All posts by Cort Johnson

Making the Case for Ampligen in Chronic Fatigue Syndrome (ME/CFS)

Ampligen has been in the FDA pipeline for so many years that it almost seems like a mirage at this point. The ME/CFS community has been praying, hoping, believing that Ampligen will be its first FDA approved drug for over twenty years. For a lot of people that hope may have died, but the drug has gotten new life recently.

A Little History

If Ampligen has failed to gain approval at least it and the company have been entertaining. Ironically, given its long and rather harrowing path through the FDA, Ampligen’s first use in an ME/CFS patient was prompted by none other than the FDA. After an ME/CFS patient with culture evidence of HHV-6 infection significantly improved clinical trials began.

Ampligen has trod a difficult path at the FDA over the past twenty years.

Ampligen has trod a difficult path at the FDA over the past twenty years.

Problems occurred early on, however, when Hemispherx Biopharma, the drug’s maker, cut the trial duration in half, and ME/CFS patients sued at one point to get access to the drug. The early Ampligen trials in chronic fatigue syndrome ultimately sparked the publication of a hilarious novel by Floyd Skloot, Patient 002.

The company came under fire early. In the early 1990’s CAA President Kim Kenney (McCleary) said “Ampligen is a good drug in the wrong hands”.  Daniel Hoth, then head of the National Institutes of Health’s AIDS drug program, went further when he told the Wall Street journal that “no professional drug company with any degree of professionalism would ever develop Ampligen the way it was developed by HEM.”

Difficult Path

Hemispherx Biopharma, though, has never had an easy time of it. In what surely must be a record for frustration for a drug company, Ampligen was moved to a different section of the FDA four times; each move eliciting a new review and different findings.

The FDA panel’s rejection of Ampligen in 2013 provided more head-shaking moments when two ME/CFS experts  unexpectedly voted against it, and several non- ME/CFS experts (citing the community’s urgent needs) voted to approve it.

Hemispherx felt blindsided at the hearing by safety issues it been told had been addressed years ago, and which it didn’t feel it was given adequate time to respond to.  (Since then FDA officials have said safety is not a major issue). It’s no wonder the company has felt at times that the deck has been stacked against them.

With the FDA asking for large drug trials that HB lacked the funds to produce, Ampligen finally seemed to be dead, but a new push to understand ME/CFS at the NIH may be producing a sea change for the drug.

Patients Push FDA To Approve Drug

More than anyone, ME/CFS patients know of the cost of having no FDA approved drugs.  Patient outcry at the FDA denial of Ampligen in 2013 – including an 11-day hunger strike by patient Robert Miller, 5,000 signatures petitioning the FDA to reconsider, and thousands of emails from patients and Congresspeople flooding the FDA – prompted the FDA to conduct a Drug Development Workshop in 2014 and publish guidance for the industry on ME/CFS drug development.

The FDA’s effort to spur drug company interest in ME/CFS appears to have failed, however, leaving Ampligen still the only drug candidate within short-term reach of drug approval for a disease that the FDA acknowledges urgently needs approved treatments.

With NIH director Francis Collin’s commitment to reinvigorate  chronic fatigue syndrome (ME/CFS) research and mentioning the possibility of an NIH funded Ampligen trial, it’s time to take another look at the “first” drug for ME/CFS.

Renewal

Equels-Thomas

Thomas Equels has vowed to make the company attractive to investors

The Board of Hemispherx Biopharma (HB) responded to the new climate of interest by replacing its longtime President and CEO, William Carter, with its Chief Financial Officer, Thomas Equels. Equels vowed to whip company into better financial shape in order to attract investors who could help get Ampligen FDA approval. FDA approval of Ampligen, he declared was HB’s number one priority, and he would work arm in arm with the FDA to achieve that.

Ampligen

Ampligen is an immunomodulator that targets a portion of the immune system that fights viruses.  Ampligen’s producer, Hemispherx Biopharma, was surely cheered by  the assignment of a major NIH study  to a neuroinfectious disease specialist, Dr. Avindra Nath.

Ampligen’s use in ME/CFS is predicated on the idea that viruses and/or immune issues are playing havoc in the disease. Ampligen is a toll -like receptor three (TLR-3) inducer. The receptor it binds to are found on antigen presenting cells such as dendritic cells that have been exposed to pathogens.

The binding of the receptor activates hundreds of genes in a cell. The side effects from most TLR inducing drugs limits their effectiveness, but Ampligen is unique among these drugs in that it does not cause cells to produce large amounts of pro-inflammatory cytokines.

Efficacy

Reports of Ampligen’s ability to dramatically improve the health of some people with ME/CFS abound.

The 90,000 doses given safely through Hemispherx Biopharma’s compassionate care program to ME/CFS patients by a handful of doctors in the U.S. have produced some startling stories of improvement and recovery.

success

Ampligen’s success stories attest to the drugs effectiveness in some people

Anita Patton, Mary Schweitzer, Bob Miller and Kelvin Lord have all documented their Ampligen success stories. Several experienced significant improvement while on it only to relapse while off it.  Anita Patton essentially went from bed bound to normal functioning on Ampligen, back to being bed bound off of it, and then again to normal functioning when back on the drug.

Kelvin Lord’s story was perhaps most representative. He’s provided the most complete (and funniest) review of an ME/CFS patient’s experience with Ampligen in a series of blogs titled “The Ampligen Chronicles”.  Faced with rapidly deteriorating health, Ampligen was Kelvin Lord’s last shot at health. To his surprise and delight it worked.

It didn’t return this businessman, flight instructor, skier and parasailor to complete health, but Kelvin did progress from being barely able to walk to be able to work 6 hours and do 45 minutes of resistance exercises a day. His brain fog, orthostatic intolerance, canker sores and extreme fatigue disappeared. He was back to being a productive human being for a major part of his day – a huge jump. (Read about it here.)  Going from bed bound to productive is probably a bigger jump, it should be noted, than most FDA approved drugs provide.

(Find other stories in Health Rising’s Ampligen Resource Page.)

Of course, examples of Ampligen’s lack of efficacy can be found as well, but this is to be expected given the  heterogeneous nature of ME/CFS.  Until the subsets in ME/CFS can be targeted with treatments unique to them, treatment efficacy even for most effective treatments, is probably going to be fairly low – perhaps around the 30-40% mark found in Ampligen.

Studies

“The drug has not received a marketing approval despite the lack of proven efficacious agents in the treatment of this disease that can be severely debilitating and is estimated to effect over one million persons in the US.” The author

W.M. Mitchell, a Vanderbilt pathologist and HB Board member, recently published an overview of Ampligen in a pharmaceutical journal. (Mitchell recently co-authored a study which reported finding a significantly more accurate blood test for prostate cancer.)

Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/ myalgic encephalomyelitis (cfs/me). Mitchell WM. Expert Rev Clin Pharmacol. 2016 Apr 5.

Thirteen Ampligen trails have been done over the past 20 years or so.  Nine occurred in severely ill prior fatigue syndrome patients; three of these were large multisite trials and five were open label trials measuring safety and efficacy.  All told over 830 different ME/CFS patients have received over 90,000 doses of Ampligen. Most of the patients in the studies had been ill for at least 6-9 years.

The results of the trials have been positive. The first 92 person trial found significant increases in Karnofsky performance scores (p<.001), quality of life, exercise tolerance and oxygen utilization during exercise. Ampligen receiving patients also used significantly less drugs to alleviate their symptoms than placebo receiving patients.

The number of patients seeking emergency room care demonstrated how severely ill the patients in the study were, and how helpful Ampligen might be if it were available.  Ampligen cut the number of patients visiting the emergency room in half (from 15% to <8%). The placebo patients stayed an average of eight days at the hospital, while the Ampligen receiving patients stayed an average of less than three days.

(In how many diseases would 15% of the patients in the clinical trial spend an average of 8 days at a hospital over the duration of the trial? This was a very severely ill cohort.)

exercise

Ampligen reduced exercise intolerance and increased oxygen utilization

The primary endpoint of next  234 person trial was exercise intolerance. The results, which barely reached the minimum standard of significance (p< .05/ p<.048), indicated that exercise tolerance increased on average about 22%. Overall Ampligen improved VO2 max results on the exercise test by 5.5%, and Ampligen receiving patients were able to stay on the treadmill for about nine minutes longer than placebo receiving patients.

Further analyses found 3 cohorts of patients with regards to exercise tolerance; high responders, mild responders and no responders. Overall patients on the drug improved significantly more than patients given placebo (p<.001).

As in the first study, hospital visits were significantly reduced in the Ampligen receiving cohort and Karnofsky performance scores were significantly increased.

The two clinical studies suggest that 30-40% of people with severe ME/CFS can be expected to get “clinical benefit” from Ampligen.

The trials were mostly successful, but did have their problems.  The company stopped the first trial early and then modified the second trial in midstream. Even though the second trial was successful a great deal of discussion at the FDA hearing involved why the trial was modified.  Records could have better kept as well.

From the ME/CFS communities perspective, though, the success of both trials  was paramount. Many felt the lapses should have overlooked given the urgent need for treatments in such a large and often disabling disease.  Many also felt that the positive testimony by doctors who had been using the drug for years should have been given more weight.

Conclusion

While there were some problems with the trials the drug did meet several important endpoints including increasing time on a treadmill and increased oxygen utilization. It should be noted that Ampligen has tried to move the needle on probably the most difficult factor of all to budge in ME/CFS: oxygen utilization during exercise.

Any drug providing clinical benefit to 30-40% of a population which has no approved drugs should be a slam dunk. (Less effective drugs have been readily approved in other illnesses). Hopefully, with new leadership, Hemispherx’s twenty plus year journey to bring Ampligen to market will end successfully, and the ME/CFS community will finally get its first drug approved.

 

 

 

 

 

 

 

 

 

New Hemispherx Prez Says Getting Ampligen Approval Top Priority

It seems like Hemispherx Biopharma – the maker of Ampligen – has been the under the gun for years.  Last year it settled a 2012 class action lawsuit alleging it made false and misleading claims about Ampligen. It endured another lawsuit in 2009 for more alleged federal securities violations. Last year it was called “a penny-stock firm with a penchant for hype” by Damien Garde at Fierce Biotech.

decline

Hemispherx Biopharma’s financial resources have declined recently

According to Investor Wired Hemipsherx’s net loss including non-cash effects, averaged about $12 million or $(0.05) a share in the first nine months of the last two years.With regards to cash, cash equivalents and marketable securities the company lost about $4 million in the first nine months of 2015  ($16,108,000 – $12,375,000).

The news has not been all bad, though. Hemispherx Biopharma was rated the ninth best performing health care stock of 2012. Citing Hemispherx’s ability to achieve additional patent protection for Ampligen in Europe through 2029, Investor Wired put Hemispherx Biopharma on its “Biotech Stocks to Watch List” at the end of last year. It’s all more of the roller-coaster for Ampligen and Hemispherx Biopharma.

The fact that Ampligen is even still around may be something of a small miracle.  It’s hard to envision a more difficult drug pathway than for a small drug company producing a drug for a controversial disease like ME/CFS.

It’s a telling sign of drug company wariness towards ME/CFS that decades after Ampligen was introduced, it’s still the only drug to go through the FDA approval process for the disease, and no other drugs are in sight. Until FDA approves the first medicine for ME/CFS, no significant investment in this disease will likely come from the pharma industry. Ampligen represents an important logjam in ME/CFS treatment that has to be solved.

For all the difficulty surrounding Hemispherx, it should be noted that the company managed to keep Ampligen alive long enough to hopefully take advantage of the changed landscape for ME/CFS.

Change at the Top

A new era for chronic fatigue syndrome (ME/CFS)  appears to be dawning at the NIH. With Francis Collins, the head of the NIH, taking the lead in the fight to understand and treat ME/CFS, a window of opportunity has opened for Ampligen.

