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Columbia & Simmaron Gut Study Uncovers Another Chronic Fatigue Syndrome (ME/CFS) Subset

With their second myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) study published this month, Ian Lipkin and Mady Hornig’s Center for Infection and Immunity (CII) and collaborator Simmaron Research are on an ME/CFS roll.  As with all CII studies, this one combined unusual rigor and the latest technological advances to cast new light on ME/CFS – and possibly  produce yet another subset.  Longtime CII collaborators, the Simmaron Research Foundation and Dr. Daniel Peterson provided samples for both studies.

precision-gut-data-me-cfs

This study used the latest technology to dig deeper into ME/CFS patients guts than ever before.

Published this week, the new study combined microflora, metabolic and immune analyses in fifty chronic fatigue syndrome (ME/CFS) and healthy controls from four clinical sites (Dr. Peterson, Dr. Lucinda Bateman, Dr. Nancy Klimas and Dr. Susan Levine). A typically rigorous study  from the Center, it matched ME/CFS and healthy controls in numerous ways (age, sex, race, geographic site and season of sampling). The goal was to take the deepest look yet at gut bacteria and their effects on metabolic pathways and the immune system.

Species, Species, Species….

This was a gut study with a twist.  All chronic fatigue syndrome (ME/CFS) gut studies to date have used a process called 16 S rRNA sequencing to characterize the gut microbiome. Unfortunately this process, which focuses on one section of the bacterial genome, is unable to differentiate approximately 40% of the species within each bacteria genera.  Because different primers can also produce discordant results, results of 16 S rRNA studies can also vary from study to study.

These studies have been valuable; they’ve have indicated that something is off in the ME/CFS patients guts, and have given us some idea about the bacterial species involved, but because they can’t differentiate between some of the helpful or harmful species in a genera, they lack specificity.

Lipkin has changed the ways researchers identify pathogens

Dr. Ian Lipkin, Columbia Center for Infection & Immunity

Enter Ian Lipkin. It’s perhaps no surprise that technological ace Ian Lipkin would be the first to produce a study that really gets at gut species in ME/CFS.  (Lipkin has invented several viral identification tools). Lipkin used a more expensive tool called metagenomic sequencing which analyses the entire genome. It has even been used to identify species new to science.

Lipkin’s ME/CFS study identified more than 350 bacterial species.  How cutting-edge Lipkin’s approach was showed up when I asked him if finding 350 species was unusual. He said he couldn’t say; the technique hasn’t been used enough in other diseases to tell. He was confident, though, that the species the study identified were correct.

The study indicated that the guts of people with chronic fatigue syndrome (ME/CFS) were harboring  a significantly different flora than the healthy controls.  As in other studies, the relative abundance of species from one phylum (Firmicutes) chiefly defined the ME/CFS.

Moving from the top down, topological  analyses and prediction models found that the relative abundances of seven bacterial genera (Faecalibacterium, Roseburia, Dorea, Coprococcus, Clostridium , Ruminococcus, and Coprobacillus) differentiated ME/CFS patients from healthy controls as well.

Getting into the species level, four gut species in particular (C. catus, P. capillosus, D. formicigenerans , and F. prausnitzii) and four others (C. asparigiforme, Sutterella wadsworthensis, A. putredinis, and Anaerotruncus colihominis) mainly differentiated the ME/CFS patients from the healthy controls.

Thankfully, the study’s general conclusions jived with the results of past ME/CFS studies which also found reductions in Faecalbacterium and increases in Alistepes bacteria.

Another Study – Another Subset

Ian Lipkin and Mady Hornig are beginning to specialize in uncovering subsets in ME/CFS. Their studies are bringing scientific definition to Dr. Peterson’s and other clinicians’ long experience of clinical subsets. First they identified a short/long duration subset, then they uncovered Dr. Peterson’s atypical patient subset and now they’ve illuminated an ME/CFS-irritable bowel syndrome (IBS) subset.

