sick

Why these patients – five years after their Giardia infection was resolved – are still ill remains a mystery, but the link between Giardia infections and subsequent chronic illnesses is growing.  A higher incidence of Giardia infection was recently found in lupus. Just this year, a study found an association between Giardia infection and the subsequent development of arthritis.  A 4,000 person study recently confirmed an association between Giardia infection and the development of irritable bowel syndrome.  That study’s findings were buttressed by an earlier study indicating that Giardia induces gut hypersensitivity in rats long after the parasite had been cleared.

How Giardia is setting some people up for subsequent illnesses such as ME/CFS, arthritis, lupus or IBS isn’t entirely clear.  It is clear, though, that particularly virulent strains of Giardia that cause more damage might be involved.  Giardiasis can damage the microvilli of the intestines and promote inflammation. Eight months after the apparent resolution of Giardia, signs of gut inflammation were present in almost 50% of the Bergen cohort. (That high number suggested that the Bergen cohort may have been hit by a particularly virulent strain of Giardia.)  Protracted levels of gut inflammation resulting in systemic inflammation – as some suspect is present in ME/CFS – could explain the fatigue and other problems that remained.

“Host responses” may be important as well. Reduced levels of gut arginine at the time of infection may result in more gut damage. Although T-cells are the big guns in the immune response to pathogens, one study suggested that one’s gut microbiome makeup played a bigger factor in preventing/allowing a serious infection to occur.

Some findings in the Norwegian Giardia outbreak mirror others seen in post-infectious ME/CFS illness states. Greater illness severity, whether characterized by increased symptom severity, more time spent in bed and/or a more difficult time ridding the body of the infection have been found to predispose people with infectious mononucleosis or giardiasis to coming down with ME/CFS.  Being female is another risk factor.

Prior illnesses may make a difference as well. Prior gut symptoms increased the risk of fatigue, etc., after a giardia infection but, interestingly, not more gut problems. This indicated, as has been shown before, that a lack of gut symptoms does not necessarily rule out the gut as a central factor in disease.

The Post-Infectious Cohort

Whether the pathogen involved is Ross-River virus, Q-fever, Epstein-Barr Virus, Giardia or other gut pathogens such as Campylobacter, Salmonella, Shigella, Escherichia coli and Trichinella spiralis, a year or so later, from 5-10% of those afflicted are still ill. Infections, whether cleared or not, clearly can have long-term consequences.  The link between infectious mononucleosis and multiple sclerosis is a classic example. Dozens of studies indicate that having infectious mononucleosis increases one’s risk of later coming down with multiple sclerosis.

The Simmaron Research Foundation is continuing its efforts to examine the role unusual infections may play in ME/CFS with its support of the Konnie Knox study examining the role that vector-borne (bird/insect borne) infections may play in ME/CFS.

 

Simmaron Goes to Washington

June 25, 2017

Simmaron, Meet CFSAC

simmaron logoStarting this week, Simmaron Research will serve as one of three non-voting organizations on the federal Chronic Fatigue Syndrome Advisory Committee that makes recommendations to the Assistant Secretary of Health and federal health agencies on the unmet needs of ME/CFS patients.

A federal advisory committee on ME/CFS may not seem like a hot topic but there’s no denying that it’s a vitally important one. Even at its current low levels, the federal government funds many times more ME/CFS research than any other entity. Federal decisions affect how this disease is diagnosed, viewed and treated.  Given that reach into ME/CFS matters, any committee with the potential to effect federal government action is vital indeed.

Since Simmaron Research is committed to redefining how ME/CFS is understood and treated, it will seek to add its voice to others on CFSAC to urge a stronger federal action plan.

An N of One

CFSAC (Chronic Fatigue Syndrome Advisory Committee) is actually special. Many advisory committees exist in HHS and its agencies, but almost all focus on broad biological issues. CFSAC is one of a select few focused entirely on one disease. Formed when the feds were under attack for misappropriation of CFS funds, CFSAC was meant to give ME/CFS insulation from the prevailing bias in federal agencies, and provide a direct avenue to decision makers at the Department of Health and Human Services.

IMG_3223It hasn’t always worked out that way. CFSAC has provided many strong recommendations to the Secretary or Assistant Secretary of Health over the years, some of which have been acted on, but many of which have not, to the deep frustration of the community.  The committee’s potential, though, is great. CFSAC’s twice yearly meetings provide one of the only constant forums for dialog between the ME/CFS community and federal health agencies, and it is a critical window into federal work, as well as a reminder of the extent of patients’ unmet need. It’s strength is its unique blend of government-appointed outside experts, advocates and federal representatives.