Equels-Thomas

Equels declared that Ampligen is Hemispherx’s number one priority

Hemispherx Biopharma’s first move to capitalize on that opportunity was to fire its long time CEO and Chairman, William Carter (and two of his relatives) and elevate Thomas Equels, former Chief Financial Officer and Executive Vice Chairman to the Presidency.

Stating that it was re-examining its fundamental priorities, Hemispherx Biopharma’s (HB’s) board pledged it would implement a “strong financial austerity plan”.  (In 2014, Carter made $2,364,874 including about $2,000,000 in cash and a $894,000 bonus.)  Equels was given a mandate to “strengthen internal controls, achieve enhanced governance, and create an environment for greater stockholder value.” Equels was brought in, in other words, to institute a new era of efficiency and productivity in order to appeal to investors.

In an interview Equels stated that “commitment, integrity and cooperation” were to be the new bylines for Hemispherx. He made it clear – in fact, he repeatedly emphasized –  that Hemispherx Biopharma’s number one goal was getting FDA approval for Ampligen for chronic fatigue syndrome (ME/CFS). To that end, Hemispherx was developing an “overarching strategy” to pull in public and private investors to move the drug forward. Acknowledging that Hemispherx’s resources were limited at this point, he said he’d be pulling the plug on all non-priority activities.

That overarching strategy includes fixing Hemispherx’s strained relationship with the FDA. There’s been no love lost between the FDA and Hemispherx Biopharma. Several advocates told me they held their breath whenever the sometimes fiery Carter spoke at the FDA hearing. Some felt Hemispherx was treated unduly harshly, and not given the opportunity to respond when safety issues the company thought were resolved came to the fore.

race for Ampligen

Can Equels finally bring Ampligen across the finish line?

The FDA, however, acknowledges that ME/CFS community urgently needs drug options, and FDA officials have said that the safety issues for the drug have been resolved. Some advocates that have met with them believe they are eager to move forward on ME/CFS.

Equels said he’d met with Janet Woodcock at the FDA to understand where the FDA sees the gaps.  He pledged Hemispherx would be there “arms locked with FDA officials” to do what was necessary to move the drug forward.  Hemispherx officials also apparently quickly talked with NINDS chief Dr. Koroshetz  not long after NIH Director Collins announced the NIH would reinvigorate ME/CFS research.

At the end of the day, Equels said, we have a proven therapy – it’s about bringing it across the finish line.

Next up: Making the Case For Ampligen

(Disclosure: Hemispherx Biopharma has contributed funding to a project underway at Health Rising.)

Are Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Immune Exhaustion Disorders?

March 21, 2016

When we think of immune problems we often think of the immune system going berserk and attacking healthy cells but another kind of immune issue called can be present. Recent studies suggest immune exhaustion may be more of a problem for many chronic fatigue syndrome (ME/CFS) and/or fibromyalgia patients than an immune system run amok.

CHRONIC FATIGUE SYNDROME (ME/CFS)

“I think what we’re seeing is an immune system exhaustion over time” Dr. Mady Hornig

Chronic fatigue syndrome (ME/CFS) has generally been thought of as an immune activation disorder. Although much of the interest in the Lipkin/Hornig 2015 study focused on the immune activation found early in the disease, the study found 13 downregulated immune factors in the plasma of longer duration patients relative to the healthy controls.  Remarkably the same cytokines that were upregulated early in the disease were downregulated later in the disease.

exhaustion

Are ME/CFS and fibromyalgia immune exhaustion disorders?

That pattern smacked of something called “immune exhaustion”. Immune exhaustion is a well-known pattern of immune depletion seen in people with chronic infections or autoinflammatory diseases.  Immune exhaustion may be the main reason why some people just can’t knock an infection.

The patterns seen in the big 2015 Lipkin/Hornig Chronic Fatigue Initiative immune blood study were intriguing but not conclusive. Studies published since then, though, suggest that immune exhaustion – not immune activation – could be the main culprit in people with longer duration chronic fatigue syndrome (ME/CFS) and fibromyalgia.

It should be noted, again, how important it was to differentiate shorter from longer duration patients. No immune abnormalities when the two subsets were mixed; only when they were differentiated by disease duration did the immune issues pop up.

The Simmaron Research/Lipkin/Hornig Spinal Fluid Study

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome.Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, Che X, Lipkin WI.Mol Psychiatry. 2016 Feb;21(2):261-9. doi: 10.1038/mp.2015.29. Epub 2015 Mar 31.PMID: 25824300

Next came the Lipkin/Hornig/Simmaron Research Foundation study examining immune factors in the spinal fluid of ME/CFS and multiple sclerosis patients and healthy controls. Not only was a broad pattern of immune inhibition found in the longer duration patients but for the first time match between blood and spinal fluid study was found: the same issues appeared to be occurring in both the central nervous system and the body.

The number of downregulated immune factors – twenty-one in all (vs 13 in the blood study) in the spinal fluid of longer duration ME/CFS patients relative to healthy controls was notable and suggested that the closer one moves to the brain the more evidence of immune exhaustion one may find.

Both ME/CFS and MS patients exhibited immune exhaustion compared to healthy controls but the degree of immune exhaustion seen in ME/CFS was greater than that seen in MS. Demonstrating how complex the immune system is, the two diseases differed more from each other than from the healthy controls.

viral infection

An upregulated chemokine suggests that a viral infection could have triggered central nervous system changes in ME/CFS and MS

In one perhaps important way, though, they were quite alike. A chemokine called CXCL10 that clears the way for the entry of natural killer cells and T lymphocytes into the brain in response to a viral infection was increased in both disorders.  Increased levels of that chemokine in conjunction with the different kinds of immune exhaustion found in both disorders suggests that either different viruses could be present or a different response to the same virus has occurred.

The fact that infectious mononucleosis or glandular fever increases the risk of coming down with either ME/CFS or multiple sclerosis is intriguing in this regard. Could ME/CFS and MS simply reflect differing responses to the same virus?

Jarred Younger recently suggested that MS may be a more damaging form of ME/CFS. Neuroinflammation is present in both, but in one (MS) the neurons are damaged and in the other (ME/CFS) they are not.

Very high levels of CXCL10, such as appear to be present in MS, are associated with nerve damage. More moderately raised levels, such as seen in ME/CFS, are not. CXCL10 levels may also be able to tell us which patients respond better to antivirals. Hepatitis C and HIV patients with higher CXCL10 levels responded less well to antivirals than patients with lower levels.

The Lipkin spinal fluid study is looking more and more like it could end up being a seminal study.  It highlighted a new subset – “the Peterson subset” and validated and expanded on the dramatic immune downregulation seen in the earlier blood study.

A follow-up Simmaron Research/Lipkin/Hornig spinal fluid study is in the works.

The spinal fluid study wasn’t the end of the trend towards immune downregulation, though; right on its heels came the large Landi-Houghton blood study.

The Simmaron Research Foundation Australian Spinal Fluid Study

Mediators Inflamm. 2015;2015:929720. doi: 10.1155/2015/929720. Epub 2015 Mar 5.Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis.

The Simmaron Research Foundation also participated with Sonya Marshall-Gradisnik at Griffith University in a small pre-pilot spinal fluid study. In this smaller study only one immune factor, IL-10, significantly differed between the ME/CFS patients and the healthy controls but the trend was the same; IL-10 was significantly reduced in the ME/CFS patients.

This study may tell us how immune depletion in one area can lead to immune activation in another. Because IL-10 is an anti-inflammatory, reduced IL-10 levels in the cerebral spinal fluid could reflect a brain with inflammation.

The Houghton-Landi Blood Study

Cytokine. 2016 Feb;78:27-36. doi: 10.1016/j.cyto.2015.11.018. Epub 2015 Nov 28. Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome. Landi A1, Broadhurst D2, Vernon SD3, Tyrrell DL4, Houghton M5.

Michael Houghton isn’t just any researcher. A Lasker award winner, he got bit by the ME/CFS bug during the XMRV saga. (He got bit so hard that the Solve ME/CFS Initiative even got him onto the federal advisory panel for ME/CFS ( CFSAC) for a while.)  Researchers of his ilk are a real asset to our community and it’s good to see him remaining engaged. In this study he worked with Bateman-Horne Center’s “Research Czarista” Suzanne Vernon.

The Landi-Houghton study examined 34 immune and growth factors in no less than 100 longer duration ME/CFS patients.  This study also found little evidence of overt immune activation. Instead,  a cluster of down-regulated immune factors ( IL-16, IL-7 and VEGF-A) popped up which suggested ME/CFS –  at least in its later stages – was more characterized by immune depletion. They also suggested that ME/CFS patients might be a aging a bit more rapidly than normal.

Early Aging?

 

Immune depletion showed up in longer duration patients in the Houghton study

Immune depletion showed up in longer duration patients in the Houghton study

IL-7 plays a critical role in NK and T-cell proliferation and induction and IL-7 levels are associated with cognitive declines during aging. The authors suggested that the immune signature they found could mimic aging. It’s not the first result to suggest early aging may be present in either ME/CFS or FM.

One FM study found cognitive declines suggestive of people who were twenty years older.  Reduced telomere lengths (a sign of aging) were found in the white blood cells for FM patients and the CDC has reported finding reduced telomere length in chronic fatigue syndrome as well.

Two Factors Stand Out

VEGF-A – VEGF-A promotes the survival and stability of endothelial cells lining the blood vessels, stimulates muscle and blood vessels and has neuroprotective factors.  It also promotes neuron growth by stimulating epithelial cells to release BDNF – which appears to be low in ME/CFS.

VEGF-A is becoming a factor to look out for in ME/CFS. For one thing it affects the blood vessels. For another reduced VEGF-A levels also popped up in the Simmaron Foundation/Lipkin/Hornig spinal fluid study and in a Gulf War Syndrome study .

Eotaxin – Eotaxin has suddenly appeared on the ME/CFS scene. It was one of only two factors upregulated in the spinal fluid study. Remarkably, high eotaxin levels have been found in long duration patients in three recent studies.

Increased levels of eotaxin have been associated with impaired learning, memory deficits and reduced neuron production in mice as they age.

These consistently increased eotaxin levels could signify either an allergic response a central nervous system infection.

FIBROMYALGIA

The results of immune studies in FM are mixed but three recent studies suggest a scenario of immune depletion may be occurring in FM as well.

A 2012 study found that immune cells from FM patients that were stimulated with an antigen failed to respond as readily as did those of healthy controls.  The dramatic reductions – from 1.5 fold to 10-fold of normal – were found across a wide range of immune factors (IFN-γ, IL-5, IL-6, IL-8, IL-10, MIP-1β, MCP-1 and MIP1-α).

Another fibromyalgia study found a “stark decrease: in the levels of three Th2 cytokines (IL-4, IL-5, and IL-13). Because the cytokines with lowered levels had anti-inflammatory effects the authors speculated that inflammation might be increased in FM. Note that reductions of these anti-inflammatory cytokines (and IL-10 in ME/CFS) might be all that is needed for normal levels of pro-inflammatory cytokines to produce inflammatory effects.

Similar trends toward reduced levels of anti-inflammatory cytokines has also been found in  depression.

Exercise Study Reveals Immune Depletion

J Neuroimmunol. 2014 Dec 15;277(1-2):160-7. doi: 10.1016/j.jneuroim.2014.10.003. Epub 2014 Oct 18.Preliminary evidence of a blunted anti-inflammatory response to exhaustive exercise in fibromyalgia. Torgrimson-Ojerio B1, Ross RL2, Dieckmann NF3, Avery S4, Bennett RM5, Jones KD6, Guarino AJ7, Wood LJ8.

Another fibromyalgia study found a marked difference between the immune and hormonal responses of healthy controls during exercise and FM patients. Four anti-inflammatory factors (IL-6, IL-10, ACTH, and cortisol) increased and two pro-inflammatory factors (TNF-a, IL-8) decreased during exercise in the healthy controls.

The anti-inflammatory response, however, was blunted in FM patients (ACTH, cortisol, and IL-10)  during exercise.

exercise fibromyalgia

Exercise was associated with immune depletion in one fibromyalgia study.

