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Is Chronic Fatigue Syndrome An Inflammatory Disease? The 2016 IACFS/ME Conference Overviews Pt II

immune-systemThe immune system’s complexity reared its head again at this conference as Dr. Montoya showcased some of the findings coming out of his large immune studies at Stanford.  Montoya’s assertions that chronic fatigue syndrome (ME/CFS) is similar to systemic inflammatory response syndrome and should be called an inflammatory disorder were intriguing indeed. It’s still, however, hard understand what is going on in the immune system in ME/CFS.

This is a long blog; if you just want the main findings a quickie overview is given at the end of it.

IMMUNE SYSTEM

Montoya’s huge (584 person!) and impressive immune studies –  the largest ever done in this disease – dominated several presentations.  The studies are bit unusual in that they contained about twice as many healthy controls (n=392) as patients (n=192).  Montoya posted an impressive list of 30 researchers he’s collaborating with at Stanford and elsewhere.

He spoke of a complex immune situation often characterized by both up and down immune activation, but which strongly suggested chronic fatigue syndrome is an inflammatory disorder.

Cytokine Study

Cytokines are molecules produced by immune cells that regulate immune functioning in many ways. Montoya tested many cytokines (51) but only two popped out in the first run of this study. That was surprising; large studies are particularly good at finding small but still significant differences, but this study found few differences between the ME/CFS patients and healthy controls than some smaller studies.

Lipkin and Hornig enhanced their cytokine study results by controlling for duration. The key for Montoya was severity. When he added severity to the picture, the immune findings popped out. In the more severely ill patients a rather eye-popping third of the 51 cytokines tested (leptin, CXCL-1, CXLC10, GM-SF, IFN-Y, GM-CSF, IL-4, IL-5, Il-7, IL-12p70, IL-13,  IL-17F, NGF, TGF-b, CCLI, SCF and TGF-a) – most of them pro-inflammatory in nature  – significantly increased.

Montoya proposed that TGF-b, traditionally thought of as anti-inflammatory, may have been acting as a pro-inflammatory cytokine. That cytokine has shown up in several ME/CFS studies before.

Interlude: Cytokine Results Still All Over the Map

The results were encouraging, but cytokine results in this disease are still all over the map. For years researchers have thought they MUST be involved in ME/CFS, but cytokine results have been stunningly inconsistent.

For example, while a 145 person Australian study did, like Montoya’s study, find increased levels of cytokines (IL-10, IFN-γ, TNF-α), none of those cytokines showed up in Montoya’s results.

igg-antibodyA 99 person study from the Klimas group measuring 16 cytokines found significant alterations in 10 of them (increased – LT-a, IL-1a, IL-1b, IL-4, IL-5, IL-6, and IL-12; decreased – IL-8, IL-13 and IL-15.) IL-4/5-were increased in Montoya’s severe ME/CFS group, but IL-13 was decreased in the Klimas study and increased in Montoya’s.

Wyller’s recent large study of ME/CFS adolescents found no cytokine differences between those diagnosed with the Fukuda criteria cytokine and healthy controls. A Japanese/U.S. study found no evidence that either sleep deprivation or exercise effected cytokine levels as well.

The large Landi/Houghton 179 person study of longer duration patients found mostly cytokine reductions instead of increases (reduced levels of IL-7, IL-16, VEGF-a, CX3CLI, CXCL9; increased CCL24). If most of Montoya’s group were early-stage ME/CFS patients, that might help explain the differences, but we don’t know that they were. (Montoya did state that he is going to filter for illness duration.)

The Lipkin/Hornig cytokine study found increased levels of 16 cytokines in early or late duration patients vs healthy controls (IL-1a, IL-1ra, IL-4, IL-12p70, Il-13, CXCL8, TNFα, SFASL, CCL2, CCL3, CD40L, MCP1, TNFSF10, SCF, CFS1, and resistin).  Only three of those (IL-12p70, Il-13, SCF) were found elevated in the Montoya study; thirteen were not.

An Australian study that tracked for severity in a different way from Montoya suggested that more severe patients do have higher cytokine levels. It found reductions in IL-1b, and increases in IL-7, IL-8 and IFN-y. Of those, IFN-y was increased in the Montoya study.

In a much (much) smaller cytokine study published earlier this year, Dr. Fletcher’s study suggested that dramatic shifts in immune functioning may occur over time. IL-a plays an important role in early ME/CFS and then declines. IL-8 levels were abnormally high early on but declined to lower than normal levels after a few years. Il-6 levels were low early on and elevated later. Ironically, the Montoya study didn’t find any of these cytokines elevated in his severely ill patients.

Conclusion (?)

Until cytokine results achieve more consistency they’re clearly not going to get traction in the medical world.  The inconsistency seems surprising as most of these studies are from good labs. It’s possible, though, that subsets are mucking up the issue. Filtering for duration is clearly needed, and Montoya’s study suggested that filtering for severity is as well. The Klimas group’s Gulf War Syndrome study suggested that  gender may need to be accounted for as well.

Dr. Peterson’s atypical patient subset may throw another loop into cytokine results. Peterson’s atypical ME/CFS subset group so dramatically affected cerebral spinal fluid results that it had to be excluded from the study altogether.  Could  this group be effecting blood cytokine results as well?

Researchers are not going to stop studying cytokines – they’re apparently too enticing – and it’s possible that studies underway may help us understand what is going on.  If Lipkin/Hornig can, in their study underway, replicate their cytokine results in different duration patients – that will be something. Ditto with several good day bad day studies underway. If Montoya can duplicate the Lipkin/Hornig duration results that would really be something. Time will tell.

It’s also possible that cytokine levels per se aren’t as important as we might think. Broderick’s models suggest that context is key; in the right context a factor can be important even if it’s levels are not raised.  His models suggest that treatments targeting just two cytokines might be able to enable ME/CFS patients to exercise again. (See upcoming IACFS/ME treatment blog).

Montoya’s network analysis indicated that Il-1B – an important regulatory cytokine associated with increased pain – was the most important factor 24 hours after exercise.  That certainly makes sense given what we know about exercise and pain.

Another possibility is that cytokines in the nervous system are more important than those in the peripheral blood. It’s thought, for instance, that cytokines must contribute to central sensitivity syndromes (CSS’s) such as fibromyalgia as well, but a similar issue with consistency apparently applies there. Staud has suggested that cytokines probably play a major in CSS, but only within the central nervous system.

No Biomarker Yet – An immune signature that shows up only in the more severely ill gives us clues about the illness but obviously isn’t going to work as a biomarker.  But what would happen if Montoya essentially shoved those people into a more severe state by having them exercise? Would adding exercise to the mix make the more moderately ill patients look like more severely ill patients?

Montoya’s Exercise Study

Would exercise make moderately ill ME/CFS patients in the throes of post-exertional malaise look like severely ill patients? The answer to that question was no.