Whether they had IBS or not, chronic fatigue syndrome patients had a different microbiome than the healthy controls. Topological analyses, however, indicated that having IBS, changed a great deal.

The relative abundance of four bacteria (Faecalibacterium species, R. obeum, E. hallii, and C. comes) were lower in the ME/CFS + IBS group than the ME/CFS – IBS group. One bacteria (D. Longicatena) that was increased in ME/CFS patients – IBS, was actually decreased in the ME/CFS + IBS patients. This appears to suggest that ME/CFS patients with IBS specialized in having lower abundances of “good bacteria”.

IBS-ME/CFS-GUT

Irritable bowel syndrome (IBS) added another overlay to the ME/CFS gut picture

Encouragingly some of those same bacteria are low in IBS studies. Low levels of these protective bacteria have been associated with gut hypersensitivity, bloating and discomfort in both animal and human studies.

That suggests that having inadequate levels of these bacteria may result in inflammation which attacks the gut lining and allows bacteria to escape to the blood.  Once in the blood the bacteria are believed to trigger a systemic immune response that may be able to affect the central nervous system.  Evidence of leaky gut has shown up in several ME/CFS studies.

Gut Triggers

Lipkin drew a possible connection between the flu-like onset in ME/CFS that many people experience and gastrointestinal infections that can precede irritable bowel syndrome. Studies indicate that gastroenteritis or the stomach flu increases one’s chances of coming down with IBS six fold – but does it also increase the risk of getting ME/CFS?

Lipkin asked if the same gut infection could trigger both diseases. Studies suggest yes. Even when treated, giardia infections can produce long lasting cases of ME/CFS. (Three years after being treated for Giardia, 50% of those affected still suffered from chronic fatigue and/or Giardia.) Tests indicated that their illness persisted long after they’d cleared the bug from their system. Dr. John Chia, of course, has long associated ME/CFS with enteroviral gut infections.

Several well-known ME/CFS patients (author John Falk, Tom Hennessey, Whitney Dafoe) experienced some sort of stomach flu before becoming ill. (I contracted Giardia about three years before becoming ill. Tests years later indicated it was still present.)

Metabolic Tweaks

We know that the bacteria in our gut affect our metabolism.  It’s in the gut, after all, where many of the metabolites that our bodies use get manufactured.  Next the researchers used a pathway analysis to try and determine what effects those differences might have on metabolic functioning.

Differences, Differences – Their metabolic pathway analysis indicated different metabolic pathways were accentuated in the different groups.  Vitamin B6 biosynthesis and salvage, pyrimidine ribonucleoside degradation, and atrazine degradation all appeared to be going gangbusters in the ME/CFS patients at large while the production of arginine, polyamine, unsaturated fatty acid (FA), and mycolate appeared to be significantly reduced relative to the healthy controls.

gut bacteria-IBS-ME-CFS

Are gut bacteria in contributing to the energy problems in ME/CFS patients with IBS?

The ME/CFS with IBS group looked far different from the ME/CFS group overall with projected increases in the production of fucose, rhamnose, atrazine degradation and L-threonine biosynthesis, reduced heme, AA and polyamine biosynthesis, and reduced purine, pyrimidine, and unsaturated FA metabolism compared to the controls. Of those pathways only the atrazine degradation and decreased unsaturated FA metabolism were similar to the ME/CFS patients without IBS.

Energy production has become a key area of study in ME/CFS but no study until this one has implicated IBS in that problem.  A mitochondrial pathway affecting the Krebs cycle was upregulated in the ME/CFS – IBS group and downregulated in the ME/CFS + IBS group.  The pathways affecting metabolites associated with the urea cycle (another metabolomic finding) also only effected the ME/CFS + IBS group.

Throughout the paper the authors cautioned that they didn’t know if bacterial issues in the gut might be causing problems with energy production or other factors.  The findings, though, lead the authors to speculate that some metabolomic findings could be caused by the inclusion of high numbers of  ME/CFS + IBS patients in their studies. That’s an intriguing question given that up to 90% of ME/CFS patients may have IBS.