This study also found normal IL- 6 levels which was a surprise given the reductions in IL-10 (another anti-inflammatory cytokine) found.  (IL-6 production by the muscle cells during exercise is believed to trigger IL-10 production.)

That odd finding suggested another way to inhibit anti-inflammatory activity. The authors speculated that FM patients’ muscles may be pumping out normal levels of IL-6, but the signal IL-6 produces to create anti-inflammatory products is simply not getting through.

They suggested that a reduced anti-inflammatory response during exercise could very well play a role in the pain FM patients associate with exercise. Anti-inflammatory cytokines stop the pain receptors on nerves from being activated. Take away those cytokines and FM patients could experience increased pain during exercise.

The authors proposed that a quick immune hit during exercise could be responsible for lasting pain, stiffness and fatigue FM patients experience after exercise.

Conclusion

While some studies differ, recent studies suggest a broad pattern of immune exhaustion may be taking place in both chronic fatigue syndrome and fibromyalgia. That exhaustion is most likely caused by what Lipkin and Hornig called an “exuberant stimulation” of the immune system due to an auto-inflammatory process or a chronic infection.

It’s possible that exhaustion in one part of our carefully balanced immune systems could lead to undue prominence of another part.  Lipkin and Hornig suggested the immune reductions in the spinal fluid found suggested that immune activation might be occurring in the central nervous system. Likewise the FM study suggested the depletion of Th2 factors suggested immune activation could be occurring even though levels of pro-inflammatory cytokines were not increased.

Immune exhaustion is a serious issue in several diseases and efforts are being made to battle it. How the medical profession is tackling immune exhaustion is a subject for another blog.

Ian Lipkin: Three to Five Years* to Solve Chronic Fatigue Syndrome (ME/CFS)

December 26, 2015

Ian Lipkin flew to Lake Tahoe this December to fundraise for work he’s doing with the Simmaron Research Foundation. In a talk covering his virus hunting career, the threat of pathogens to humanity, and his work with chronic fatigue syndrome (ME/CFS), he dropped a bombshell: he stated that he believes it’s possible to solve ME/CFS in three to five years. 

On that hopeful note, let’s learn more about Dr. Lipkin, his work, and his collaborations with Simmaron.

Dr. Peterson’s Introduction

Lipkin’s Columbia Center for Infection and Immunity (CII) has established close ties with the Simmaron Research Foundation. Only a couple of months before, his chief collaborator, Mady Hornig (and Simmaron Scientific Advisory Board member) had given a talk.  Now Ian Lipkin was here.

Dr. Peterson started his introduction of Ian Lipkin by noting that he’d known him since they crossed paths in the 1980’s when Dr. Peterson sent him patients suffering from HIV/AIDS.

Lipkin has changed the ways researchers identify pathogens

Lipkin has changed the ways researchers identify pathogens

Ian Lipkin began a new era in pathogen detection when he became the first researcher to isolate a virus (Borna disease virus) using genetics.  He identified the West Nile Virus that had throw New York City into a panic, developed technologies to identify SARS and then hand carried 10,000 test kits to Beijing at the height of the outbreak. He most recently discovered a highly dangerous virus that recently jumped into humans called MERS (Middle Eastern Respiratory Syndrome Coronavirus).

Lipkin has pioneered many technological breakthroughs in finding pathogens including the use of MassTag-PCR, the GreeneChip Diagnostic, and High Throughput Sequencing. His latest breakthrough is the development of a new screening technique that enhances researchers ability to find viruses 10,000 fold.

Called the top virus hunter in the world, Ian Lipkin runs the Center for Infection and Immunity at Columbia, and is the director of the Center for Research in Diagnostics and Discovery (CRDD) at the NIH. He also worked closely with Steven Soderbergh on his film Contagion.

Ian Lipkin Talks

Who says brilliant scientists can’t be a hoot to listen to as well? Ian Lipkin’s presentation was both enlightening and at times hilarious. Exhibiting a wry sense of humor, Lipkin poked fun at himself and virtually everyone around him.

The last time he was in Lake Tahoe, he said, was in 1984 and he hearkened back to the HIV/AIDS patients Dr. Peterson sent him in the early 1980’s.

“When you come to a fork in the road – take it!”

He stated the guiding principle in the search for pathogens could be summed up by the great Yogi Berra’s adage “When you come to a fork in the road – take it!”.

HIV/AIDS was the beginning of many changes. Even after the medical community knew it was being passed in the blood it still took them 2 1/2 years to find it. (In a Discover interview,  Lipkin noted that he ran the first clinic in San Francisco that would treat HIV/AIDS (then called GRID) patients with neurological problems. Note an iconoclastic element to Lipkin that showed up early in his career: he was willing to see patients others wouldn’t. Check out Lipkin’s fascinating story of how HIV/AIDS lead to him to study infectious diseases.)

Lipkin-chronic-fatigue-syndrome

Lipkin first showed a willingness to support underserved groups early in the HIV/AIDS epidemic

Lipkin then worked on a virus which demonstrated the effects a persistent viral infection can have on the central nervous system.

Next, in another story with possible overtones for chronic fatigue syndrome (ME/CFS), he investigated patients who’d come down with what appeared to be a mysterious psychiatric disorder. It took him two years but using a new method involving genetic cloning he uncovered the Borna disease virus. It was the first virus discovered using genetic means.

The Borna virus discovery was a game-changer for pathogen community. Jump forward thirty years(after it took the medical community almost three years to find HIV, and viruses are being discovered using molecular means every week. The Center for Infection and Immunity itself discovered 700 new viruses from 2009-2015.

Lipkin was aware of and interested in ME/CFS in the eighties but there was no money. In 1999 he and Britta Evangaard found no evidence of the Borna disease virus in ME/CFS. From there we jump forward to 2010 when NIH Director Francis Collins tasked Lipkin to determine if a retrovirus, XMRV, was causing ME/CFS. XMRV turned out to be a laboratory artifact, and the paper was retracted – something Lipkin said was not all that unusual in science. (He emphasized that he and Dr. Peterson were very careful to put out studies that would stand the test of time.)

The XMRV discovery tanked but proved to be a boon for ME/CFS by heightening the attention around it. Lipkin had kept an eye on ME/CFS for years and after being hired by the Chronic Fatigue Initiative to take it on, he was back in a big way.

In the next portion of his talk he turned to viruses and humans.

Viruses and Humans

How are most viruses getting into humans? From animals. After it’s jump from primates to humans, HIV is, of course, the most familiar example, but viruses are also escaping from bats, birds, pigs, rodents, insects and even camels into humans.

A sea change in the viral field occurred in 1999 when a mosquito-borne virus – the West Nile Virus – had the audacity to attack the residents of the New York City. Lipkin shifted his work from the West to East coasts to search for the virus and ultimately identified it. As the outbreak spread, it got the attention of Senator Joesph Lieberman who sponsored the first big initiative to learn how viruses spread from animals to humans. Politicians, Lipkin noted, can be important allies.

Infections

Most pathogens have yet to be identified by humans.

New York City may be an ideal transit stop for new viruses. Twenty-one million passengers traveling to and from 72 countries pass through New York city airports every year. Animal products including bushmeat – all potentially contaminated with nasty viruses – pour into New York City regularly.

Many more viruses are undiscovered than have been discovered. A survey of one species of bats found fifty-five viruses, fifty of which were new to science. Lipkin estimated 320,000 viruses were still unknown and they’re bumping up against humans all the time. Lipkin next demonstrated how quickly they can jump from animals into humans.

Bats –  Called to investigate an ill Saudi Arabian man (with four wives), he uncovered a new virus called MERS (Middle East Respiratory Syndrome) similar to those found in bats. (Asked if there were any bats in the area, he was told no. The next video showed bats flying every which way in the area :)). If the bats weren’t biting the humans, though, how was the bat virus jumping into people?

Lipkin found MERS was present in about 75% of the camels in the country. Further research indicated that MERS jumped into camels in the 1990’s, and then rapidly escaped into humans around 2010.

MERS

Since its escape into humans around 2010 MERS has spread to 26 countries.

MERS is not particularly easy to transmit but once it gets transmitted, watch out. Death rates are high. It took just one Saudi Arabian to spread MERS to South Korea this year where it killed several dozen people, put several thousand others into quarantine and basically threw the country into a panic. Schools were closed, tourists stopped coming, and parts of the economy slumped as South Korea fought off the virus. It has since been found in 26 countries. It’s the kind of virus that keeps public health officials up at night.

It’s not surprising that Lipkin is wary of pathogens. He noted that he rarely shakes hands but darting a glance at Dr. Peterson said he’d made an exception that evening.

(If you haven’t seen Steven Soderbergh film “Contagion” and can handle apocalyptic scenario’s you might want to give it a try. Lipkin consulted extensively on the movie which involved a worst-case scenario of a virus wiping out much of humanity. The film was praised for its scientific accuracy. (Spoiler alert – we do survive in the end :)).

Ticks –  Coming closer to home Lipkin believes chronic Lyme patients who are not recovering from antibiotics may have gotten another infection from the ticks. He found that over 70% of the Ixodes scapularis ticks associated with Lyme disease carried at least one pathogen and 30% carried more than one in New York. Last year he identified a rhabdovirus (Long Island tick rhabdovirus) new not just to ticks but to science itself. A small survey suggested that 15% of residents may carry antibodies to the virus.

Rats- Lipkin’s  study of New York City’s second most common resident – rats – revealed they carried an amazing array of pathogens including Escherichia coli, Clostridium difficile, and Salmonella enterica, Bartonella spp., Streptobacillus moniliformis, Leptospira interrogans, and Seoul hantavirus.

In one of his many asides (did you know he loves Sinatra?) Lipkin referred to the hamburger and French fries lunch that he and Peterson  usually have. (“Do as we say not as we do” he said). How does Lipkin reportedly like his meat? “Burn it” he tells the waiter. The man is taking no chances – he knows too much.

Infection and Disease

timing-infections-lipkin

The timing of an infection is just one of many factors that determine the effects it will have.

A pathogen is just one of the players, however, in a vast swirl of factors which ultimately determines whether one is going to have a chronic illness. Timing, for instance, is a key factor.

If you expose a mouse to a pathogen at one stage of pregnancy, it’ll stop moving around its cage. If you expose the same mouse to the same pathogen later in pregnancy, it will run round and around its cage unceasingly.

A large autism study underscored the complex role timing plays in humans. The 120,000 person autism birth cohort study found that if a mother comes down with a fever after the first trimester, her chances of giving birth to a son with autism go up three-fold.  If she treats the fever with acetaminophen, her chances of giving birth to an autistic child drop significantly.  If she takes acetaminophen for any other problem than a fever, her risk of giving birth to an autistic child goes up again.

Three to Five Years – An ME/CFS Timeline

How does all this relate to ME/CFS? Likpin cited the findings of their work to date.

  • The suspected pathogens don’t appear to be the problem (the CII is reportedly looking further at herpesviruses.)
  • Evidence suggests altered microbiomes (gut flora) are present
  • Striking differences in immune expression between shorter and longer duration patients suggest profound immune changes have occurred
  • Preliminary evidence suggests that levels “X” and “Y” metabolites and, at least, one immune protein are significantly altered in ME/CFS. (Lipkin embargoed this information pending publication of the paper. One of them is a shocker.)

Lipkin emphasized, though, that ME/CFS is not a one-size fits all disease. For instance, it’s possible that fungi may be a problem for some patients. That’s an intriguing idea given the recent fungi funding in Alzheimer’s disease published in Nature.

Lipkin timeline chronic fatigue syndrome

Lipkin’s timeline for solving ME/CFS given enough resources – a mere three to five years.

Then Lipkin made his bold declaration “We’re going to solve this in three to five years”. It came with a significant proviso “provided the resources are made available” but indicated that he believes ME/CFS is a mystery that can be cracked fairly quickly.  That sounds really fast, but Lipkin’s time-frame is not that far off from Ronald Davis’s 5-10 year time-frame (provided he gets the resources as well.) (or Dr. Montoya’s).