CFSAC has had it’s shining moments. Its rejection of Dr. Reeves’s reappointment as CDC ME/CFS chief almost certainly played a role in his ouster when the Obama administration came in. Arguably the most important report in ME/CFS’s history, the Institute of Medicine (IOM) report “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness“, came out of CFSAC recommendations and was initiated by the committee’s Designated Federal Officer. Similarly, the “NIH Pathways to Prevention” report on ME/CFS research needs, which provided the foundation for the upcoming establishment of the first NIH Research Centers for ME/CFS in over 15 years, emanated from CFSAC recommendations and NIH’s ex-officio to the committee.

A New CFSAC Member (Who Isn’t New to CFSAC)

Robert Miller and patients seek NIH funding at CFSAC, 2010

Robert Miller and patients seek NIH funding at CFSAC, 2010

ME/CFS advocate and Simmaron board member, Courtney Miller, will represent Simmaron Research and the ME/CFS patient community at CFSAC for the next two years. Married to longtime patient Bob Miller, Courtney is an experienced advocate who will continue to push the federal government to increase the resources this disease so desperately needs.

The Millers’ advocacy efforts, which date back decades, include many presentations at CFSAC and participation at ME/CFS meetings and conferences, such as the NIH State of the Knowledge Conference, the FDA Advisory Committee on Ampligen, the NIH Pathways to Prevention Working Group, and the Institute of Medicine Workshop.  Over the years, she and Bob Obama and Courtney questionhave met with numerous high-ranking federal officials, including soliciting a promise from President Obama at a Town Hall meeting which led to a high-ranking official from his administration engaging in ME/CFS matters. Working with many advocates, Courtney has helped prepare pages of recommendations to NIH to inform its renewed research program. Their goal has always been stronger research funding and access to treatments for ME/CFS patients.

A Look to the Future

Simmaron Research believes great opportunity for an impactful federal program on ME/CFS is ahead of us.

The compelling IOM and P2P reports and increasingly prominent ME/CFS research publications (including Simmaron collaborations) marked a turning point in 2015 for the federal government and the disease. Director Francis Collins announced a renewal of NIH’s ME/CFS research program and brought it under the leadership of Dr. Walter Koroshetz, Director of the National Institute for Neurological Diseases and Stroke (NINDS).  A comprehensive NIH Intramural Study is underway and new NIH research centers will soon be funded. A reinvigorated community advocacy campaign led by SolveMECFS and MEAction is generating increased Congressional and media scrutiny. The building blocks of a sustained, permanent program to improve federal action on ME/CFS are starting to come together.

Sacramento Millions Missing Rally June 2017

Sacramento Millions Missing Rally June 2017

“Given the advances in science and increased recognition of ME/CFS over the last couple of years, I believe we are facing the best opportunity in this disease’s history for a federal response worthy of patients’ crushing unmet need. And yet, we have a long way to go. I hope to work together with advocates to build on the momentum of CFSAC to achieve increasingly higher levels of interaction and engagement with federal agencies responsible for our health. The government’s primary goal has to be finding evidence-based treatments for seriously ill patients.” Courtney Miller

Simmaron hopes to continue the strong advocacy of the patient organizations that served for the last two years on CFSAC and the experts who continue to serve.

CFSAC:  The Nuts and Bolts

One of ten advisory committees overseen by the Office of the Assistant Secretary of Health (OASH), CFSAC is tasked with providing “advice and recommendations” to the federal government on everything from federal research efforts to disability to provider information.

CFSAC consists of 13 voting members from the research, healthcare and patient communities, 8 non-voting ex-officio members from branches of the federal government (CDC, NIH, FDA, etc.)  and 3 non-voting members from patient organizations.  The three non-voting members from patient organizations now include Simmaron Research, The Massachusetts CFIDS/ME & FM Association and ME Action.

CFSAC holds two two-day meetings a year: a webinar-based meeting and a public meeting.  The meetings usually contain presentations on ME/CFS from invited experts, patients and caregivers; reports from internal CFSAC groups on topics of interest; reports from the NIH, CDC and other branches of the federal government on their activities; and conclude with recommendations to the Assistant Secretary of Health from CFSAC itself.