Similarities – Problems with fatty acid metabolism proved to be one of the ties that bind: the reduced activation of those pathways in ME/CFS patients with and without IBS suggested that problems with fatty acid metabolism could be producing inflammation in both groups.

Enhanced vitamin B-6 synthesis was also a hallmark of  both the ME/CFS + and – IBS groups. Dr. Wessely, of all people, suggested way back in 1999 that poor Vit. B6 synthesis in ME/CFS could be causing central nervous system issues. A further analysis nailed increased atrazine  (a pesticide) degradation as a key factor in both the ME/CFS and ME/CFS + IBS groups compared to the controls.

Conclusion – Some important similarities in bacteria activated metabolic pathways are present in both ME/CFS patients with and without IBS, but important differences were found as well.

 Immune Study

Mady Hornig sits on the Simmaron Research Foundations Board. She and the Simmaron Research Foundation are frequent collaborators.

Dr. Mady Hornig, Columbia Center for Infection & Immunity

In a recent blog, Dr. Hornig pointed out that it’s clear that the bacterial communities in our gut shape our immune response. For all the bacterial differences found in this study, though, none were linked to changes in cytokine levels – a somewhat surprising finding since bacterial alterations are believed to produce their effects via immune activation.

Dr. Lipkin, however, suggested that too few short duration ME/CFS patients with upregulated immune systems were present in the study to pick up immune differences. It could also be that a bigger patient sample would have detected them as well.

Some important immune differences were found, however. One of the master pro-inflammatory immune factors in the body – TNF-a – was increased in the ME/CFS group.  Plus Jarred Younger’s big finding – leptin – plus another CXCL immune factor showed up in the ME/CFS + IBS group.  CXCL-8 has not been found in ME/CFS before but another chemokine CXCL-9 was significantly reduced in Dr. Peterson’s atypical subset, and in Houghton’s cytokine study

 Symptoms

The differences in gut makeup didn’t show up in immune system changes but they did appear to effect symptoms. Increased levels of  several species (R. gnavus, C. bacterium, C. bolteae, and C. asparagiforme) were associated with better vitality, health change, and motivation scores. Decreased relative levels of F. prausnitzii and C. catus were associated with worse emotional well-being scores, while levels of R. inulinivorans and D. formicigenerans were associated with improved motivation scores.

 A Focus on Faecalibacterium prausnitzii

good-bacteria-reduced-me-cfs

A good bacteria that was reduced in ME/CFS is also reduced in IBS, IBD, asthma, depression and other diseases.

F prausnitzii is not your ordinary gut bacteria. Making up about 5% of our gut bacteria, F. prausnitzii is one of the most abundant and consequential bacterium found in our guts. Unlike many other gut bacteria, F prausnitzii hangs out in and around our gut lining.    It mainly  produces short-chain fatty acids such as butyrate (remember the fatty-acid synthesis problem?) through its fermentation of dietary fiber. It also appears to have anti-inflammatory effects including  the induction of IL-10 and TGFB-1.

F. prausnitzii is considered a “clostridial microbe” – a bacteria that’s distantly related to the dangerous Clostridium difficile. While C. difficile causes inflammation, bleeding and sometimes death by diarrhea, other clostridial microbes such as F. prausnitzii work to soothe our immune systems and strengthen our gut lining. F. prausnitzii was recently highlighted in a Scientific American article “Among Trillions of Microbes in the Gut, a Few Are Special“.

Reduced levels of F. prausnitzii have been associated with both gut diseases  (irritable bowel syndrome (IBS), Crohn’s Disease, inflammatory bowel disease, ulcerative colitis) and others including asthma, psoriasis, and depression, of course, now chronic fatigue syndrome.   It’s considered a potential prime candidate in the treatment of inflammatory bowel disease.  It was the only gut species that showed up in a meta-analysis of irritable bowel syndrome gut studies.  It appears to be an indicator of general gut health.