These eminent researchers believe that given the technology present today we could understand ME/CFS fairly quickly – if enough resources were brought to bear.  Lipkin pointed to a slate of researchers in his lab working on ME/CFS to signify the major shift he’s seen happen in just the last couple of years. He said “I couldn’t have gotten them five years ago”.

He highlighted two places the patient community can make an impact:

  • Funding Pilot Studies –   The community can fund pilot studies which can be turned into big grants
  • Advocacy – Lipkin is a savvy researcher. He knows how the NIH works, and once again he emphasized the need for the ME/CFS community to push harder legislatively – to talk to their representatives in the House of Representatives, in particular – and get them to push the NIH for more funding.

Lipkin’s Bucket List

Ian Lipkin has clearly developed a special relationship with ME/CFS, Dr. Peterson, the Simmaron Research Institute. He hadn’t been in the Lake Tahoe area for decades, yet he and two of his assistants had flown across the country to support the Simmaron Research Institute’s spinal fluid work. He was even shaking hands.

lipkin bucket list chronic fatigue

Lipkin’s Bucket List contains two items: solving ME/CFS is one of them.

I shook my head – not for the first time – about Ian Lipkin. How had we gotten so lucky? Lipkin oversees the work of 65 researchers in the U.S. and 150 more across the globe. The New York Times reported that on any given day his lab had 140 viral research projects underway. The head of the National Institute of Allergy and Infectious Disease, Anthony Fauci said, “Lipkin really stands out from the crowd.”

Yet, here he was in the Lake Tahoe area in mid-December exhorting the audience to support an important Simmaron study that he believed needed funding.

What had driven the “The World’s Most Celebrated Virus Hunter” to take on our disease? I asked his assistants. They told me that Ian Lipkin wants to do two things more than anything else before he retires: he wants to solve ME/CFS, and he wants to solve autism. We’re on his bucket list.

That floored me even more (:)) so I asked – but, but…..doesn’t  he care what other people think about this neglected disease? That question left them almost gasping for breath. After they had been able to calm down, they assured me: no Ian Lipkin doesn’t care.

The Simmaron Research Foundation’s Next Spinal Fluid Study

Lipkin was at the event to support the Simmaron Research Institute’s next spinal fluid study. The results of the first one – the most extensive spinal fluid study ever done in ME/CFS – were eye-opening. Using Dr. Peterson’s suggestion to separate atypical from typical ME/CFS patients, and focusing on patients with a longer duration illness, they’d found evidence of an immune dysregulation almost equal to that found in MS. The difference was that instead of being raised, the cytokine levels were reduced in ME/CFS.

That finding surely left a big smile on Lipkin’s and Hornig’s faces.  Earlier they’d found evidence of a profound reduction in immune functioning in the blood of later-duration ME/CFS patients.  Now a similar reduction was showing up in their spinal fluid. These unprecedented findings suggested they were uncovering system-wide problems.

No wonder Lipkin was eager to begin a new and larger spinal fluid study: it’s part of achieving his bucket list.

SR_Donate_6.9.14_1

Triple Your Support! – Between now and Dec 31 triple your support for Ian Lipkin’s work with the Simmaron Research Foundation (SRF). A generous donor is offering to match $2 for every $1 donated before Dec 31. The funds will support the SRF’s collaborations with Drs. Ian Lipkin and Mady Hornig at Columbia University.

 

Dr. Peterson Talks – On Severely Ill Chronic Fatigue Syndrome Patients

November 23, 2015

(This blog was based on Dr. Peterson’s recent talk in Sweden. I added several sections such as the Mike Dessin interlude. They are outlined in parentheses.)

Dr. Daniel Peterson

Dr. Peterson was at the epicenter of Incline Village outbreak three decades ago that helped put chronic fatigue syndrome on the map. He’s been on the cutting edge of immunotherapies and antivirals ever since. He’s been using and gathering data on Ampligen for decades. He was the first to dare to use the powerful antiviral Vistide in ME/CFS and he used it successfully.

Dr. Peterson

Dr. Peterson has been treated people with ME/CFS for over 30 years.

Long before VO2 max exercise equipment showed up in ME/CFS experts offices he was using it. He saved his spinal fluid samples for decades waiting for the right investigator to show up. He was the first to recognize the possibility that non-Hodgkin’s lymphoma is increased in ME/CFS and pushed for studies.

His work with the Simmaron Research Institute has led him to collaborate with research groups around the world. A superb diagnostician, his recent characterization of ME/CFS patients into typical and atypical patients resulted in a successful spinal study – and introduced a subset researchers now need to be aware of. He and the Simmaron Research Institute produced the Immunology Workshop in an attempt to make immune testing a standard part of a physician’s protocol. He may have treated more people with ME/CFS than anyone else in the world.

Dr. Peterson recently spoke on severely ill ME/CFS in Sweden – a place he’s returned to again and again. Thankfully the Swedes have been videotaping their conferences for years. Let’s see what he had to say.

The Severely Ill

Peterson has a reputation for saying it like it is. He started off his talk stating that the really severely ill are like the elephant in the room everyone has danced around for years. Not because they’re not important but because so little is known about them. That, however, is changing.

Peterson pointed that prevalence estimates of the severely ill (25%) are simply guesses at this point. The really severely ill are so debilitated that they rare show up in doctor’s offices, and almost never participate in studies. They are often self-diagnosed and most lack insurance. Visits to the emergency room are rare simply because the emergency room has nothing to offer them and often makes them worse.

Interlude – Mike Dessin’s Story

Mike Dessin is one of the few severely ill ME/CFS patients to have fully recovered. He has an interesting tie-in with Dr. Peterson. When Mike was still relatively healthy he meet Dr. Peterson and afterwards sent his test results to him. Peterson never treated Mike but Mike’s test results were all wrong end and Peterson predicted Mike was in for rough times.

He couldn’t have been more correct. Mike’s health continued to worsen until he was forced to retreat first to his Dad’s house and finally, too sensitive to endure human company, into an apartment. For over a year Mike lived in a blacked out apartment room wearing eye shades even in the dark. He became unable to tolerate foods and became emaciated.

He’s provided a stunning account of what the very severely ill experience.

Dessin,-Mike---emaciatedI was completely bedridden and unable to lean up more than a few inches. I was unable to read, write, understand words when spoken too, or complete a thought process. I would not be able to tolerate touch, whispers or even be able to sustain a mere thought process without getting over stimulated!!! If I was pushed too far mentally I would have a seizure from the over-stimulation.

He believes the overstimulation problems are the most problematic severe ME/CFS patients face.

I believe by far this is the most debilitating and confining element of severe M.E. This is what drives people with M.E. into complete isolation.

Simply getting to a doctor’s office was challenging. Wearing eye shades and ear muffs he said:

“I crawled into my dad’s car. We arrived at the doctor’s office where I crawled my way into the lobby. I laid in the lobby until my name was called. Dad lifted me up onto the table and the doctor walked in. At this point I could only stay conscious when I was stimulated so he put his hands on my shoulders to awaken me.”

The first sign that Mike was beginning to recover was finding a blob of fat on his tush. He began to recognize the items around him, to tolerate light, eat and read short sentences.

Mike Dessin is living proof that it’s possible to go right up to the edge and almost fully recover. He’s also a living example of how difficult it is treat the severely ill.  Other patients visited his doctor yet none responded as Mike did.

Dr. Peterson’s characterization of the severe or very severe ill patients as being “bed bound” at some point in their illness brings up the question whether people who are bed bound at some point in their illness end up being the most difficult to treat. That idea would seem to fit the Dubbo findings which indicated that people with the most severe symptoms after an infection were most likely to come down with ME/CFS.

How sick did you get in the first couple of years – and how are you now? Take

Peterson noted, however, that ME/CFS is not unidirectional – that relapses and remissions can occur unpredictably.

(One of Dr. Peterson’s patients, Corinne Blandino, provides a poignant example of this unpredictability. When she first saw Dr. Peterson she had been wheelchair bound for many years. She improved to the point where she was able to get out and drive and travel but then suddenly and unexpectedly she relapsed. Later she was found to have a spinal fluid lesion.

A Health Rising survey indicated that a subset of patients experience dramatic remissions that are often at some point followed by relapses. Some have undergone several cycles of remissions and relapses.)

exhaustion

If you become bed bound at some point are you less likely to get better?

Peterson also noted that a CDC study found that unless significant recovery began in the first five years of the illness complete recovery is unlikely. When asked later about the importance of treating patients early he said it took him years to learn that the best approach with acute post-infection patients – people who have recently become ill – was to immediately aggressively treat them with immunoglobulin and antivirals.

What about longer term patients – the ones that are probably most prone to be severely ill. Dr. Horning cautioned that the CFI’s immune study showing drops in immune activity after three years needs to be replicated but suggested that immunomodulating drugs like Ampligen and Anakinra could be helpful in longer duration patients.

Dr. Peterson noted that the severely ill are the most difficult patients to treat and have the most guarded outcomes.

(Whitney Dafoe is a good example of how difficult to treat these patients can be. Whitney is located in the San Francisco Bay area – as ME/CFS knowledgeable a place as any. Whitney has had the resources to try many different options but all have failed and some have made him worse. The same was true for Mike Dessin. Glutathione IV’s, alpha lipoic acid and other detoxification treatments that have been helpful for some patients left him worse off and may have set the stage for his almost complete relapse.

Neither were rapid onset either. While both probably had infectious onset their slide to debilitating health was a gradual one. They just kept slipping backwards.

Many doctors probably don’t know where to start and are probably justifiably worried if they treat the severely ill aggressively they’re going to do something to kill them. These patients are delicate in the extreme.)

Basic Support

Dr. Peterson stated, however, there are basic things any doctor can do. Hydration, nutrition, appropriate physical therapy and “intervention based on present pathophysiology” are standard approaches to ME/CFS that can be employed. He recommended the Primer for Clinical Practitioners produced by the IACFS/ME for a good symptom by symptom approach to ME/CFS.

Peterson cautioned that rigorous pacing and energy conservation should not be considered the only treatments but strongly recommended them. He’s found the use of heart rate and blood pressure monitoring devices such as the Fitbit and Apple Watch to be helpful in keeping patients “in the zone”.

saline-chronic-fatigue-syndrome

Regular use of saline can be helpful. A study underway will tell us more about salines effect on ME/CFS.

The effects of immobilization can be high. He recommend simple stretching to reduce muscle atrophy and joint problems; saline, midodrine and florinef to combat orthostatic intolerance; and IV nutrition to combat malnutrition. Peterson stated that he starts IV nutrition early.

Turning off the TV, reducing exposure to computer screens, wearing sunglasses, etc. can help with over stimulation.

In the discussion period Dr. Peterson said the question he always asks all patients is what is the one symptom you want most dealt with – just don’t choose fatigue. If brain-fog is a big problem he uses brain scans (SPECT, MRI) to inform his treatment options.  Increased intracranial pressure might lead to the use of Diamox, inflammation could trigger the use of anti-inflammatories, brainstem problems could result in Nuvigil or even amphetamine-based drugs. If orthostatic problems show up that interfere with blood flows to the brain Dr. Peterson said he goes after those aggressively.

When asked about long term anti-inflammatory therapy Dr. Peterson said he’s seen good short-term responses (increased energy and mental clarity) with steroids but worried about their long term effects.  He hasn’t had much experience with fecal transplants to assess them but feels he’s seen enough people trying stem cell transplants to suggest they’re not a viable option.

Drugs

Ampligen

The good news on the drug front is that Ampligen has been approved for use in Europe and Turkey. Ampligen is an immune stimulator and antiviral that’s been approved for limited use in the U.S. since 1988. It’s not easy to get, though, and is quite expensive. It’s one of the few drugs shown to increase NK cell activity. Dr. Peterson gave Ampligen a strong endorsement stating that it’s the only therapy he’s seen in his three decades of work that’s been able to return ME/CFS patients to full health. He gets about a 70% response rate (not all of which get such strong results.)