Montoya’s maximal exercise test produced opposite results from the cytokine study done in patients at rest.  This time, exercise reduced the levels of four cytokines (TNF-a, IL-8, CCL4, ICAM-1) while increasing the levels of only 1 (CXCL-10).

Both TNF-a and IL-8 increase during exercise in healthy people, however. The fact that both went down in ME/CFS patients may be notable.  If immune exhaustion is present then perhaps one might expect cytokine levels to drop when the body is faced with an exercise stressor.

A 2014 review of exercise studies reported that while exercise does appear to effect the complement system and gene expression and increase oxidative stress in ME/CFS, it does not appear to effect cytokines. Montoya’s results suggested the opposite.

Genomics Study Suggests Chronic Fatigue Syndrome is an Inflammatory Disorder

At the Stanford Symposium, Montoya announced that the gene expression results indicated that ME/CFS was similar to a disease called systemic inflammatory response syndrome or SIRS. He repeated that assertion again; this time stating that ME/CFS was a “100% match” to SIRS.  (The abstract was a bit more cautious, stating that the gene expression results were “very similar” to it and similar diseases).

SIRS

SIRS has been called a
“cytokine storm”

The concept of SIRS came out of ten years of work at a Toronto trauma lab by Dr. William Nelson. SIRS is  a kind of cytokine “storm” – a term sometimes used in ME/CFS – which refers to a positive feedback cycle that results in higher and higher levels of cytokines.  SIRS also effects both pro and anti-inflammatory cytokine levels as well.

SIRS refers to a state of systemic inflammation after infection or some other insult and can result in organ dysfunction and failure. Intriguingly, given the Australian metabolomic group’s suggestion that the metabolomic results in ME/CFS are similar to sepsis, it’s closely related to sepsis.

SIRS has other manifestations that some may find familiar. Increased heart rates, lower or higher than normal body temperatures, rapid breathing rates, and low white blood cell counts found in SIRS have also been found in ME/CFS. The rapid breathing rates, by the way, are associated with either increased metabolic stress due to infection or inflammation or may signal inadequate perfusion because of the onset of anaerobic cellular metabolism.

Other possible links include fibrin deposition, platelet aggregation, and coagulopathies aka Dr. Berg’s findings in ME/CFS some years ago. Dr. Montoya’s immense gene expression study almost couldn’t have uncovered a more interesting disease to link to ME/CFS.  How serendipitous as well – if this all turns out – that Ron Davis and some members of his Open Medicine Foundation team have done an enormous amount of work on sepsis.

How is SIRS treated? In some ways (blood volume enhancement, anti-anaphylaxis drugs, selenium, glutamine, eicosapentaenoic acid, and antioxidants) that can be helpful in ME/CFS.

Epigenetic Modifications Point at Immune System and HPA Axis

Montoya’s epigenetic study suggested an infection (or some other insult) had indeed occurred in ME/CFS. Greatly increased rate of methylation in ME/CFS patients’ immune regulatory genes suggested some infection or other environmental insult had occurred.

Other epigenetic modifications were found to affect HPA axis genes.  Given the strong interaction between the HPA axis and the immune system, it wouldn’t be surprising at all to find that some event had tweaked both the HPA axis and immune genes in many ME/CFS patients. (The Montoya group is currently engaged in a promising HPA axis study.)

Other gene groups affected by methylation (epigenetic modification) include genes that play a role in, yes, metabolism.  One gene highlighted in a whole genome polymorphism study has been implicated in lactic acidosis (NUFS7). A polymorphism in this gene, which transfers electrons from NADH to CoQ10, could result in increased oxidative stress and reduced mitochondrial output.

Is Chronic Fatigue Syndrome an Inflammatory Disease?

Finding increased immune activation in severe ME/CFS patients, and with gene expression results a close match to SIRS, Montoya asserted that ME/CFS is an overactive immune disease and proposed that its new name should include the word “inflammatory.” Montoya results suggest this, but it’s hard to see how any consensus can be reached until we get more consistent results from the cytokine studies (???).

Pathogens

When asked about retroviruses, Montoya suggested there was no cheese down that tunnel. In several of his newsletters Montoya promised “exciting” new findings regarding pathogens but none were presented at this conference.

Allergy Study Reveals Intriguing Subset

Dr. Levine’s allergy study was, for me, one of the surprise highlights of the conference. This nice big study demonstrated how valuable a resource the multi-site ME/CFS experts centers are, and how valuable a tightly integrated network of research centers will be.

In one of the bigger ME/CFS studies to date, Levine queried 200 patients in five sites regarding the incidence of allergic symptoms/conditions and found that the presence of sinusitis and hives distinguished ME/CFS patients from healthy controls.  (My guess is that the presence of sinusitis is overlooked and understudied in ME/CFS).

allergy subset ME/CFS

An allergy subset appears to have increased pain sensitization as well

The fact that having either of those conditions resulted in patients experiencing more pain suggested that an immune process was ramping up their pain levels.   That hypothesis was strengthened when Levine found that this group also had a much, much higher incidence of migraine, tension headaches, back pain, neck pain, and fibromyalgia.  Plus they had more gut and inflammatory symptoms. Something clearly appeared to be driving a pain sensitization process in these patients.

What is the tie that binds these findings together? Levine suggested it might be mast cell activation. Plus, Dr. Levine noted that both mast cells and neurons secrete two factors: nerve growth factor and substance P, known to increase pain. Then there’s tryptase to consider. A recent study suggested that modification of a tryptase gene could be behind some cases of EDS, POTS, IBS, ME/CFS and FM. Another suggested mast cell activation may be occurring in ME/CFS

This is the kind of study that makes you wonder why the heck it hasn’t been done before. The study was surely not expensive, yet it might illuminate much about ME/CFS.  It was funded by the Hitchens Foundation.

POSTER: RNase L Returns? Novel Isoform of Ribonuclease L Shows up in Fibromyalgia

The idea that an important immune enzyme called RNase L had been broken into pieces and was not only no longer working properly but was actually causing channelopathies and other issues raised a great deal of interest in ME/CFS the 2000’s. At some point work on the enzyme stopped but RNase L was not forgotten.

In a surprise a Spanish group looked for and found the broken-up bits of the enzyme in fibromyalgia. The results were too variable for the 37 dKA form of the enzyme to be considered a biomarker but they did suggest that a subset of FM patients carried it.

Even more surprising was their finding of another broken up bit of RNase L (70 kDa) which was almost totally associated with the FM patients (p<.0001). They’ve create custom-made antibody to identify it and will apparently keep working on it.

PATHOGENS

POSTER: EBV Rides Again

We’ve heard so much about EBV over the years that we forget what a special virus it is. It’s’ true that almost everyone has been infected with EBV, and most have no problem with it, but EBV is no walkover.