Reduced levels of F. prausnitzii (and one other bacteria) were the strongest predictors of having ME/CFS in this study.

Treatment (Treatment?)

“Much like IBS, ME/CFS may involve a breakdown in the bidirectional communication between the brain and the gut mediated by bacteria, their metabolites, and the molecules they influence. By identifying the specific bacteria involved, we are one step closer to more accurate diagnosis and targeted therapies.” Ian Lipkin

One of this study’s strengths was it’s ability to identify specific bacterial species. A targeted prebiotic-probiotic approach could presumably use findings such as these to jack up the levels of beneficial bacteria in hopes of producing a healthier gut. In a U.K Times interview, Lipkin speculated that given the dire need for effective ME/CFS treatments, some people were going to try to do just that.

“The ME/CFS community is very eager to find solutions. I expect there will be people immediately trying to modify their microbiota. In the end we think all this needs to be done in a full clinical trial but there will be people acting on this.”

I asked Dr. Lipkin if we were ready for a focused pre and probiotic treatment for ME/CFS.  As always he warned against one-size fits all prescriptions for ME/CFS but stated that we were getting there….

 Getting there. Treatment for ME/CFS won’t be a one size fits all. We anticipate that some people will benefit from pre and probiotics.

He also provided an interesting teaser: some upcoming studies from his group will suggest that different types of ME/CFS patients will benefit from immune or neuro-modulating drugs.

 In work we are preparing now for publication we see clues that that some people will also benefit from drugs that modulate immune responses whereas others will benefit from drugs that modulate neurotransmission.  

A Growing Field

ME/CFS may not be ready yet for a targeted probiotic treatment but the probiotic drug field is growing. Like any new field it’s going through its growing pains. A startup named Seres, valued at $130 million when it went public last year, failed at a clinical trial aimed to treat C. difficile infections with drug derived  from human feces.

Theoretically it should have worked. OpenBiome says it’s successfully treated 15,000 cases of C. difficile infection  since 2012 using raw poop donated by volunteers. Seres simply provided a well characterized mixture of what it thought were the right bacteria species.

The NIH is helping to move things along, so to speak, by funding a fecal transplant registry that sequences the microbiomes of fecal transplant patients pre and post-transplant in an attempt to uncover which bacterial strains work best.

A recent small autism fecal transplant clinical trial, on the other hand, went swimmingly well. Like ME/CFS, altered gut microbiomes and irritable bowel symptoms are common in autism. (Bob Naviaux finds similar patterns of metabolites in both diseases.)

First the kids got an antibiotic, and a gut cleanse to clear the gut of bacteria. Then they got a dose of “standardized human gut microbiotia” (either orally or rectally) in combination with a stomach acid suppressant (Prilosec) for 8 weeks to repopulate it. According to a Medscape article “Fecal Transplants May Yield Lasting Benefits in Autism“, autism scores went down significantly.

Autism and gut tests eight weeks later indicated the improvements had persisted and that many of the new bacteria had permanently colonized the gut. A much larger placebo-controlled, double-blinded trial is being planned.

It’s clear that Dr. Lipkin believes that targeted pre and probiotic treatments will be able to help some people with ME/CFS. He’s certainly not alone in believing the probiotics are going to help with disease. Money is being pumped into several companies aiming to produce probiotic drugs. Here are some examples.

After a Japanese researcher identified 17 clostridial species  including F. prausnitzii that were able to halt runaway pro-inflammatory activity in mice, Vedanta Biosciences, a Massachusett’s company, pulled in $50 million in venture capital to produce live bacterial drugs to treat inflammation, infections or cancer. Vedanta asserts that the “here today, gone tomorrow” bugs found in yogurt are too transient to do much good.