Anakinra

IL01B

Dr. Peterson believes cytokine blockers could be helpful.

Anakinra – a soon to begin placebo-controlled, double-blinded trial in the Netherlands, Anakinra presents an intriguing possibility. Anakinra blocks the production of two cytokines, IL-1b and TNF-a, that are greatly increased in some ME/CFS patients. A safe drug, Dr. Peterson saw no reason not to test it and other cytokine blockers on the market right now.

(The Anakinra sudy authors noted that concentrations of cytokines in the blood rarely reflect what is happening in the brain. They proposed, therefore that the only way to accurately assess a cytokine’s contributions to a disease is to block them using drugs and see what happens.

Rituximab and Cytoxan

He also pointed to the Rituximab and Cytoxan trials now underway in Norway as possible treatments.

Caregivers are an incredibly important factor for the severely ill. Dr. Peterson encouraged caregivers to get more support for themselves, to take time for themselves and get counseling if necessary.

Hope for the Future

Open Medicine Foundation Study - Dr. Peterson highlighted the Ron Davis/Open Medicine Foundation severely ill big data study and proposed that ME/CFS’s signature does indeed burn more brightly in them. While welcoming it, he added some cautions regarding the small sample size and the enormous data set that will be generated.

He added that newer technologies such as Next Generation Sequencing (NGS) will enable more and more patients to be assessed more cheaply. (Ron Davis has reported that most of the methodological issues the study posed have been taken care and the study will begin soon.)

CDC Study – The huge, (huge) CDC multisite study will search the serum and saliva of 800 people (!) for biomarkers using RNA/DNA analysis and other techniques. This phase will also include 40 severely ill patients. That’s just five people per site but these patients are hard to find, and Peterson said that even his office was having trouble finding them.

Australian Work – The Australians are also beginning to differentiate immunological markers in the severely ill from moderately ill and healthy controls.

The Lipkin/Hornig CFI immune study Dr. Peterson and the Simmaron Research Foundation participated in suggested that longer duration patients – who are probably more likely to be severely ill – may suffer from immune exhaustion. That finding needs to be replicated but if its true immune enhancers may be more likely to help the more severely ill.

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Tea Time at Simmaron Pt II: The Infectious Cluster Study

KKnox

Konstance Knox, PhD Chair, Simmaron’s Scientific Advisory Board

In a recent  Simmaron Tea event, Simmaron’s research collaborators talked about their work to propel discovery in our disease. In Part 2 of our summary, we review Dr. Konstance Knox’s presentation on her collaboration to identify insect-borne pathogens in ME/CFS patients.

Dr. Knox, CEO of Coppe Healthcare Solutions, is a longtime collaborator of Simmaron Research and Dr. Daniel Peterson. A contributor to Simmaron’s spinal fluid studies, she has done years of viral testing and research in patients with ME/CFS and other diseases.

Dr. Konstance Knox – Insect-Borne Diseases and Chronic Fatigue Syndrome

From malaria to dengue fever to Lyme disease, “vector-borne”  (primarily mosquito and tick-borne) illnesses are among the more difficult challenges facing the medical community. While they are often associated with developing countries, people in the U.S. are not immune from them. Over 20 insect-borne illnesses occur in the U.S. and more are emerging.  A new tick-borne virus (Heartland Virus) was recently identified in the Midwest and Eastern U.S. and the dangerous tick-borne Pawossan virus was recently found in the eastern U.S. The first case of West Nile Virus in the Western Hemisphere was identified in New York in 1999. Five years later it was found in every state of the Union.

Bacteria ME/CFS

Many pathogens have been associated with ME/CFS but no one has looked at insect borne pathogens until now.

We know that infectious onset of chronic fatigue syndrome (ME/CFS) commonly occurs. We know it can be triggered by many different types of infections (Epstein-Barr virus, parvovirus, Giardia, SARS, hepatitis, etc.).

No study, however, has examined the extent of insect triggered illness or looked for regional clusters of such illnesses in chronic fatigue syndrome – until now.

Simmaron Research and Dr. Knox were awarded residual samples from the NIH XMRV study to comprehensively assess the incidence of insect-borne illnesses in ME/CFS patients across the U.S. Dr. Konstance Knox will lead the first study allowed to use the rigorously collected and characterized samples from the XMRV study.

The study builds on historical associations with ME/CFS that have been bypassed in recent years.

History Repeating Itself?

Insect-borne pathogens by their nature tend to form clusters of illness, and chronic fatigue syndrome, of course, first became well-known when clusters popped up in Incline Village/Lake Tahoe, Lyndonville and other cities in the early 1980’s. Dr. Knox reported that since 1934 at least 12 clusters have been identified in the U.S. including six in the Lake Tahoe region alone.

culex mosquito

Could your “flu” have come from a mosquito?

Over the past 20 years there’s been little focus on clusters.  From the Norwegian Giardia and Canadian SARS to the Ebolavirus outbreaks, however, every significant infectious outbreak has left behind a cluster of ME/CFS-like patients.

This study will look for clusters of regional insect-borne illnesses in ME/CFS patients in the U.S.  It is driven by the hypothesis that for some people the “flu” they never got over was not caused by some innocuous cold bug but resulted from a mosquito or tick bite.

Comprehensiveness is a keyword for this study. Now only will it involve hundreds of ME/CFS patients from across the U.S., it will also examine almost all possible insect-borne illnesses found in the U.S. including some that are rarely studied.  Studies of this size and scope have rarely been done in ME/CFS. The pathogens tested for include:

Tick-borne Pathogens

  • Borrelia burgdorferi – Ixodes scapularis, I. pacificus –found across  the U.S.
  • Tick-borne encephalitis virus (TBEV) – Europe and Russia, poorly studied in U.S.
  • Anaplasma phagocytophilum – Ixodes scapularis, I. pacificus – mostly eastern U.S.
  • Ehrlichia chaffeensis – Lone Star Tick – southeastern/southcentral U.S.
  • Babesia microti – Ixodes scapularis – northeastern/midwestern U.S.
  • Rickettsia rickettsia – American dog tick (Dermacentor variabilis), Rocky Mountain wood tick (Dermacentor andersoni), and brown dog tick (Rhipicephalus sanguineus) – across the U.S.
  • Coxiella burnetii – associated with cattle/goats/sheep – spread through dust – across the U.S.

Mosquito-borne Pathogens

  • West Nile Virus (WNV) – across the U.S.
  • Dengue Virus (DENV) – southeastern U.S./Texas
  • Eastern Equine Encephalitis Virus (EEEV) – eastern U.S.
  • Western Equine Encephalitis Virus (WEEV) – west of the Mississippi
  • Louis Encephalitis Virus (SLEV) – eastern and central U.S.
  • California Encephalitis Virus (CEV) – California
  • La Crosse Virus (LCV) – California

Possibly High Misdiagnosis Rates

Dr. Knox believes misdiagnosis rates of these infections could be high. Some are poorly studied and most doctors don’t know about many of them, anyway.  Plus unless severe symptoms are present many are rarely tested for . Sudden seizures or blindness may get you tested for West Nile virus, for instance, but more moderate flu-like symptoms it often produces probably will not.

Lyme disease map

Lyme disease is endemic in several parts of the U.S.

Post-infectious fatigue states following insect-borne infections appear to be common. Over 50% of people with an active West Nile Virus infection still experienced fatigue, cognitive problems, headaches and muscle weakness eighteen months later.  Dengue fever, which has re-emerged in the southeastern United States is known to leave behind an ME/CFS-like condition in some patients. Descriptions of virtually all these infections note the “long-term sequelae”; i.e. the long term effects they can leave behind.

Resolving a Medical Mystery?

Plus, a virus like tick-borne encephalitis virus (TBEV) could hold a clue to controversy that’s roiled the medical profession. Different groups assert that Lyme disease is either a) a relatively rare disease that responds well to antibiotics or b) a common disease that often does not respond to antibiotics and often persists in a chronic state.

Ticked Off? Simmaron is doing the research.

But what if they’re both looking in the wrong place? What if that tick bite transmitted a different infection along with the Borrelia – an infection that is resistant to antibiotics? Could the chronic Lyme disease patients are suffering from be a different, undiagnosed tick-borne illness?

Konstance Knox believes a good candidate may be tick-borne encephalitis virus (TBEV).  TBEV is common in Europe and Asia but has been inadequately studied in the U.S.  It can produce fatigue that can persist for years and it can be transmitted quickly.  People who pluck off a tick before it’s been on them for 24 hours may be relieved that it hasn’t transmitted Borrelia, but TBEV– which is almost never tested for in the U.S. – can be transmitted in fifteen minutes.

Simmaron Research | Give | Donate | Scientifically Redefining ME/CFS Dr. Knox believes she will find a much greater prevalence of exposure to insect borne infections than anyone expects at this point. She hopes this will be the first of many studies examining these illnesses.

Associating ME/CFS with an increased prevalence of insect borne infections would, of course, further legitimize the disease, but the most intriguing impact of the study may be the recognition that some people have undiagnosed but treatable insect borne illnesses.

Resolving a Medical Catch-22

Patients with chronic Lyme disease and those with ME/CFS both suffer from a medical catch-22. If antibiotics don’t return people with Lyme disease to health it’s assumed they have psychological problems. On the flip side, if test results from patients with ME/CFS don’t indicate a recognized disease is present, then their illness must be in their heads as well.

Maybe, just maybe, an infection triggered by a recognized (or unrecognized) pathogen set disturbed the immune systems of both sets of chronically ill patients.

The Simmaron Research Institute believes research holds the answers patients need. This study is the first step. Join Simmaron’s quest for answers.

If you missed Part 1 of our review, find it here:  Tea-Time at Simmaron I: Mady Hornig on the “Peterson Subsets”, Immune Exhaustion and New Gut Findings In ME/CFS

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Tea-Time at Simmaron I: Mady Hornig on the “Peterson Subsets”, Immune Exhaustion and New Gut Findings In ME/CFS

The Simmaron Research Foundation is out to redefine ME/CFS scientifically.  In an recent event called A Simmaron Tea, collaborators talked with patients about their recent work to propel discovery in our disease. Part 1 of our summary will review Dr. Mady Hornig’s presentation, including some early results from Columbia’s ongoing gut studies. Part 2 will summarize Dr. Konstance Knox’s study of mosquito and tick-borne pathogens in ME/CFS patients. Stay tuned!

Simmaron has collaborated with Dr. Hornig on half a dozen studies unfolding the immuological anomalies in ME/CFS. A doctor-scientist by training, she is Associate Professor of Epidemiology and Director of Translational Research at Columbia University’s Mailman School of Public Health.Simmaron Research | Scientifically Redefining ME CFS | #ShakeTheCFSstigmaSimmaron’s collaborations with Columbia on spinal fluid studies mark our signature contribution to ME/CFS research. Simmaron is continuing this research by funding a second phase of this work to compare metabolomics and proteomics in ME/CFS and MS patients.

Mady Hornig

“We now know that the same changes to the immune system that we recently reported in the blood of people with ME/CFS with long-standing disease are also present in the central nervous system,” Dr. Hornig

In her presentation, Dr. Hornig first reviewed the recent finding from the Chronic Fatigue Initiative-funded study run by the Columbia team: massive immune up regulation in short duration ME/CFS patients and immune down regulation in longer duration ME/CFS patients.  The same immune factors, interestingly enough, that were upregulated early in the illness were squashed later in the illness. One key viral fighter called IFN-y that was hugely important in early ME/CFS but significantly down regulated in later ME/CFS pointed an arrow at a process called “immune exhaustion”.

Immune Exhaustion

collaboration

The blood and spinal fluid findings matched

The first cerebrospinal fluid study using Dr. Peterson’s carefully collated samples found a similar pattern of immune system down regulation. That study (supported by CFI and Evans Foundation) included only longer duration patients.  These two studies – the first to find similar issues in these two different compartments of the body – suggested that the immune system had taken a system wide punch to the gut.