When one is exposed to EBV later in life, it causes infectious mononucleosis (glandular fever) and is associated with several forms of cancer (Hodgkin’s lymphoma, Burkitt’s lymphoma, gastric cancer, nasopharyngeal carcinoma, central nervous system lymphomas). Evidence suggests that EBV infections result in a higher risk of many autoimmune diseases including dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, and multiple sclerosis. Lastly, while hardly mentioned in the medical world (ME/CFS is not even mentioned in the Wikipedia article) but foremost in ME/CFS patients minds, EBV is a well-known trigger of ME/CFS.

EBV must have a multitude of tricks up its sleeve to contribute to so many illnesses. The idea that it plays a major role in ME/CFS has risen and fallen over the years. Right now, that idea seems to be more in its descendant phase, but as Dr. Klimas’s study shows, it ain’t over until it’s over; EBV may still very much figure in this disease.

Micro RNA’s – small bits of RNA – regulate which genes get expressed. It turns out that EBV, tricky virus that it is, encodes viral miRNA’s of its own. (EBV was the first virus found able to do this. Given the immense amount of EBV research being done (over 25 studies published in November alone) that was perhaps no surprise.)

HHV-6

HHV-6 appears to contribute to symptoms in ME/CFS

Peripheral blood mononuclear cells (PBMCs) were collected from ME/CFS patients and healthy controls before, during and after exercise, and various tests were done to assess EBV miRNA’s.  Preliminary results suggested that ME/CFS patients’ cells express higher levels of EBV proteins than normal and thus might be more likely to support EBV reactivation.

Plus some strange features emerged. The immune cells in ME/CFS tended to be smaller and have less volume (Ron Davis has found something similar). Instead of forming a classic “pump” shape the ME/CFS nuclei take on a puckered and wrinkled look as if they were aged. Plus, when a key immune transcription factor called STAT I gets activated, presumably by the virus, it ends up in the wrong part of the cell – a pattern indicative of viral reactivation.

All of this suggests that EBV may be tweaking ME/CFS cells in strange ways and that the virus may still play a part in ME/CFS.

POSTER: A Better HHV-6 Test

It’s clear that herpesvirus tests leave something to be desired and Nancy Klimas’ group is attempting to find a way to improve the diagnostic effectiveness of the Elisa test. The current test are provide only  yes-infected or no-not infected answers and are particularly unreliable at the high and low ends of the spectrum.

This study, involving Dr. Govindan from Tufts University and four Florida researchers, used various statistical tests to see if they could develop a truly “quantitative” Elisa for HHV-6.

The intercept they developed allowed them to accurately stratify patients, and showed that the HHV-6 intercept they produced was negatively associated with physical functioning; i.e. the higher the intercept – the worse the ME/CFS patients physical functioning was. This suggested that a) HHV-6 does contribute to the symptom burden in ME/CFS, and b) that this new test could aid doctors in determining when to apply antiviral therapies.

POSTER: Enterovirus Brain Infection Found

Dr. Chia’s work to get the medical world to take enterovirus infections in ME/CFS seriously continues. He gave a workshop on enteroviruses and seemed to be in demand; every time I saw him he was engaged in conversation with a group of people.

His poster highlighted the possible effects of enteroviruses in the most dramatic way. It told the story of a young man who first developed gut problems and then severe ME/CFS. Tests for herpesviruses were normal, but his Echovirus antibody levels were sky-high.  Stomach and colon biopsies stained positive for enteroviruses but enterovirus RNA was not detected in his blood (it often isn’t).

Unfortunately, the young man failed to respond to either alpha or gamma interferon or to SSRI’s, benzodiazepines or acid suppressants. Repeated MRI’s of his brain and spinal chord were normal. Six years into his illness, at the age of 29, he committed suicide.

His ending was tragic, but his story was not over. His harvested brain provided clues as to what may have happened. Neither a brain culture nor an RT-PCR picked up signs of enterovirus, but a western blot found protein bands which were similar to those found in the young man’s stomach biopsies (but different from those found in tuberculosis and lymphoma).

Dr. Chia concluded that this finding replicated a similar finding dating back to 1994.  He concluded that the

“finding of viral protein and RNA in the brain specimens ….is consistent with a chronic, persistent infection of the brain causing debilitating symptoms. EV is clearly one of the causes of ME/CFS, and antiviral therapy should be developed for chronic EV infection.”

Like herpesviruses, most enteroviral infections are passed off quickly, but like herpesviruses, enteroviruses are also associated with serious disorders including polio, meningitis, myocarditis, hand, foot and mouth disease and others. According to Wikipedia, treatment for enterovirus infections is primitive, consisting mostly of relieving symptoms such as pain as they occur.

One hopes at some point an independent lab will take up Dr. Chia’s work and give it the replication it needs and he deserves.

Conclusions

The cytokine findings are disappointingly inconsistent, but the immune system is a vast place and gene expression, epigenetic modeling and other studies continue to point a finger at it.  The Montoya studies should tell us much, plus the entry of noted researchers such as Ian Lipkin and Mady Hornig,  Maureen Hanson, Derya Unutmaz, Michael Houghton and Patrick McGowan into the field ensure that we’ll be learning much more about the immune system in the years ahead.

Marshall-Gradisnik’s NCNED team is churning out immune studies at a rapid rate, Broderick’s early modeling  studies suggest an immune focused 1-2 punch may knock out post-exertional malaise, and Fluge and Mella are testing another autoimmune drug, cyclophosphamide, in clinical trials.

Both Fluge/Ron Davis believe an immune process may be targeting energy production in our cells, the same may be true for ion channels, and it’s now clear that an autoimmune process is producing POTS in some patients. Every microbiome study thus far suggests altered microbial diversity and/or gut leakage into the blood could be sparking an immune response.

The Simmaron Foundation’s expanded spinal fluid study should give us a better handle on what’s happening in the brain just as new techniques to measure the amount of neuroinflammation present in the brain come online.

Finally, it’s encouraging that researchers are getting serious about subsets – and finding them when they look for them.

Major Findings

  • Increased levels of pro-inflammatory cytokines are associated with increased severity in ME/CFS;
  • Exercise, on the other hand, appears to down-regulate cytokine levels in ME/CFS including several cytokines that are typically increased during exercise in healthy people;
  • Gene expression results suggest ME/CFS is very similar to a sepsis-like condition called systemic inflammatory response syndrome (SIRS) which shares some other characteristics with ME/CFS;
  • Epigenetic modifications suggest that events may have altered the expression of genes involved in both the HPA axis and immune systems in ME/CFS;
  • One subset of ME/CFS with sinusitis and/or hives also falls prey to other pain sensitization type disorders such as migraine, fibromyalgia, headache and back pain. Mast cells could be implicated;
  • A broken up form of RNase L, an important enzyme involved in fighting pathogens, showed up in fibromyalgia;
  • Higher levels of EBV proteins in ME/CFS patients’ cells plus structural abnormalities in their cells suggest EBV reactivation may occur more frequently in ME/CFS;
  • A quantitative Elisa test suggests that HHV-6 contributes to the symptoms of ME/CFS as well;
  • Enteroviral proteins in the brain of a young man with ME/CFS who committed suicide suggested that enteroviruses have infected the brains of some people with ME/CFS.