Synlogic brought in $70 million over a couple of years to develop a “smart” bacterial based drug that responds to different conditions in the gut.  A San Francisco company, Second Genome, recently scored $43 million to develop a bacterial-based drug for inflammatory bowel disorder. The military gave Gingko Bioworks almost $2 million last year to produce a “probiotic vaccine” to protect U.S. troops against the bad bacteria they encounter overseas.

 Intellect and Compassion

Ian Lipkin has a reputation as a hard-nosed scientist but he has a strikingly compassionate side as well. He was one of the few doctors willing to treat AIDS patients early in the epidemic. While everyone who could left China during the SARS epidemic, Lipkin flew on an empty plane bringing medicines to China. In a Times UK article titled “Gut bacteria linked to chronic fatigue” Lipkin made a direct appeal to ME/CFS patients to hang on.

“We don’t think this could be a panacea. It is a complex disorder. But we do think there are a group of people who may be helped. It is our fervent hope to find real solutions. People become despondent and even suicidal. I want them to realize that we are working on this. Please hang on.”

Next Up for the Lipkin/Hornig Team

I asked Lipkin what was next for his group. After laying out his desire for a comprehensive and integrated approach to ME/CFS, he noted that despite the NIH’s increased funding, a thicker shoestring is still a shoestring and once again called for a much more funding.

We are currently putting the finishing touches on our NIH Collaborative Research Center proposal. And, we are integrating clinical, microbiome, metabolomic and gene expression data using mathematical programs with the goal of achieving precision medicine for the ME/CFS community. What we need is a moonshot akin to what will be done for cancer. Our challenge is to do it on a shoestring.

lab testing

The CII is one of probably 7 or more sites vying to become an NIH funded research center

Lipkin has the samples to do this. He and Hornig gathered samples at different time points over a year in many ME/CFS patients but inexplicably weren’t given the funding to analyze them. Had he finally gotten that funding yet?  It turned out that even with a successful research center application he will still need more money. (With the heavy administrative reporting needs baked into the research centers and the need to bring in outside researchers, $1.2 million is not going to go a long way).

 Wish we did.  In the event we are successful with our Center application—and that is by no means certain because many excellent teams are putting in applications—we will still be significantly short because there is so much to do. Continued community support is critical!

The competition will be intense indeed for those three NIH funded ME/CFS research centers. Applications are believed to be going in this week from at least seven groups: Ron Davis, Nancy Klimas, Ian Lipkin/Mady Hornig, Jarred Younger, The Nevada Center for Biomedical Research (formerly WPI), Dr. Montoya and Maureen Hanson. Others may be applying as well.

Conclusion

The Center for Infection and Immunity was able to distinguish ME/CFS patients with and without IBS from healthy controls using  analyses of their gut flora. Underlying alterations in gut flora were common to all ME/CFS patients but having IBS as well had a  major effect on the gut flora and possibly on ME/CFS patients’ metabolism.

Using a technique that was better able to identify more gut species than past studies, the group found marked differences not just in the gut flora of ME/CFS patients with IBS but in the metabolic pathways those differences are believed to effect. Problems with ATP production and the urea cycle might be more associated with ME/CFS + IBS patients while problems with fatty acid metabolism appear to be common to all ME/CFS patients. The study suggested that infectious gut illnesses might be common triggers of  both ME/CFS and IBS.

The Simmaron Research Foundation

Three studies – three subsets identified using clinical expertise, cutting-edge technologies, and precision medicine. With your support the Simmaron Research Foundation is  redefining how ME/CFS is understood and treated.

SR_Donate_6.9.14_5

Peterson’s Atypical Subset Opens New View of ME/CFS in Columbia/Simmaron Publication

“We now have biological evidence that the triggers for ME/CFS may involve distinct pathways to disease, or, in some cases, predispose individuals to the later development of serious comorbidities.” Dr. Mady Hornig. 

The Subset Makers

Simmaron Research | Scientifically Redefining ME CFS | #ShakeTheCFSstigmaOver the past couple of years the Simmaron Research Foundation and Center for Infection and Immunity at Columbia University and others have begun to pump out some long awaited subsets. This week, new findings were published by Columbia and Simmaron that define 2 subsets.