What could cause this kind of immune exhaustion?  Dr. Hornig stated it’s usually associated with chronic infections. In a scenario reminiscent of the wired and tired problem in ME/CFS, the immune system gets revved up, stays revved up and ultimately crashes.

That nice concurrence between immune findings in the spinal fluid and in the blood was encouraging, and the group is digging deeper into those CSF samples. Thus far a factor called cortisol binding globulin (CBG) has popped up in protein analyses. This intriguing factor which facilitates the transport of cortisol in the blood, has shown up in chronic fatigue syndrome before and families with certain polymorphisms in their CBG genes have increased fatigue and low blood pressure.

The Peterson Subsets

Earlier, Dr. Hornig noted Dr. Peterson’s exceptional foresight at collecting cerebrospinal fluid samples over many years and his skill at characterizing them. Now she appeared almost dumbfounded at his ability to pluck out subsets in his patients. At Dr. Peterson’s urging, the Columbia team examined the cerebrospinal fluid of what he called “classical” ME/CFS patients and “complex atypical” patients. Dr. Peterson has been talking about the “classical” set of ME/CFS patients vs other types of patients for years, but this was the first time his intuition was put to the test.

subsets ME/CFS

Finding subsets was crucial to the success of both studies

The classical patients typically present with infectious onset while ME/CFS in the atypical patients has been associated with post transfusion illness, cancers and other factors. No one before has suggested or attempted to determine if these patients differ biologically.

Dr. Peterson’s intuition that they would be different biologically proved to be correct. Columbia found dramatic differences in the CSF of classical versus atypical patients. Virtually all the immune factors tested were higher in the complex atypical vs the classical patients. The researchers are taking a deeper look at the cerebrospinal fluid in these two types of patients.

The findings also demonstrates how vital it is to tease out subsets. Without breaking patients up into early and longer duration subsets the findings of the CFI’s big immune study would have been negative.  Similarly, without excluding Peterson’s subset of  atypical patients, the cerebral spinal fluid study findings would have been insignificant. Given the size, expense and prominence of the CFI blood study, in particular, the negative results would have provided a significant impetus for the field to move away from the immune system.

Instead, there is now great interest in immune alterations in ME/CFS. The inability to ferret out biologically important subsets has undoubtedly smothered potentially important findings in ME/CFS in the past. In a short period of time the CFI investigators and Dr. Peterson have added two factors ME/CFS researchers need to consider in their studies: duration of illness and classical vs non-classical patients.

This is an example of “translational medicine” – going from the bench (lab) to the bedside (clinic) and vice-versa – at its best. It can only occur when researchers interact closely with practitioners they trust and vice-versa.

The Gut Work

gut chronic fatigue syndrome

Mady Hornig believes the gut may hold answers to ME/CFS. The preliminary gut results suggest she may be right.

Columbia’s Center for Infection and Immunity has  completed the testing of samples from 50 patients and 50 healthy controls started in the CFI study and extended in an NIH-funded study to analyze ME/CFS microbiome. They are completing analysis of the samples now.

They’re finding evidence of significant changes in the gut flora of ME/CFS patients vs healthy controls. For one, altered levels of butyrate producing bacteria have been found in the ME/CFS patients. Noting that similar differences have been found in autoimmune diseases, Dr. Hornig proposed that an autoimmune process may be fueling the symptoms in a subset of patients.

Another finding suggests substantial serotonin dysregulation may be present in ME/CFS. (Most of the serotonin in our body is found in our gut.) Dr. Hornig described serotonin as a major immune regulator. Thus far they’ve found that serotonin is more likely to be undetectable in shorter duration patients than longer duration patients, and those reduced serotonin levels are associated with increased immune activity including a very significant increase in IFN-Y – an important antiviral factor.

Tryptophan is metabolized to either serotonin or kynurenine.  If serotonin levels are low, the levels of kynurenine are likely high. Plentiful serotonin results in feelings of well-being, emotional resilience, and immune balance. High levels of kynurenine, on the other hand, have been associated with a host of neurological and neuropsychiatric disorders. Dr. Hornig has called the kynurenine pathway her favorite pathway because it’s been implicated in so many diseases.

The low serotonin findings in ME/CFS were apparently significant enough for Columbia to begin developing new tests to more accurately assess the presence of kynurenine metabolites. It appears that they’ve been successful in doing that, and we can expect more fine-tuned analyses of the role that pathway plays in ME/CFS.

In discussion afterward the presentation, Dr. Hornig said she was struggling a bit how to relay ideas of low resilience to stress in ME/CFS – some of which low serotonin levels could play a role in – without ruffling feathers.  She’s certainly not advocating the SNRI’s or other antidepressants in ME/CFS. In fact, she noted that she was sure ME/CFS patients were amongst the “treatment resistant depression” patients she’d seen when working as a psychiatrist early in her career.

The fix for the serotonin problem – if it is validated in a subset of ME/CFS patients – will clearly come from another direction. A recent review article suggested using the gut flora to affect serotonin-based brain disorders and that is probably the track Dr. Hornig will take. She said she is especially keen to look at the effects of nutraceuticals, probiotics and fecal transplants in ME/CFS.

Dr. Hornig is clearly intellectually excited by her work, but one thing that happened during her presentation indicated her strong emotional connection to it as well.  The presentation of a small quilt to her from ME/CFS patients strongly affected her and left her having to momentarily gather herself emotionally.  It was a surprisingly moving moment.

Dr. Hornig sounded confident about the direction of their research and stated that they were veSimmaron Research | Give | Donate | Scientifically Redefining ME/CFSry much looking forward to what the next few years will bring.  She said she was cautiously optimistic that the IOM and P2P reports, the positive immune study, plus the signs that the National Institute of Neurological Disorders and Stroke (NINDS) may be interested in taking ME/CFS on, indicate that a turnaround for ME/CFS funding is in store.

Help Simmaron continue to fund this pivotal work, as we seek to deepen immune findings in ME/CFS and turn them into potential treatments.

The Epstein-Barr Virus, Magnesium and ME/CFS Connection (?)

August 22, 2015

Magnesium may be the most commonly used supplement in chronic fatigue syndrome and fibromyalgia.  Some people think a smoldering Epstein-Barr Virus infection may be common in ME/CFS.  In something of a shocker, recent research into EBV and magnesium suggests that low magnesium and EBV infections may sometimes go hand in hand.

Mg2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D. Benjamin Chaigne-Delalande,1* Feng-Yen Li,1,2* Geraldine M. O’Connor,3 Marshall J. Lukacs,1 Ping Jiang,1 Lixin Zheng,1 Amber Shatzer,4 Matthew Biancalana,1 Stefania Pittaluga, et. al, Michael J. Lenardo1† 12 JULY 2013 VOL 341 SCIENCE

The authors had recently characterized a primary immunodeficiency disease in people with chronic Epstein-Barr virus infection called XMEN.

XMEN disease

XMEN is a rare genetic disease that combines low magnesium levels and Epstein-Barr virus infection. Could it help explain ME/CFS?

XMEN disease is a rare genetic disease mostly appearing in men that is caused by mutations in the MAGTI magnesium transporter gene. People with XMEN disease suffer from increased infections including upper respiratory infections, sinusitis, otitis media, viral pneumonia, diarrhea, epiglottitis, and pertussis.

They also typically have high levels of Epstein-Barr virus infection and are at increased risk of coming down with EBV associated lymphoma.

The link to lymphoma and the recurrent infections were explained when they discovered that increased magnesium levels are required for natural killer (NK) and T-cell activation.

XMEN disease is not chronic  fatigue syndrome and vice versa, but the two diseases may share four intriguing  factors: EBV reactivation, poorly functioning NK and T-cells, the need for magnesium supplementation and possibly increased risk of lymphoma.

The Magnesium – Immune System Connection

The vast majority (95%) of the magnesium in our body is bound in our cells but it’s the 5% that’s unbound that makes the difference in our immune response.  The XMEN patients studied – some of whom had developed lymphoma – had normal levels of bound magnesium in their cells but reduced levels of unbound magnesium.

Interestingly, all experienced repeated minor viral infections and had elevated levels of active EBV in their blood.  Tests indicated that their immune systems knew the virus was there – it was producing normal levels of the  EBV specific memory T-cells – but their NK and cytotoxic T-cells – the cells tasked with killing EBV – were having trouble killing it.

The question was why. First they looked at the receptors on the NK and T-cells that activate them in the presence of EBV infected cells.   If the receptors are not present or are damaged the cells are effectively blind to EBV.

They  found reduced levels of the NKG2D receptors needed to turn NK and T cells into killing machines. They knew the genetics of the XMEN patients prevented them from taking up magnesium properly.  When they pumped their NK and T-cells full of magnesium (by culturing them in magnesium sulfate) the NKG2D receptors started working again. The cytotoxic T cell killing  problem was partially resolved and the NK cell killing problem was fully resolved.

magnesium

Low levels of free magnesium turned off NK and T-cells – and allowed EBV to take up residence in the cell.

They also found, importantly, that reducing magnesium levels abolishes NKG2D activation in normal T-cells; i.e. proper magnesium levels are needed for T-cell functioning. (Other receptors on NK and T-cells were not affected by magnesium levels – only these specific receptors.)

Next the researchers tested their hypothesis on humans. Upon being provided oral magnesium gluconate small but significant increases in free magnesium and a “modest restoration” in NKG2D levels were seen in an XMEN patient. A decline in the number of his B-cells harboring EBV suggested that his NK and perhaps T-cells were, indeed, more effectively targeting EBV infected  B-cells.

When the patient went off the magnesium supplementation the situation reversed itself.

Further testing indicated that infusions of magnesium sulfate and oral supplementation of magnesium threonate were more effective.

This was an early study (which did make it into Science) but it suggests that something as simple as magnesium supplementation may reduce the rate of infections and possibly the risk of lymphoma in XMEN patients.

EBV infections don’t necessarily lead to or are even associated with these problems: only one type of EBV patient was shown to have them in this study.  People with chronic active EBV infections (CAEBV) or something called X-linked lymphoproliferative disease (XLP) did not have reduced basal free levels of Mg2+ or problems with magnesium transport.

The ME/CFS Connection (???)

ME/CFS and FM  are not XMEN disease. They’re not rare and active EBV is not commonly found. Nor does magnesium supplementation, as common as it is, lead to a cure as it might for XMEN disease.

Because neither the MAGTI transporters or the NKG2D receptors found to play a role in XMEN disease have been assessed in ME/CFS, we have no idea if these transporters are functioning correctly in ME/CFS or FM.

Several features in ME/CFS and XMEN disease overlap...

Several features in ME/CFS and XMEN disease overlap…

Research into rare, genetic diseases, however, often gives us insight into more common disorders. That could be the case with ME/CFS.

EBV triggered infectious mononucleosis, after all is common in ME/CFS, natural killer and T-cells are dysfunctional, magnesium supplementation is rampant, and some ME/CFS patients do very well on antivirals targeting EBV. Recurrent (upper respiratory) infections can be found in some ME/CFS patients as well and increased rates of lymphoma have been found in early studies. (Could the increased rates of lymphoma found ME/CFS due to undiagnosed XMEN disease?).  Some researchers and doctors believe a special kind of EBV reactivation often occurs in ME/CFS.

Further studies in this area could impact ME/CFS or FM in several ways. They could elucidate problems with magnesium transportation and they could uncover other ways to fight EBV.

Indeed, the National Institutes of Allergy and Infectious Diseases (NIAID believes that further research into magnesium associated EBV reactivation could help patients with chronic EBV disorders.

Because chronic EBV infections afflict patients of other disorders, this information may be useful for designing general therapies against EBV. National Institute of Allergy and Infectious Disorders

Whether or not  ME/CFS falls into chronic EBV infected group largely depends on who you’re talking to.  An EBV ME/CFS researcher was, however, recently given a major NIH grant to study EBV infection and the Simmaron Research Foundation is engaged in similar research (see below).