Courtney Miller will be presenting on Simmaron’s behalf in the next CFSAC meeting in four days on June 29th from 1:30 to 2:30 pm EST. Check out CFSAC’s agenda and listen to her’s and other’s presentation using this call in number (1-888-788-9429) and Passcode: 4510479

The Evolution of a Chronic Fatigue Syndrome (ME/CFS) Researcher? CBT Proponent Calls for More Herpesvirus Research

At times Dr. Wyller of Oslo University has seemed more like a Norwegian version of Simon Wessely than anything else. He’s shown that biological issues were present in ME/CFS, but always manages to come back to the psychological or behavioral elements he believes are perpetuating the disease. His new research, however, is taking him in another direction.

anxiety-fear

Wyller appears to believe that the fatigue in ME/CFS is the result of a false alarm in the same way that pain is in fibromyalgia

Wyller’s research group has highlighted sympathetic nervous activation and inflammation in chronic fatigue syndrome (ME/CFS) adolescents. His “sustained arousal” hypothesis, however, is a mishmash of physiological (infections, genetics) and psychological components (psychosocial challenges, illness perceptions, poor control over symptoms, “inappropriate learning processes”, personality traits, etc.).

That hypothesis posits that a “false-fatigue alarm” state exists in ME/CFS which is largely held in place by classical and/or operant conditioning. That conditioning can be ameliorated by behavioral techniques which tamp down the “alarm” and the sympathetic nervous system activation.

Wyller’s belief that ME/CFS is an infection/stress triggered disease of sympathetic nervous system (SNS) activation, however, took a hit when clonidine – an SNS inhibitor – actually made ME/CFS adolescents worse. Since SNS activation is arguably present and would certainly contribute to the inflammation in ME/CFS, that result probably shocked just about everyone. It suggested, though, that just as in some cases of POTS, the sympathetic nervous system activation found might be a compensatory, not pathological, response to the illness.

Wyller  admits that that CBT’s “effect size” is “modest” and that there is little evidence that it helps sicker patients, but asserts that the evidence-base is “so-solid” that it should be attempted in every patient.

“We believe the evidence base for cognitive behavioural therapy is so solid that all patients with chronic fatigue syndrome/myalgic encephalomyelitis should be offered this treatment.” Wyller et. al.

Wyller 2017: the Evolution of an ME/CFS Researcher?

Wyller may be a CBT/GET apologist, but he’s mostly done physiological research, and whatever his CBT/GET beliefs, it’s difficult to pigeonhole him. His failed Clonidine trial constituted a biological approach to ME/CFS plus his 2016 followup study suggested that a genetic polymorphism in the COMT gene may be responsible for reduced physical activity and impaired sleep and quality of life in some ME/CFS patients.

It’s Wyller’s latest study, however, that takes him into entirely new ground. To his credit, he’s allowing the data to lead him where it will.

Wyller is clearly heavily invested in CBT/GET, while his Norwegian counterparts, Drs. Fluge and Mella, eschew CBT/GET and focus on Rituximab and immune modulation. Wyller mentioned Rituximab in his 2015 overview, but not surprisingly gave it short shrift because of the lack, what else, of follow up studies. But here’s Wyller in 2017 with a study that’s pointing an arrow right at the B-cells in ME/CFS and perhaps even Rituximab.

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival. Chinh Bkrong Nguyen,1,2 Lene Alsøe,3 Jessica M. Lindvall,4 Dag Sulheim,5 Even Fagermoen,6 Anette Winger,7 Mari Kaarbø,8 Hilde Nilsen,3 and Vegard Bruun Wyller. J Transl Med. 2017; 15: 102. Published online 2017 May 11. doi:  10.1186/s12967-017-1201-0

Using his own definition of ME/CFS, Wyller and his research team took a deep look at gene expression using a technology called high throughput sequencing (HTS) which has not been used before in ME/CFS. You never know what exploratory studies like this will turn up.

The 176 genes whose expression was highlighted in the ME/CFS group most prominently featured a down-regulation of genes involved in B-cell differentiation. The activity of five genes involved in B-cell development, proliferation, migration and survival were significantly reduced in Wyller’s ME/CFS adolescents.

Wyller chronic fatigue syndrome

Wyller’s research is leading him into some unexpected areas

This finding, Wyller reported, jived with findings from the Australians of decreased levels of some B-cells and increased levels of others. (Decreases in the gene expression of genes regulating B-cell proliferation could result in either reductions or increases in different types of B-cells).