SR_Donate_6.9.14_1

 

 

The Pridgen Revolution? Dr. Pridgen on Bringing His Antiviral Approach to Fibromyalgia To Market

The Pridgen Revolution?

Almost three years ago, Dr. Pridgen threatened to turn the world of fibromyalgia treatment on its head. Few had connected fibromyalgia with viruses or even immune problems when Pridgen announced that a) FM is caused herpes simplex virus reactivation and b) that it could be treated with antivirals. Then he shocked a chronic fatigue syndrome community (ME/CFS) well acquainted with antivirals with his assertion that one antiviral drug was not enough.  (Pridgen believes the same process is going on in ME/CFS). Pridgen wasn’t done, though, instead of using the usual anti-herpes virus drugs he used an anti-inflammatory (Celebrex) that had antiviral properties as his second antiviral.

pridgen_skipPridgen was knocking down received wisdom at every turn. One would not have been remiss to think that he and his unusual protocol would, as other supposed cures have, disappear at some point, but he hasn’t.

Instead, touting his success with the drug combo, Pridgen embarked on the long and difficult task of bringing a new treatment to market. After joining up with a University of Alabama virologist, Dr. Carol Duffy, Pridgen formed a biotech company aptly named Innovative Med Concepts, hired an ex-Pfizer vice-president, put together a strong scientific board, raised the money for a Phase 2 trial, and embarked on toxicology testing.

The Phase II trial was successful enough for the drug combo to move forward. Then Innovate Med Concept got a break when FDA granted fast-track status to its IMC-1 formulation, allowing the drug combo to move forward as quickly as possible.  (Fast-track status is granted to serious diseases that have “substantial impact on day-to-day functioning.”)

Now comes the real work – raising money for some very, very expensive Phase 3 trials. It’s been about a year since we checked in. In an interview, I asked Pridgen how it was going.

The Pridgen Interview

The Phase II trial results were certainly quite good, but they weren’t spectacular.  How did the Phase II trial inform the Phase III trial and how will it be different?

We wanted to prove the concept first with a dose that we knew would be effective.  Additionally, we chose this lower dose, as it would allow us to begin without first performing the very expensive and time-consuming toxicology studies. We will be beginning the final 2 toxicology studies necessary to be Phase 3 ready, this month, and we expect to have these completed late this winter or in early spring 2017.

This was a year to prep for the big Phase III trials. How much money do you need to raise? Do you need to do one or two trials and how big does the trial or trials need to be? How much money do you need to raise?

Typically, two Phase 3 studies are required, the studies require 500-1000 patients per study, and these studies cost $25-50 million each.

One report suggested that some pharmaceutical companies have shown interest. Can you say anything about that?

drug-developmentWe have met with a dozen different pharmaceutical companies. All knew that we would be either forming a strategic partnership, or continuing the drug development ourselves once we near Phase 3 readiness. We will meet with these pharmaceutical companies to discuss a possible partnership at the upcoming JP Morgan meeting Jan 2017 in San Francisco.

We’ve seen a couple of high-profile Phase III trial failures recently. One may have been due to doctors misidentifying a side effect as something else and using a drug that interfered with the results. Another got excellent results in the Phase II trial but then didn’t meet its primary endpoint (but did meet some of its secondary endpoints) in the Phase III trial.  In another trial a very high placebo rate surfaced. What can you do to ensure that IMC-1 trial goes as well as possible?

We have actually been using a variant of this combination at my office for 2-3 years, so we are extremely confident in, not only its efficacy, but also know the combination is quite well tolerated and safe. Though providing the necessary optimal dose is incredibly time-consuming for the office staff, and complicated for the patients, we endure this hardship because of the dramatic improvement they experience.

Dr. Pridgen remains very, (very) confident in the effects of his protocol; he’s so confident that he anticipates raising the bar for the primary endpoint of his Phase 3 trials. Drugs have failed because they chose the wrong primary endpoint or too difficult of a primary endpoint, but Pridgen reports the study will use the most difficult primary endpoint to attain of any fibromyalgia trial to date:

Finally, because IMC-1 is so effective, we will use a primary endpoint that represents the highest bar ever used for any of the drugs previously studied for FM. We feel that this will negate to some degree the placebo effect.

We can see from studies and patient comments that the fibromyalgia population is pretty heterogeneous one. Some people do well on Lyrica – others do terribly. Low dose naltrexone works very well for some and others do poorly on it, etc., etc. The heterogeneity seen in the reactions to pain medications, in general, is pretty daunting. Is there any way you can target FM patients who are more likely to do well on the drug?

Again, Pridgen waxed confident in how efficacious this drug combination is. He believes his is the only protocol that gets at the source of fibromyalgia.

We believe IMC-1 is targeting the possible cause of fibromyalgia, not just modifying the body’s perception of pain.

Emedicine lists four antivirals (Famvir, Valtrex, Acyclovir, Penciclovir) used to treat herpes simplex infections. You’ve found that you need to add Celebrex to Famvir to get the best results in FM. Why do you think this is?

Penciclovir is not available in the PO form because it is not well absorbed, so it is a better topical agent.  Actually, Famvir turns into the active form, penciclovir, once it is acted on by human and viral enzymes. Celebrex is effective as an antiviral also. Herpes viruses are known to up-regulate the Cox-1 and Cox-2 enzymes to maximize viral activation. Though Celebrex (celecoxib) is known as a Cox-2 inhibitor, it actually has substantial Cox-1 inhibition.

viral-attack-cfsAre the herpes simplex infections harder in FM harder to get at than in other diseases? Do you need to reach into the central nervous system?

Essentially all adults have HSV-1, but we believe there is an immune defect in place in some patients, which results in an inability to force the virus into dormancy after an acute infection. In other words, patients with FM, have an ongoing HSV-1 infection, which we feel results in a chronic stress response. The meds can act centrally, however, the virus lives in the Trigeminal, and Nodose ganglia which are intracranial, but technically not in the CNS. The dorsal sacral root ganglia are the third major site (in the pelvis) where the virus resides.

Note: The herpes virus is known to hide out all three of these ganglia or cell bodies.

  • Trigeminal ganglia – is the largest and most complex of the 12 cranial nerves. The trigeminal ganglia provides sensations to the face and other parts of the head. It also sends signals that allow us to chew and even helps with balance. People with trigeminal neuralgia can experience high levels of pain when doing things like brushing their teeth or putting on makeup.
  • Nodose ganglia – are sensory ganglia or nerve cell bodies of the vagus nerve that are found near the top of the spine..
  • Dorsal sacral root ganglia – are associated with vertebrae in the pelvic area. The nerves emanating from them impact all areas of gut and pelvic functioning. In between bouts of genital herpes virus reactivation, the herpes simplex virus hides in these ganglia.