The Future

We are going to learn a lot more how about how magnesium is transported into and out of cells, though.  Lenardo and Chaigne-Delalande are currently examining how other magnesium transporters work.  That’s good news for diseases like ME/CFS and fibromyalgia in which magnesium supplementation is common. They’ll also continue to examine magnesium’s role in chronic EBV infection.

(One question not examined in the study was whether EBV be somehow damaging magnesium transporters in order to turn off NK and T cell activity…)

More Epstein-Barr Virus News

The smoldering EBV infection hypothesis for ME/CFS recently got a boost when Ohio State University professor Dr. Vance Williams got a major NIH grant to study it. Williams earlier studies indicated that unusual EBV proteins rarely seen in humans can produce many of the symptoms found ME/CFS. Williams multi-year, multi-million dollar NIH study will further investigate the effects these proteins are having in this disease.

Simmaron Research | Give | Donate | Scientifically Redefining ME/CFS The Simmaron Research Foundation‘s NIH study examining the extent of autoimmunity and non-Hodgkin’s Lymphoma in people with ME/CFS and their family members will focus on similar ground. This study will determine whether antibodies to the same EBV proteins Williams uncovered in ME/CFS are present. Finding antibodies to these unusual proteins would a) implicate EBV as a key player in ME/CFS and b) strongly suggest ME/CFS is an autoimmune disorder.

Please support the Simmaron Research Foundation as it scientifically redefines how ME/CFS is understood and treated.

More is Better: Rituximab Trial Boosts Hopes for Chronic Fatigue Syndrome

The Rituximab  Story

“I was completely revitalized. Suddenly, I could be sociable again. I would go to work, go home, eat dinner and feel restless.” An ME/CFS patient in the study

The Rituximab story started in 2004 when Fluge and Mella two Norwegian oncologists noticed that some of their cancer patients with chronic fatigue syndrome were doing very well on a drug called Rituximab. In fact, they were doing too well. Not only had their cancer gone into remission but so had their chronic fatigue syndrome symptoms.

tweaking treatment protocol RItuximab

In this study Fluge and Mella tweaked their original treatment plan to produce more powerful and lasting results

Fast forward 11 years, one case series and another study later and we find Fluge and Mella not just treating ME/CFS patients with Rituximab but aggressively tweaking their formula to achieve a lasting remission in the responders and to provoke a remission in treatment resistant patients.

In the initial Rituximab trial published in 2011 Fluge and Mella gave 30 chronic fatigue syndrome patients two Rituximab infusions  two weeks apart and then followed them for 12 months. Three months into the trial there was no evidence the drug was working but 6-12 months later two-thirds of the participants had responded and some had responded in truly dramatic fashion. Years of disability and pain dropped away as some patients almost miraculously achieved normal lives.

Many of the responders, however relapsed later. In this study Fluge and Mella tried to do something about that. They gave Rituximab to 29 ME/CFS patients more often and for longer and they followed them for longer.

Rituximab

Rituximab induces B-cells to kill themselves by attaching to the CD20 receptor on them. It also enhances the ability of natural killer cells to kill them.

Originally developed and FDA approved to treat cancer (lymphoma) Rituximab is also FDA approved to treat rheumatoid arthritis and is used off-label to treat multiple sclerosis, lupus, chronic inflammatory demyelinating polyneuropathy, autoimmune anemia, Sjogren’s Syndrome and many others.  Chronic fatigue syndrome may be the first disease outside of known autoimmune disorders, that Rituximab has been tested in.

The Study

B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O, Mella O. PLoS One. 2015 Jul 1;10(7):

After the two infusions in the first two weeks (500 mg/m2 (maximum 1000 mg) Rituxmab was given four more times at 3, 6, 10 and 15 months (500 mg/m2 (maximum 1000 mg) and the patients were followed for no less than three years. The participants assessed their symptom levels every two weeks and health related quality of life using the SF-36 form.

Lymphocyte subpopulations, including CD19 positive B-cells were assessed before the infusions and at 3, 6, 10, 15, 20, 24, 30 and 36 months.

In an attempt to boost their response seven of the patients who showed slow and gradual improvement after twelve months received up to six additional infusions at two month intervals.

The Participants

This was Norway but the study population looked like that found anywhere else. Sixty-nine percent of the participants were women and 31% were men. The average age was forty and the average duration of illness was nine years. The severity of their illness ranged from mild (n=5), mild/moderate (n=4); moderate (mainly housebound) (n-13), moderate/severe (n=4), severe (bedridden) (n=3). Almost 60% associated an infection with their illness, 34% did not and 7% were not sure.

Seven patients had had Rituximab before but relapsed later and three had tried it and received no or a minimal response. Nine participants had been in the placebo arm of the former study.  All met both the Fukuda and Canadian Concensus Criteria for ME/CFS.

The Results

The Responders

As in the first trial over 60% of the participants reported significant clinical improvement; i.e. they achieved an improvement in their Fatigue score ≥ 4.5 for at least six consecutive weeks. Fourteen or 78% of those  who did were described as “major responders” and four (22%) were described as moderate responders.

more is better Rituximab

More was indeed better as many of the responders maintained their response a year and a half after receiving their last treatment

Some evidence suggested that the major responders were close to functioning normally or in some cases were fully recovered.  With their average SF-36 scores showing remarkable increases it appeared that many of the responders really responded. (More is better with the SF-36).

The average social functioning score – which denotes how much a person is inhibited from functioning socially – increased from 18.4 to 70.8, the average vitality score tripled from  17.7 to 61.3, the average physical functioning score – probably a really difficult one to improve on in ME/CFS – almost doubled (42.9 – 83.3), and bodily pain scores more than doubled (32.2 to 72.3).

At the end of the trial the responders average SF-36 score meet population norms; i.e. you wouldn’t be able, using this test, to tell them from healthy people. It didn’t mean they were all healthy- the test is not precise enough for that – but they were much, much improved.

Some limited Sensiware armband data validated the findings: the number of steps the responders took at the end of the trial indicated they were about as active as normal people.

The Non-Responders

The ten people who did not respond – really didn’t respond; no significant increases in any of the SF-36 scores were seen. It appears that most of the responders do pretty well while nothing much happens for the non-responders.

Maintaining Health – the Maintenance Strategy Mostly Works

The maintenance strategy of providing Rituximab more often to produce a longer-last effect was mostly successful.  Again, those who responded to it responded well. Those did not respond – really did not respond.

The duration of the response zoomed in the responders from 25 weeks (half a year) in the first study to almost 100 weeks (two years) when taking maintenance infusions in the second study.  The responders stayed healthier longer once they were off the drug as well. Three years after beginning the treatment and a year and a half after their last infusion  the treatment was sticking for about 60% of the responders. Some former patients were clearly well.

“Eleven of the 18 responders were still in remission three years after beginning the treatment, and some have now had no symptoms for five years,” Fluge.

B-cell tests indicating the B-cell numbers of all the responders were back to normal suggested their systems may have been reset. If they’d had an autoimmune problem it had disappeared during their long period of immune suppression.

The maintenance dose did not enhance the duration of the response in everyone, however; about forty percent had relapsed a year after receiving their last dose.

The More Is Not Better (Except When it Is) …..Group

Giving Rituximab more often (at the end of one year) to patients who’d had a moderate initial response to it failed to turn them into major responders.  One person, however, who didn’t respond to the two-dose first trial, did respond to five dose second trail.

More doses of Rituximab early on, then, might help but if a year of increased dosage is not helping then it’s time to try something else. Why some people respond and others don’t isn’t clear. Sophisticated immune analyses, however, are underway to attempt to figure that out.

Concerns

Placebo Response

There’s concern about the lack of a placebo group. No treatment will ever get approval without having a placebo controlled study but I wonder how serious the placebo concern is. The long time to the response seen (several months) and the long duration of the response argue (a year and a half in some) argues against a placebo response making a difference for many.

Study Size

A bigger concern is probably the small study size.  Thus far we have  response data on a small slice of the ME/CFS population in an ethnically homogeneous region.  (The upside to doing the study in Norway is that they can apparently get things done pretty quickly; the downside is that the country simply doesn’t have the ethnic diversity the U.S. has.)

subset

The biggest questions facing the two studies done so far is how closely the study participants resemble the ME/CFS population as a whole.

We can say that Rituximab works well  and sometimes very, very well in a subset of patients but we don’t know how big that subset is. I expect the response rates to drop as more types of ME/CFS patients sample the drug. Even a thirty or twenty percent response rate would be very exciting.

The results from the multicenter trial will not be available until 2017 or 18 – two or three years. If the 152 person trial goes well it’s hard to imagine – at least from this layman – that large trials will not quickly open up in the U.S. The infrastructure and the network of physicians needed to engage in a major trial is present. They will simply need access to the drug.  With all the federal reports citing the need for better treatments a way has to be found to get the” big lug” to mount a major trial.

The Severely Ill Study

Thus far in a separate study none of the four severely ill ME/CFS patients in a small open-label study have responded to Rituximab. Four more patients are being assessed. They do not encourage the use of this very strong drug in the severely ill at this time.

The Autoimmune Question – If it Looks Like A Duck…

Chronic fatigue syndrome with it’s female predominance, it’s often infectious trigger, it’s symptoms and the changes that sometimes occur in pregnancy has always looked like it might be, at least in part, an autoimmune disorder.

Fluge and Mella’s autoimmune hypothesis ties several aspects of ME/CFS together in a neat package. First an infection triggers the body to produce antibodies that target the blood vessels and stop them from delivering normal amounts of blood to the tissues. The drop in oxygen to the mitochondria resulting from explains the fatigue, lowered aerobic capacity and exercise problems. Given the brain’s enormous need for oxygen it also explain the brain fog. Several studies back up the muscle and brain issues – the question is whether antibodies are the result.

duck autoimmunity ME/CFS

If it looks like a duck and walks like a duck… is it a duck?

Thus far the Rituximab findings suggest autoantibodies play a role at least in a subset of patients. As before the responders took their sweet time – several months – to respond to the drug.  That several month time lag, though, is about how long it would take Rituximab to clear auto-antibodies from the body. That time-lag strongly suggests an autoimmune process is going on.

Increased rates of autoimmunity (41%) in the first-degree relatives of the patients buttressed the autoimmune hypothesis; a genetic predisposition is often present in autoimmune disorders.

If auto-antibodies are the key Fluge and Mella and others, however, have not found them yet.  They do have a hypothesis, though that ties several aspects of ME/CFS together in a neat package. They believe an infection triggers the body to produce antibodies that target the blood vessels and stop them from delivering normal amounts of blood to the tissues. The drop in oxygen to the mitochondria resulting from the reduced blood flows explains the fatigue, lowered aerobic capacity and exercise problems. Given the brain’s enormous need for oxygen it also explains the brain fog. it’s a theory with a nice foundation: several studies back up

We should see a paper explaining Fluge/Mella’s hypothesis soon and studies embedded in the 150 person trial will help assess whether their hypothesis is correct.

Norway!

It’s worth noting again what a remarkable role the small country of Norway has played in this unlikely scenario.  Size doesn’t always matter – and one suspects that it may be a hindrance in some cases. Two Norwegian physicians birthed the Rituximab findings, Norwegian advocates raised money and pressured the Norwegian government to do what nobody else has been able to do – fund and produce a very expensive and large treatment trial.  Not only did they do that but they did much more quickly than anyone else.

It’s a scary thing to have to depend on a small country with almost no history of ME/CFS research or on private donors in another country to follow up on the most exciting treatment finding in ME/CFS’s history.  If Rituximab works out – and it’s hard to imagine that it will not at least in part work out – the worldwide ME/CFS community will owe the two doctors, the Norwegian advocates and the Norwegian government a huge debt.

The UK is on board. It may be that UK advocates – driven by their awful circumstances – try harder when it comes to jumping on a hot treatment finding. Since June, 2013 Invest in ME has raised over $600,000 US dollars for its own Rituximab trial. According to Dr. Jonathan Edwards, who pioneered Rituximab’s use in autoimmune disorders, Invest in ME has enough money now for a small trial involving 30-40 patients.