At the same time the B-cells in his ME/CFS adolescents were taking a hit, the expression of their innate immune system genes were being upregulated. Interestingly, given the idea that a pathogen is whacking the B-cells in ME/CFS, the expression of several genes associated with pathogen defense were increased in ME/CFS. (Wyller, in fact, reported this was the first time that increased expression of genes associated with innate antiviral responses has been seen in ME/CFS.)

Then, remarkably, Wyller – who recently criticized antivirals as he argued that CBT/GET should be the treatment of choice in ME/CFS – asserted that this finding could reflect problems his ME/CFS adolescents were having with clearing latent herpesviruses.

They “might suggest less efficient viral clearance or reactivation of latent viruses such as members of the herpes virus family, in the CFS group” Study Authors.

Then Wyller suggested that “inefficient viral clearance or reactivation” or chronic viral infection-triggered immune dysfunction warrants further study in ME/CFS.

Then he referred to a remarkable 2014 German study which suggested that a deficient B- and T-cell memory response to EBV may be making it difficult for ME/CFS patients to control EBV infections. That’s really no surprise to the ME/CFS community; it’s long been clear that infectious mononucleosis is a common trigger for people with ME/CFS and FM – but it’s for a CBT proponent to make the connection.

Herpes viruses continue to show up ME/CFS research

Herpes viruses continue to show up ME/CFS research

Finally, Wyller’s study suggested that neither inactivity nor mood disorders had any effect on the biological findings presented. (One of his earlier studies discounted the idea that deconditioning was a relevant factor. )

Wyller’s findings are good news, not just because he’s been so committed to his idea that “classical or operant conditioning” perpetuates ME/CFS, or that he’s been such a robust CBT/GET advocate, but because he has shown the ability to get funding.

His next step is to determine how effectively the B cells in ME/CFS are responding to EBV antigens (VCA, EBNA-1) before and after the introduction of stress hormones. If he finds that B-cells are not doing their job with respect to EBV, then both Wyller and the ME/CFS research field are going to have a take a closer look at the role EBV plays in ME/CFS. What a switch that would be!

Wyller isn’t the only one diving back into the herpesviruses.  Two Solve ME/CFS Initiative studies are examining metabolic issues in B-cells and cells infected with HHV-6. Plus studies into B-cell issues in ME/CFS are continuing.

One wonders what further positive results would do to Wyller’s view of the appropriate treatments for ME/CFS. Given the tendency of herpes viruses to reactivate during stressful situations, stress reduction techniques (CBT, meditation, MSBR) might, in fact, be useful, but more importantly, so might antivirals, and immune  modulating drugs like Rituximab or cyclophosphamide.

It’s possible that at some point that researchers on both sides of the ME/CFS divide will someday meet in the middle.

 

Making Music – and a Difference – for ME/CFS

May 28, 2017

Making Music For ME/CFS

For the second time this month, the loved one of an ME/CFS patient has dedicated talent and sacrifice to raise funding for Simmaron Research and awareness of the disease more broadly.

Michael Jasper met Terry’s husband, Silvestre, 13 years ago and over time the two couples became best friends, even like family to each other but for a while they were a family with a mystery: Terry would mysteriously disappear at times. When the Jaspars were told she had something called “chronic fatigue syndrome” the explanation helped even as it obscured.

terri sylvestre

Terri Gilmete – in her scooter – advocating for ME/CFS

It wasn’t until Michael and his wife Marie saw a screening of “The Forgotten Plague” earlier this year that they really began to  understand what was going on. Terry wasn’t just tired – she was really sick! They’d seen her only on her best days, which unfortunately were few and far between.

“The Forgotten Plague” turned out to be a line of demarcation for them. They’d pounded Terry with questions about the disease after that. They now know the history, they know the neglect, they know the seeds of change that are sprouting now and they wanted to do something for their friend.

Several months later Michael asked for a meeting and when Terry was well enough Michael and his family broke the news: he was resurrecting his music career and wanted to dedicate the song “Beachwalk” to Terry and the ME/CFS community. He’d composed it years before, and when he and his daughter, Marissa, got to work on the album, it was the first song they’d worked on.

Michael told me that he’d played in the greatest garage bands that never made it. Along the way, he’d played and toured around the world with many figures in the music industry. Now as he re-emerged into the music scene he was putting those connections to good use – having them join him on the new album he and his daughter – who, having just graduated from college with a degree in music –  were going to release in December.  Merging old and new –  his old-school R & B and funk roots with her contemporary pop and dance sound – the album will have a unique sound.