Like the other herpesviruses, almost everyone is infected with HSV-1, and when reactivated these infections can be pretty harmful. They’ve been shown to cause gastrointestinal and esophageal disorders, acute viral encephalitis, and approximately 25% of all genital herpes infections. Fibromyalgia is a bit different; it causes widespread pain, fatigue, sleep and sometimes mood problems as well as other symptoms- and is thought more of as a central nervous system disorder than anything else. Can you explain what the herpes simplex virus is doing differently in FM to cause this extraordinary range of symptoms?

The ongoing stress response affects nearly every system in the body. The immune response to this stress response over time affects sleep, mood, anxiety, thyroid, adrenal function, GI tract, HA’s and much more.

Dr. Duffy was reportedly writing up a paper on her gut findings. Can you tell us that the status of that is?

We have one last sample (of 60 total) to obtain to complete the study.

(At a conference Duffy was reported to find HSV-1 in 100% of FM gut biopsies and a protein found only in cells that are actively infected with HSV-1 in 80% of patients.)

With another year under your belt have you learned anything new treating FM using Famvir and Celebrex?

We have found that anything that was previously part of the functional somatic syndrome will improve on this treatment. At the risk of sounding like a snake oil salesman, we have patients who have chronic non-seasonal sinusitis, HA’s, brain fog, and even libido issues who swear by IMC-1.

Dosing – I also asked Dr. Pridgen about dosing information. He replied that the dosing information has to be proprietary right now. This is because pharmaceutical companies or other funding sources would not back a product composed of already approved drugs if the dosages were put in the public realm. Given the enormous costs of the Phase 3 trials, Pridgen’s drug combo would never make it to market without their backing.

That means FM patients will have to wait before Dr. Pridgen publicly reports on the appropriate dose. For many people this conversation is moot – their doctors would not prescribe antivirals now anyway. People seeing Dr. Pridgen or people seeing doctors in touch with Dr. Pridgen will obviously get the right doses.

If the trials are successful and the FDA approves the IMC-1 formulation everyone should be able to get a shot at these drugs.

Can you give us a timeline regarding the Phase III trial(s)?

They will start next year.

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For more on Dr. Pridgen’s antiviral approach to fibromyalgia:

Post Lyme Disease and Chronic Fatigue Syndrome (ME/CFS) – Are They The Same?

August 6, 2016

Post treatment Lyme disease syndrome (PTLSD) occurs when someone is treated for Lyme disease but never recovers. This mysterious illness has all sorts of possible interconnections with chronic fatigue syndrome (ME/CFS). Symptomatically it’s quite similar, and of course, as so often occurs in ME/CFS, it’s triggered by an infectious event, from which one never recovers.

The list of possible infectious triggers for chronic fatigue syndrome is a long one (Epstein-Barr virus, parvovirus-B, enteroviruses, Giardia, Ross River virus and others). (With the Simmaron Research Foundation involved in a study looking at the incidence of insect borne diseases in ME/CFS more infectious triggers may be added to the list.)

lyme disease

Is chronic Lyme Disease the same as chronic fatigue syndrome (ME/CFS)

Some think Borrelia burgdorferi - the pathogen causing Lyme disease – should be on that list. Lyme disease is transmitted by a tick carrying the Borrelia burgdorferi bacteria. Early on the bacteria can cause a red spreading rash and fever, muscle aches, headaches, fatigue etc. If untreated it can cause some horrific problems but even if treated it can cause lifelong problems in some.

That suggests that a problem with the immune response may be involved. Like ME/CFS the symptoms of post treatment Lyme disease syndrome (PTLSD) very much look like immune symptoms. Typically when researchers assess immune functioning they measure cytokines and other immune factors but these researchers and others like them are more and more taking a different route.

Cytokines can help us understand what’s happening in the immune system but they don’t tell us what is causing the problem. Examining the genes that turn on those cytokines (and many other genes) might. At the very least it provides researchers with a much wider inquiry.  The upside to this kind of inquiry is lots of information – and so is the downside; researchers have to filter through that information to figure out what is relevant and what is not – not an easy task.

It is a task, though, that more and more researchers inside and outside the chronic fatigue syndrome field are embracing.  In this case a look at the gene expression of people who came down with Lyme disease and then were treated for it proved to be quite illuminating.

The Study

Using “next-generation” techniques this study examined the gene expression of the PBMC’s in the blood

  1. just after people got Lyme disease
  2. three weeks after they get treated for it
  3. and then six months later.

This same kind of study has been done twice in ME/CFS to mixed results. In this case the results were exciting enough for the Director of the NIH, Francis Collins, to devoted one of his recent blogs to it.

Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease. Jerome BouquetaMark J. SoloskibAndrea SweicChris Cheadleb, Scot FedermanaJean-Noel BillauddAlison W. RebmanbBeniwende Kabrea, Richard HalpertdMeher BoorgulabMBio. 2016 Feb 12;7(1):e00100-16. doi: 10.1128/mBio.00100-16.

The Results

The study revealed the startling fact that even after antibiotic treatment almost half the patients (13/29) had lingering effects (new-onset fatigue, widespread musculoskeletal pain involving ≥3 joints, and/or cognitive dysfunction) from the infection six months later. Four met the new criteria for post-treatment Lyme Disease Syndrome (PTLDS). (See the new criteria which is similar to some ME/CFS and FM criteria - here. )

The infection initially caused a massive change in gene expression involving over 1200 genes. Surprisingly three weeks of antibiotic treatment, which presumably had wiped out the bacteria, the gene expression was still greatly altered with over 1,000 genes acting up (or down) in the Lyme disease patients.

A pathway analysis indicated that the types of genes one would expect to get involved with an infection did; the inflammatory, immune cell trafficking, and hematologic system pathways were all upregulated.

lyme-gene-expression

Lyme triggered a massive and possibly permanent change in gene expression

The big surprise, though, came in the last blood draw which showed that six months after treatment the gene expression of the Lyme patients (well and ill) and the healthy controls was still quite different.  The researchers clearly expected that six months after the antibiotic treatment, with many former Lyme patients fully recovered, that they would look, once again, like the healthy controls but they didn’t.

Some important immune genes had been turned off; genes associated with the toll-like receptors which alert the body to a pathogen, for instance, were no longer activated. Almost 700 other genes, however, were still significantly upregulated or downregulated in the Lyme disease patients.

This suggests, as we’ve seen before, that significant infectious events can have long term consequences.

The gene expression analysis, unfortunately, provided no clues why some people with Lyme disease recovered after antibiotic treatment while others remained ill. That was probably due to the fact that only four Lyme patients meet the criteria for post treatment Lyme disease syndrome (PTLDS); i.e. the sample size was very small and that small sample size brings up a question.

A Missing Group?

Where to draw the line symptomatically between a disease and non-disease state has dogged ME/CFS researchers since the disease began. A more stringent criteria has the benefit of ensuring that a more ill patient group is identified but it can also cut out those who are still ill. That may have happened with this Lyme study.