That’s great and Norway  has already produced a much larger study and is years ahead of everyone.  That quick start is important given how long these treatment trials take and how long it can take to get approval for a drug.

A Rituximab Timeline

Let’s look at a Rituximab timeline. Fluge and Mella identified their first Rituximab responsive ME/CFS patient in 2004. Their three person case study was published in 2009.  Their 30 person placebo-controlled study was published in Oct. 2011. They began the 152 person multicenter trial at the end, if I remember correctly, of 2014. That study should end in late 2016/early 2017. It will take some time to analyze the results and then get them published. Perhaps we’ll see a paper in early 2018.

You can argue that moving from a small case-study in 2009 to a large multi-center trial beginning in 2014 is good progress and it probably is, but it’s still five years in the life of an ME/CFS patient.

The Big Lug

Much of the innovative research, both inside and outside the public sphere, is occurring in the U.S. but the Rituximab trials might never have happened for all the work that’s been done here. That’s something that ought to give one pause.  A possible new treatment for a disorder with no FDA-approved drugs occurs and the biggest and richest country in the world does nothing.

head in sand

The country with the biggest medical system in the world hasn’t figured in the Rituximab story at all yet

How does that happen? Norway got funding from both advocates and the government. UK advocates have raised $600,000 by themselves. No group has mounted a serious effort in the U.S. and federal funding for clinical trials is difficult to achieve.

It’s pretty clear right now that nothing’s going to happen around Rituximab in the U.S. until the Norwegian trial ends up in mid 2017. Say the Norwegian results published in 2018 are impressive and the U.S. gets a major year-long trial started in early 2019.  The results are in by mid-2020, they’re submitted for publication in early 2021, are published in mid-2021. The FDA examines the data from the US, Norwegian and UK trials and in early 2022 seven years from now, approves Rituximab for use in a subset of ME/CFS patients.

When U.S. – because of bureaucratic or institutional barriers or whatever, is simply sitting on the its hands everything takes longer. In another disorder the Oct 2011 Fluge/Mella study might have sparked an extensive U.S. treatment trial in 2012.  The first results of that multi-year trial might have been published in say 2015.  In this scenario with the big Norwegian study underway we’d have enough data to apply for FDA approval in two years.

An Unlikely Ally

The two studies have created an unlikely ally. Simon Wessely – the foremost proponent of the idea that ME/CFS is caused by poor coping and deconditioning – has been impressed enough by the results to call for a large trial. “There is now a strong case” he said  “to be made for a larger trial”.  Whatever you think of Wessely that’s a very helpful statement coming from a man of his background.

The silver in the lining of the United Kingdom’s embrace of CBT/GET is the extent to which they’ve funded it. The UK, per capita, has been far more generous with ME/CFS funding than the U.S. and they’ve shown the willingness to put significant dollars (or pounds) behind a treatment trial. Drug trials in the U.S., on the other hand, appear to be almost solely funded by pharmaceutical companies. Wessely – recently knighted – has a lot of pull in the U.K.  Could Wessely prod the UK government to get behind an enlarged Invest in ME Rituximab study? That would a be flip of major proportions.

Wessely also said “The belief that [CFS] is all in the mind has been around since the beginning,” he says. “It’s tragic that it might take a study like this to take sufferers seriously.” That’s quite a statement given his history. Check out how that statement jives with Wessely’s past ones in Simon Wessely’s Big Shift? CBT Icon Calls For Big Rituximab Trial

Conclusions

It was a remarkable thing to see almost half the study population exhibiting normal or near normal SF-36 and activity scores after three years.  Even if this is a small study the almost identical response rates (a strong 60 plus percent) found in it and the first study  are encouraging.

This study also demonstrated that give doses more often eliminates many of the relapses that dogged the patients in the first study and it presented more evidence that this powerful drug  is generally safe for use in ME/CFS patients.

As promising as the results of the first two studies are it should be noted that they are small studies and surprises may show up in the larger study underway. It is using the same improved treatment protocol used in this study. It’s results will probably not be published for several years.

In the meantime, this study prompted a major CBT advocate to call for larger studies and a smaller UK trial is in the process of being produced. (You can support that study here.)

Quantum Leap in Viral Detection Could Impact ME/CFS and Fibromyalgia

June 7, 2015

“I firmly believe that new technology drives science and generally has a much larger impact than individual basic science discoveries.” Stephen Elledge

Breakthrough findings in an individual disorder are special, but developing new technology that expands our ability to understand many diseases is something else entirely. It provides the potential to make a difference on a truly vast scale. Those types of breakthroughs are coming with increasing frequency.

research lab tests

Technological advances in medicine are appearing at a stunning rate.

  • Last month Mark Davis and his huge immune machine determined that exposures to herpesviruses, in particular, vastly altered the states of our immune system.
  • Just last week researchers uncovered a lymphatic network in the brain that provides a new window on neuro-immune disorders.
  • This week the journal Science published a breakthrough study that has major implications for understanding the role pathogens play in illness.

Each one could shed light on diseases like chronic fatigue syndrome and fibromaylgia

The astonishing thing for us in the ME/CFS community is that two of the three researchers mentioned are also working on ME/CFS.

Pathogen Detection on Steroids

“Now that we can look at all viruses, it’s a complete game-changer.”

Steven Elledge, a Harvard researcher, is one of them. He pioneered a technique that quickly and thoroughly determines both the antibodies present in the blood and the strength of that response. Antibodies are produced by B-cells in response to pathogens. Because they continue to be produced for decades after an infection antibodies provide a library of past infective events. Until now, though, the search for antibodies has been a plodding, arduous one.

Viruscan test

Elledge’s new test presents a quantum leap in screening for pathogens.

Pre-Elledge –  researchers and doctors determined whether antibodies to a pathogen are present one antibody at a time. Post-Elledge – they’ll be able to look for all known antibodies to all 216 viruses known to infect humans a person – in a single blood sample – for about $25. This isn’t just a major leap in efficiency – it’s a quantum leap.

It doesn’t get much better than creating breakthrough results cheaply. Ian Lipkin called the feat “a technological tour de force and stated “This is a powerful new research tool.”

The Study

Comprehensive serological profiling of human populations using a synthetic human virome George J. Xu, Tomasz Kula, Qikai Xu, Mamie Z. Li,  Suzanne D. Vernon, Thumbi Ndung’u, Kiat Ruxrungtham,  Jorge Sanchez, Christian Brander, Raymond T. Chung,  Kevin C. O’Connor, Bruce Walker,  H. Benjamin Larman,  and Stephen J. Elledge Science 5 June 2015: aaa0698 [DOI:10.1126/science.aaa0698]

The new technology was used to screen for antibody reactions to more than 1,000 strains of 206 viruses in over 500 people across the globe. It found that the average person had been exposed to about ten viruses but that some had been exposed to as many as 25.

Not surprisingly, Epstein-Barr virus (EBV) lead the list. Almost 90% of the people tested had been exposed to this ubiquitous virus. Herpesviruses, rhinoviruses, adenoviruses, influenza viruses, respiratory syncytial virus, and enteroviruses were most commonly found viruses. Not surprisingly, the older you get, the more viruses you’ve been exposed to.

The test is not perfect – it misses some very low-level antibodies and may not pick up antibodies in people with depleted immune systems (such as some ME/CFS patients). Antibody responses that decline over time also make it more difficult to find antibodies to very early infections.  While the test was completely accurate for people exposed to HIV or hepatitis C, it uncovered evidence of chicken-pox exposure in only about 25-30% of those who’d had it.

Elledge said, however, that improvements to the test will enable it to pick up those antibodies.

He’s not stopping at viral antibodies. He’s working on similar tests to assess autoantibodies and antibodies to bacteria and fungi.

The Chronic Fatigue Syndrome (ME/CFS) Connection

“That’s what happens when you invent technology — you can’t imagine what people will do with it. They’re so clever.” Steven Elledge

Autoimmune disorders such as multiple sclerosis – long believed to have a pathogen connection – and cancer were the first diseases mentioned in connection with this technology. The test is so cheap, though – a mere $25 –  there’s no reason it can’t be run in many diseases – including those for which pathogens are not suspected. A virology professor at University of Nottingham, Dr. Will Irving, noted it could be valuable in any disease of “unknown etiology “.

“Indeed in any other disease of unknown aetiology – identifying specific virome reactivity could give a major clue as to a causative agent.” Dr. Will Irving

viruses

Antibodies to over 200 viruses scanned – in a drop of blood

Irving noted the test may be helpful in determining the cause of primary biliary cirrhosis (PBC), for instance. PBC is a liver disease that produces extreme fatigue, autonomic dysfunction and a symptom profile very much like ME/CFS. It’s one of the fatiguing disorders Dr. Julia Newton has been studying alongside ME/CFS.  Irving suggested the new test could help determine if PBC is triggered by viruses.

The recent antibody findings in postural tachycardia syndrome – and the infectious triggers commonly found in that disorder – make it another obvious choice. Fibromyalgia – which is often triggered by a virus – is another possibility.

As to ME/CFS – Elledge is already studying it. He’s one of the new researchers, Suzanne Vernon, a co-author of the new study, enticed into the ME/CFS field as Research Director of the Solve ME/CFS Initiative. Vernon got Elledge to study ME/CFS simply for the cost of shipping samples to him. (ME/CFS patients were in the Science study.)

The Solve ME/CFS Initiative announced Elledge was trolling ME/CFS patients blood for antibodies using his new technique last year. ME/CFS is obviously on the Harvard team’s minds. Tomasz Kula, a co-author of the study, highlighted chronic fatigue (syndrome) as a prime candidate for this technology.

Earlier Elledge talked about the ME/CFS research he’s been doing with the Solve ME/CFS Biobank samples

“We have developed a technology that reveals all the viruses targeted by the antibodies in a blood sample. We plan to use this technology to examine the blood from people with and without CFS in order to find viruses that are associated with CFS. We hope this study will identify a pathogen as a likely causative agent of the disease in order to focus future study.

We also have a related technology that reveals all the targets of autoantibodies in a blood sample.  We also plan to apply this technology to the sample blood samples to look for evidence of immune dysfunction in people with CFS.

In a recent Facebook post Suzanne Vernon talked about ME/CFS and the Science study.

“It was so fun to work with this remarkable team on this really cool approach to test for more than 200 viruses (and more than 1,000 virus strains!) in a drop of blood. Blood from ME/CFS patients was included along with blood samples from around the world. George Xu, Steve Elledge and I will continue to dive into the data to see if there are virus patterns unique to ME/CFS.”

In response to a query whether the technology would allow research to discern ME/CFS clusters based on enteroviral, herpesvirus, or mixed patterns of infection, Suzanne replied “Exactly”.

Stephen Elledge

 

“I have always wanted to make an impact on the world, to have my life on earth count for something,” he said. “By contributing to basic research, I hope my work can accelerate discoveries to improve the lives and health of people.” Steven Elledge

Stephen Elledge Ph.D., a geneticist, runs the almost 30-person Elledge Lab at Harvard Medical School. He’s co-authored almost 300 papers over the past thirty years.  He was drawn to biology and genetics early by the promise the work had to transform biology. ”

“The potential for transforming biology was very clear, even stunning. And I decided I wanted to be a part of that.” Steven Elledge

In 2012 he (and another ME/CFS researcher, Dr. Michael Houghton) were awarded the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science.

Not Ready for Prime Time – Yet

The test has not been commercialized yet.  The study, published in one of the most prestigious science journals in the world, has gotten enormous publicity which will surely help develop the technology into a commercial product.

Cutting Edge Work From Within the ME/CFS Community

From Unutmaz to Elledge to Mark and Ron Davis the ME/CFS community is getting access to top researchers and their cutting-edge technology. It’s also in some cases getting access to technology  being developed specifically to understand this disorder.

Gordon Broderick’s modeling efforts at the Institute for Neuro-immune Medicine, Ron Davis’s development of ways to analyze the HLA regions of our genome, and the methods Julia Newton developed to analyze muscle cell activity were all developed in-house to better understand ME/CFS.