Beachwalk-flyerBeachwalk’s melody described for him a simple pleasure that few people with ME/CFS could enjoy:  a relaxing walk on the beach, the sun overhead, the sand in their toes – a walk that left them relaxed and rejuvenated. Such an easy thing to contemplate for most people but just a dream for Terry and so many others.

For me I heard the keyboards, horn and guitar singing a song of triumph; a song celebrating someone finally making it to their beach after years of effort. It was an uplifting feeling.

Music for Simmaron

It was out of a vision of Terry, their good friend of many years, and others with ME/CFS finally taking their well-deserved walk on the beach, that Michael is donating 50% of the proceeds from the sale of Beachwalk to the Simmaron Research Foundation to help people with ME/CFS.

Please take a  walk on the beach with Michael Jaspar, his daughter Marissa  and other as they play for Terry Gilmete and others with ME/CFS to support Simmaron. You can find Beachwalk:

Check out Jaspar 3D’s Facebook page here. Michael didn’t stop his advocacy with Beachwalk – he’s fully engaged and promoting ME/CFS events on it – including the June 2nd Millions Missing Rally in Sacramento.

Millions Missing Rally & a Song in Sacramento on June 2nd

The problem, of course, is that people with ME/CFS aren’t able to walk far, if at all. They’re largely missing from the rounds of daily life – an absence dramatically evoked by the MillionsMissing rallies featuring ME/CFS supporters and their shoes.

Millions Missing

Terry Gilmete and Linda Tannenbaum

This Friday, June 2, patients and loved ones will gather on the steps of the Capitol in Sacramento for a MillionsMissing Rally and a live debut of the Jaspars’ Beachwalk.

The Sacramento Rally featuring Terry Gilmete, Michael Jaspar and others has a story all its own. The woman who organized it, Marilyn Yu, also created “The Forgotten Plague” screening which opened Michael Jaspar’s eyes and got him, his wife and daughter involved. In 2016, Marilyn, who’s had ME/CFS for three years, got West Sacramento, Elk Grove and Sacramento to do proclamations of their own. She’s gotten the Sacramento City buildings lit up in blue for the  past 2 years. The Sacramento Convention Marque featured May 12 as ME/CFS Awareness Day. Marilyn also created a virtual run last year in which she raised some money for Simmaron.

On May 18th, a number of California patients including Terry Gilmete and Marilyn Yu met with Senator Glazers and Moorlach to sponsor SCR-40 which proclaimed May 12th ME/CFS Awareness day and the month of May Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Month in California. Senator Moorlach passionately spoke of his friend’s daughter who’s been disabled from ME/CFS for 18 years.

The striking and, in many ways, beautiful California resolution resolved that…

  • WHEREAS, ME/CFS has been found by the National Academy of Medicine to be “a serious, chronic, complex, and systemic disease that frequently and dramatically limits the activities of affected patients,” leaving them with a lower quality of life than patients with multiple sclerosis, stroke, renal failure, heart failure, and other chronic diseases; and
  • WHEREAS, The lack of tracking for ME/CFS by the CDC and the grossly inadequate NIH funding for research based on disease burden have hindered progress in diagnosing and treating ME/CFS, such that there is no FDA-approved treatment for the disease; and
  • WHEREAS, ME/CFS is a tragic and disabling disease that destroys the lives of many patients and imposes a severe toll on their families, friends, and caretakers;
  • WHEREAS, The economic impact of ME/CFS in the United States is estimated to be $20 billion to $50 billion per year (CDC February 2016) and likely costs the California economy billions of dollars in health care costs, patient care, lost productivity, and lost tax revenues;
From Australian Rally

From Australian Rally

The Legislature hereby proclaims May 12, 2017, as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Day, and declares the month of May 2017, and each May thereafter, as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Month, to help spread awareness of the disease and the need for increased research funding, and to support individuals living with ME/CFS;…

On June 2nd, Michael Jaspar, Marilyn Yu, Terri Gilmete and others will all be at ME/CFS Millions Missing Rally in Sacramento at the CA State Capitol Steps-south side on June 2 from 11:30-1:30. A shoe exhibit will be on display from 10:30-4. The music will be an inspiration all our own in the ME/CFS community.

  • When: June 2, 2017, 10:30-4:00 shoe display, 11:30-1:30 rally and musical debut
  • Where:  CA State Capitol Steps-south side

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