In the beginning of the article, the authors asserted that Lyme patients who remained ill after antibiotic treatment were a) a minority and b) unusual. They stated that these patients tended to have more severe symptoms in the beginning, had greater spread of the pathogen through their body, and had had delayed antibiotic treatment. The vast majority of Lyme patients (about 90%) who were treated appropriately with antibiotics, on the other hand, tended to “recover rapidly and completely”. 

This study, however, found that almost half (13/29) the Lyme disease patients, all of whom were presumably appropriately treated with antibiotics, said some of their symptoms persisted at six months.  Because they didn’t meet the PTLDS criteria they weren’t included in the analysis between recovered and non-recovered patients. (Apparently they were included in the recovered group.)

Nor would they be included as post-Lyme disease patients by a doctor using the PTLDS criteria, and might very well be considered depressed, malingerers or whatever. This not to say the PTLDS criteria is a bad one; it’s designed to produce a group of quite sick post Lyme patients for studies, but that criteria – particularly any criteria based on symptoms – is going to have problems.

Disease Similarities

The study indicated that the gene expression responses to an infection can vary dramatically  and in unexpected ways. The researchers compared their gene expression results to those of five other infections.

Early in the disease, for instance, Lyme disease looks more like viral influenza than other bacterial infections such as Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli. (Even with influenza, though, the response at the gene level is far different with the two infections sharing just 35% of activated/downregulated genes.)

pathogens chronic fatigue syndrome

This study indicates that infections can cause surprising results at the gene expression level.

All five of the infections analyzed did trigger the upregulation of two immune pathways (TREM1,TLR) involved with infection but interferon signaling pathways – often believed to be active in viral infections – were upregulated only in Lyme disease and influenza.

Genes identified with activated B-cell pathways were prominently featured in the early phases of all the infections except for Lyme disease.

Plus, Lyme disease was the only disease to exhibit a down-regulated EIF-2a (cellular stress response) pathway. Because that pathway was down-regulated at all three blood draws it could play a major role in Lyme. The fact that the same pathway is down-regulated in lupus suggests Lyme disease could have something in common with autoimmune disorders and the authors suggested a lupus treatment might be helpful in Lyme. )

The takeaway message is that the body’s response to an infection is probably unique to that infection. That suggests that the many infections that trigger ME/CFS may produce very different gene expression responses – and that many different pathways to ME/CFS may exist. Whether they all merge upstream at some point to produce ME/CFS or if a bunch of entirely different pathways to ME/CFS exist is a question that can’t be answered at this time.

The Chronic Fatigue Syndrome (ME/CFS) Connection

At the gene expression levels Lyme disease appears, at this point, anyway, to be little like ME/CFS. While some similar pathways were seen in the two diseases in the end only 18% of the same genes and about a third of the same pathways showed up in both diseases.

At this point Lyme disease looks much more like lupus (60% of pathways in common) than ME/CFS, and the authors suggested that circulating immune complexes might be a tie that binds those two diseases together.

I found two ME/CFS studies with a similar design; each assessed gene expression during an infection and then afterwards and then determined if the results varied between those who recovered and those who got ME/CFS.

An early small Lloyd study (2007)  found significant gene expression differences in those who developed ME/CFS after infectious mononucleosis compared to those who recovered. A 2011 gene expression study (n=36) by the same group, however, that compared ME/CFS patients with infectious onset (EBV, Ross-River, Coxiella virus) and healthy controls over time, found so little difference over time between still sick and recovered patients the papers ended stating that “further investigation of the peripheral blood transcriptome is not warranted.”

Some researchers beg to differ. Five years later with several groups (Ron Davis – Open Medicine Foundation, Derya Unutmaz – Bateman-Horne Center,  Lipkin/Hornig – Center For Infection and Immunity, Nath – Intramural NIH Study and Dr. Montoya – Stanford ME/CFS Initiative) are mounting major efforts to understand the ME/CFS “transcriptome” and other “omes” using better techniques.

genomics chronic fatigue syndrome

Genomics and other “omics” studies will provide new and probably unexpected insights into ME/CFS and other diseases

Unutmaz, for instance, proposes to use gene expression and other technologies to uncover immune subsets that he believes will irrevocably alter how ME/CFS is viewed and studied. Some time ago, he threw some samples from the Solve ME/CFS Biobank into his big immune machine. The data that popped out was enticing enough for him to spend a considerable amount of time working up an NIH grant proposal. That work paid off and he recently scored a major grant from the NIH.

While the Lyme disease study didn’t help researchers understand what goes awry in people who are still sick after getting an infection (and after being treated for it) – which is what we really want to know – a larger study is underway to determine that.  Researchers were also working on identifying 50-100 genes they hoped could finally produce a early diagnostic test for Lyme disease.

The study demonstrated the power of this technology to reveal new things about disease. Several things popped out in this study that weren’t expected:

  • Every infection probably triggers a unique response
  • a Lyme infection may irrevocably change how our genes are expressing themselves (even after treatment)
  • Early in the course of the disease Lyme looks more like viral influenza than other bacterial infections
  • Lyme disease has some important similarities to lupus and rheumatoid arthritis that could suggest new treatment possibilities
  • That some commonalities exist between ME/CFS and Lyme disease but the diseases appear more different than similar

Seeing gene expression differences emerging between different infections suggests this work provides a kind of precision that we very much want to see.  That precision, though, requires an enormous amount of data, and with that ironically, can come some muddiness.  Where gene expression has generally let us down in ME/CFS has been the difficulty of  consistently identifying the specific genes on which the disease may turn.

Hopefully the more powerful machines and analytic techniques being used by ME/CFS researchers will help provide the diagnostic biomarkers and new treatment options that other research efforts have not been able to. If this study is any indication, as researchers dig more deeply into the molecular underpinnings of ME/CFS, we’ll probably be in for some surprises.

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.

 

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

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

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.

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.

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

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

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

How it Happened

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

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

herpesvirus

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

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

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

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

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

Fixing What’s Broken

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

fixing what's broken

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

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

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

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

Herpes Simplex Virus-1

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

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

neurons HSV--1

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

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

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

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

The First Trial

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

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

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

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

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

The Next Trials

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

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

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

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

Confident

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

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

recovery from fibromyalgia

Prigen asserts many people have gotten well using his protocol.

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

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

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

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

Dr. Pridgen Talks

When do you expect the study to be published?

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

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

Many general surgeons perform endoscopies in their practice of medicine.

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

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

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

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

neurons

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

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

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

What can you say about the gut tissue biopsy results?

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

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

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

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

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

big fibromyalgia studies are next for Pridgen

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

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

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

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

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

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

Plans are underway for the near future.

 

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

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

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

HSV-1

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

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

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

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

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

The Triad

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

Famvir

Famvir

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

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

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

The Newcomer – Herpes Simplex

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

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

HSV-1

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

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

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

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

Conference Abstract Provides Results

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

stop-pain

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

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

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

Improving Efficacy Efforts Underway

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

Phase III Trial Will Tell the Tale

tablets

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

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

Big Trial Ahead

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

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

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

Could the Epstein-Barr Virus – Autoimmunity Hypothesis Help Explain Chronic Fatigue Syndrome?

( Find a ‘quick’ summary at the  bottom of the blog)

 

The Epstein-Barr Virus Question in ME/CFS

We recently saw evidence suggesting that  increased viral loads of EBV (in whole blood) may be common in Chronic Fatigue Syndrome.We also saw that  ME/CFS patients  antibody responses to some proteins produced by EBV may be are impaired as well.

Those findings made sense given anecdotal evidence from doctors and study evidence from Dr. Lerner and Dr. Montoya indicating that  antivirals can be very helpful in some patients. Dr. Montoya’s recent review of anti-herpesvirus antivirals  indicated he believes they play a role but these results conflict with the Lipkin/Chronic Fatigue Initiative study which found almost no active herpesvirus infections in either Dr. Montoya’s or in the CFI’s study groups.

smoldering fire

Some researchers think the tests used by Dr. Lipkin are not sensitive enough to pick up the kind of ‘smoldering’ infection they believe is found in ME/CFS

How to reconcile these findings ? Kristin Loomis of the HHV-6 Foundation and Dr. Chia have stated that while the method Dr. Lipkin used to detect herpesviruses (in plasma) works very well in people with highly active herpesvirus infections, they do not believe it would pick up the type of smoldering, lower-level infection suspected in ME/CFS.

The existence of that ‘smoldering infection’ is, of course, controversial. It’s possible, even probable,  that most researchers outside this field including Dr. Lipkin do not believe that such a small infection could have such serious consequences.

Indeed, the ‘increased viral loads’ in the German study did not indicate a highly active infection was present, but they were still significantly higher in the ME/CFS patients than in the controls. Dr. Lerner, Kristin Loomis and others believes that’s significant and that’s the result they believe Dr. Lipkin would have received if he had used a different technique.

After XMRV it’s no surprise to see controversy in the pathogen field. The bottom line is that EBV is still a possible culprit in ME/CFS. Given that and the Rituximab findings suggesting that an autoimmune component may be present in ME/CFS, let’s look at a fascinating hypothesis that ties EBV infections and autoimmunity together and could have implications for ME/CFS.

Epstein-Barr Virus and Autoimmunity

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis. Pender MP. Autoimmune Dis. 2012;2012:189096. doi: 10.1155/2012/189096. Epub 2012 Jan 24.

If this hypothesis is right, Epstein Barr Virus – still the virus most closely associated with ME/CFS – has a very, very close connection to autoimmune disorders.

EBV

Pender believes an EBV infection of B-cells sets the stage for autoimmunity in people with impaired T-cell responses

About a decade ago Michael Prender proposed being exposed to EBV is a prerequisite for having autoimmune disorder. In doing so he tossed aside the usual EBV mimicry hypothesis; that proteins found in EBV confused the immune system into attacking the body and put forth a much encompassing idea. He proposed that EBV’s residence in B-cells – which are ground zero for an autoimmune response – was responsible for most types of autoimmunity. His hypothesis, a decade later, remains alive  and well.

B-cells produce antibodies and autoantibodies. As we learned in the Rose autoimmune talk, the production of autoantibodies primed to attack the body is a natural outcome of an immune system that must defend the body against microbes containing proteins that are very similar to those found in humans. The immune system has ways to deal with these autoantibodies and in most cases it succeeds. When it doesn’t you have an autoimmune problem.

An Admiring Look at a Virus

In some ways you’ve really got to give it up to Epstein-Barr Virus (EBV). EBV  just happens to be the only virus known to survive in B-cells. In fact, EBV doesn’t just survive in B-cells they are its home. Somehow B-cells have managed to thrive survive in the  very cells that are designed to attack them.  That takes a special kind of viral hutzpah..

Every time EBV infects a B-cell it tells it to reproduce and when the cells does, EBV inserts itself into the B-cell’s ‘germinal center’ where it will reside, largely untouched, for the rest of the B-cells life. Every time the B-cell replicates EBV hijacks its reproductive machinery to produce more EBV virions.

EBV

EBV – A remarkable virus

Because B-cells aren’t long-lived and because EBV can’t replicate in them when they’re pumping out antibodies, EBV has found ways to keep B-cells alive and in a state of latency for longer and longer periods of time.

EBV has found ways in induce B-cells to undergo what’s called ‘clonal’ expansion in which B-cells produces EBV infected clones of themselves. One way EBV does this is by tricking the immune system to believe an pathogen is present, thereby causing it to ramp up B-cell production.

Keeping the immune system on high alert, though, can cause problems. Think of our missile defense system. If it’s on high alert the risk of a catastrophic mistake  increases greatly, and here is where Pender and his hypothesis comes in.

Cytotoxic T-cells and A Numbers Game

“CD8+ T-cell deficiency would appear to be a general feature of human chronic autoimmune diseases. ” Pender et.al.

EBV infections in the body are usually tightly controlled by killer or cytotoxic T-cells (CD8+ T-cells). These CD8+ T-cells kill EBV infected B-cells when they proliferate.

cytotoxic t-cell

Pender believes reduced cytotoxic T-cell functioning plays a key role in EBV triggered autoimmunity. Some evidence suggest cytotoxic T-cell functioning is reduced in ME/CFS.

Pender and other researchers believe an inherited defect in cytotoxic T-cells that prevents them from controlling EBV may be behind a lot of autoimmunity. (A Simmaron Research Foundation project involves looking for inherited problems in T-cells, B-cells and NK cells killing capacity.) It turns out that a long list of autoimmune disorders are, in fact, characterized by low cytotoxic T-cell levels.

In what is essentially a numbers game, Pender believes that poorly functioning cytotoxic T-cells allow more EBV infected B-cells to proliferate. Because EBV induces these B-cells to proliferate at a higher than normal rate the outcome of a less controlled EBV infection is simply more and more B-cells. That means more autoantibodies (remember they’re a natural feature) for the immune  system to filter out, and more possibility of a catastrophic mistake being made; i.e. a full-blown autoimmune or autoinflammatory disorder.

Cytotoxic T-cells and Chronic Fatigue Syndrome

CD8+ T-cells have not received a lot of attention in ME/CFS, but early evidence suggests they’re not working too well. A recent German study found a reduced frequencies of an EBV specific T-cells  in people with Chronic Fatigue Syndrome and an Australian  group found reduced cytotoxic T-cell (and NK cell) killing capacity in ME/CFS.

In fact, given the similarity in the killing systems in cytotoxic T-cells and NK cells, it wouldn’t be surprising to find the same dysfunction in both NK cells and CD8+ T-cells.  (If your NK cells aren’t doing so hot, it’s possible your cytotoxic T-cells aren’t doing so well either.)

If that’s true, your cytotoxic T-cells may not be taking out as many EBV infected B-cells as normal. That fits Pender’s hypothesis to a T.

Another Numbers Game

Timing could be everything in EBV, ME/CFS and autoimmunity.   An EBV infection in young children usually doesn’t cause symptoms. It turns out that infants have very high levels of cytotoxic T-cells that allow them to stop the virus in its tracks.

By age sixteen, however, those cytotoxic T-cell levels are a third of what they were at age two. That means that an infection which most infants wouldn’t even notice often causes infectious mononucleosis (glandular fever) and a greatly increased risk for ME/CFS and multiple sclerosis in adolescents.

from youth to old age

Being exposed to EBV later in life greatly increases the difficulty the body has in fighting it off. How many people with ME/CFS were first exposed to EBV later in life?

It appears that the Western fanaticism with cleanliness is pushing the date most children are exposed to EBV further and further forward. In the developing world most children are exposed to EBV by age three, and almost 100% are exposed by age ten, but some studies suggest about half the children in the developed world  have not been exposed to EBV by the time they’re ten.

As many as 50% of these children may come down with a symptomatic, infectious mononucleosis-like illness and during that illness as many as half of B-cells in their blood may become infected with EBV  –  producing a huge reservoir of highly active EBV infected B-cells.

The Jason Northwestern ME/CFS study estimates as many as 10% of college students will come down with infectious mononucleosis. The increased IgM antibody rates in the ME/CFS patients in the German study suggested they may have been suffering from a primary (first-time) infection as well.

Data is lacking on date of first time EBV infection in ME/CFS, but the German study with its high IgM levels  suggests a substantial number of ME/CFS patients may have encountered EBV later in life when their immune systems are less prepared to deal with it. Could ME/CFS in some people simply be the consequence of encountering EBV later in life?

Pender ties in other autoimmune factors, many of which are found in Chronic Fatigue Syndrome as well.

Heritability

Autoimmune disorders are have a higher degree of heritability than most disorders – an intriguing factor given that cytotoxic T-cell functioning is largely governed by heredity.  The heritability factor in ME/CFS and Fibromyalgia has not been the subject of many studies, but one study suggests that heritability may be even higher in these disorders than in autoimmune disorders.

Location and the Vitamin D3 Connection

Living further from the equator also increases the risk of autoimmune disorders such as multiple sclerosis and rheumatoid arthritis. Reduced sunlight and vitamin D3 could aggravate  cytotoxic T-cell problems thus imperiling control of EBV. It turns out that cytotoxic T cells contain more vitamin D3 receptors than any other immune cell.

Dr. Bateman was astonished at how low the Vitamin D3 levels were in her ME/CFS and FM patients but people with ME/CFS and FM probably get less exposure to sunlight than do healthy people. People who are bedridden, of course, get very little exposure to sunlight.

Gender

Cytotoxic T-cells are believed to be hormonally regulated (with increasing estrogen reducing Tc levels) and women tend to have fewer cytotoxic T-cells than men. The gender imbalance found in FM and ME/CFS as another.

Reduced cytotoxic T-cell functioning, high heritability, reduced vitamin D3 levels, and female predominance all appear to be present in ME/CFS and all fit Pender’s paradigm for an EBV induced autoimmune disorder.

Treatment

Rituximab

Rituximab is high on Pender’s list of treatment options for people with EBV induced autoimmunity

Pender’s treatment recommendations for EBV triggered autoimmune disorders are enticing given what we know about Chronic Fatigue Syndrome. They start with none other than Rituximab.

“Improvement of an autoimmune disease with rituximab therapy would be consistent with an essential role of EBV in the development of the disease”

Pender asserts an EBV triggered autoimmune disorder could be treated in two ways.

(1) Depleting B-cells with monoclonal antibodies such as Rituximab would reduce total B-cell levels which would reduce the levels of EBV infected B-cells and autoantibody production. ( Since Rituximab would also reduce the levels of non-EBV autoreactive B-cells a successful course of Rituximab does not constitute proof.)

(2) Boosting immunity to EBV – Getting EBV under control is another option.

  •  the gp350 vaccine – vaccinating young adults with recombinant gp350 has been shown to stop the development of infectious mononucleosis after EBV infection. If Pender is right, gp350 vaccination could be one way of cutting down ME/CFS rates in adolescents. This would simply require determining which adolescents have not been exposed to EBV and vaccinating them. Given that Jason expects perhaps as many as 10 percent of college freshman to come down with some form of infectious mononucleosis this would seem to be a really good idea.
  • using monoclonal antibodies against gp350.
  • Intravenous infusion of autologous EBV-specific cytotoxic CD8+ T cells after expansion in vitro
  • interleukin-7, which expands the population of functional virus-specific CD8+ T cells in chronic viral infection

Summary

  • Michael Pender, has proposedthat exposure  to Epstein-Barr virus, a virus that takes up residence in the B-cells, is required for autoimmunity.
  • All B-cells produce autoantibodies that would, if the immune system didn’t filter them out, attack the body.
  • EBV prompts B-cells to produce EBV infected B-cells which live longer and produce more B-cells than usual. Their longer lifespan and higher productivity means EBV infected B-cells also produce more autoantibodies than normal B-cells.
  • Pender believes high numbers of autoantibodies produced  by these B-cells overwhelm the immune system causing an autoimmune disorder.
  • The key problem in autoimmunity Pender believes, then, is large numbers of EBV-infected B-cells.
  • Since cytotoxic T-cells kill EBV-infected B-cells, a poor cytotoxic T-cell response may be the key, and indeed reduced cytotoxic T-cell responses appear to be common  in autoimmune disorders.   (Two studies suggest reduced cytotoxic T-cell responses are present in ME/CFS  as well.)
  • Because cytotoxic T-cell responses decline over time, someone exposed to EBV as an adolescent typically has a much more difficult time fighting off EBV than a young child does. (Could late exposure to EBV be a common feature in Chronic Fatigue Syndrome?)
  • ME/CFS shares  factors like low Vit D3 levels,  a high degree of heritability and gender predominance with autoimmune disorders.  All these plus the increased EBV viral loads, the reduced antibody response to the latent stage of EBV and the possibly reduced cytotoxic T-cell functioning suggests ME/CFS could very well fit Pender’s hypothesis of an EBV triggered disorder.

Conclusions

The role Epstein Barr virus or autoimmunity plays in Chronic Fatigue Syndrome is unclear, but Pender’s hypothesis suggesting that poorly controlled EBV infections cause many autoimmune disorders is intriguing given recent study evidence of increased EBV viral loads in ME/CFS.  Time will tell but the  reduced cytotoxic T-cell functioning, gender imbalance, the low Vit. D3 levels, the high heritability factors, and the positive response to Rituximab reported all suggest Pender’s EBV/autoimmune hypothesis is something we should keep an eye on.