They’re not the usual suspects (infectious trigger vs non-infectious trigger; gradual onset vs acute onset). In fact, they involve subsets few would have predicted a couple of years ago. They suggest that we might be in for some real surprises over time.

Short Duration vs Long Duration Subset: Two years ago, the Simmaron Research Foundation collaborated with Ian Lipkin and other doctors to uncover a subset few had anticipated: short duration patients vs long duration patients.

The Atypical Patient or “Peterson Subset”:  Now comes a subset of atypical chronic fatigue syndrome (ME/CFS) patients (the “Peterson Subset”) that Dr. Peterson had long wondered about. These patients had ME/CFS but tended to follow a different course. Some had had unusual exposures (unusual infections, blood transfusions); others developed serious illnesses (cancer, autoimmune diseases, etc.) that Dr. Peterson didn’t see in the rest of the population.

Dr. Hornig talked about how the atypical subset came about. Like so many breakthroughs in medicine it took a careful and observant doctor/researcher to bring it about. This study, she said, was a testament to:

“Dr. Peterson’s clinical acumen, his long-term follow up of this patient population and his attentiveness to the full range of complex, serious medical disorders that might develop. The classical group had been followed for similar lengths of time but had not developed these more severe, serious comorbidities.”

The atypical vs classical distinction was pre-established by Dr. Peterson before the analysis. Based on his wide-ranging clinical experience, the atypical group stood out for either: 1) the presence of unusual precursors (triggers) of ME/CFS or; 2) the development of more unusual and severe comorbidities over varying (and often long-term) intervals after ME/CFS onset.”

atypical subset

The atypical group turned out to be quite different

Dr. Peterson felt the unusual outcomes weren’t just the result of chance: something different was going on – something that he felt as a doctor needed to be identified. What if, he thought, there was a way to identify these unusual patients before they started developing these significant illnesses. Then he could do more extensive cancer or immune screens and watch these patients more closely.

Plus, these patients could be inadvertently bollixing up the results of ME/CFS studies. Peterson was so sure, in fact, this subset was different that he had its effects assessed during the first Simmaron/CII spinal fluid study. Peterson turned out to be right: the atypical subset had such an effect on the results that it had to be removed.

The next step was a study comparing the two groups. Using Dr. Peterson’s spinal fluid samples, The Center for Infection and Immunity (CII) at Columbia found that “Peterson Subset” not only had markedly different immune findings but displayed a different pattern of immune results as well. Dr. Peterson is Scientific Advisor to Simmaron and Gunnar Gottschalk was its Research Manager.

Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations M Hornig1,2, CG Gottschalk3, ML Eddy1, X Che1, JE Ukaigwe1, DL Peterson3 and WI Lipkin. Translational Psychiatry (2017) 7, e1080; doi:10.1038/tp.2017.44; published online 4 April 2017

 The Atypical Subset

What does a typical chronic fatigue syndrome (ME/CFS) patient look like? Something like someone who suddenly comes down with a flu-like illness and never recovers. They may get better or they may get worse, but they don’t come down with cancer, an autoimmune illness, seizures or other significant illnesses.

An atypical patient, on the other hand, might have a history of viral infection (viral encephalitis) or have been exposed to unusual pathogens during foreign travel or had a blood transfusion before becoming ill. They also tended to be more severely cognitively impaired and had more neurological complaints.  They tended to suffer from severe diseases as well.

Many of these illnesses appeared long after the ME/CFS diagnosis. In fact, at the time of diagnosis these patients looked like a typical ME/CFS patient. This study suggests, though, that very early on, something different was happening in their central nervous systems.

The Atypical Patients in the Study (the “Peterson Subset”):

  • Atypical multiple sclerosis – 3
  • Other autoimmune/inflammatory disorders – 4
  • Cancer – 8 (brain-3, breast-2, lymphoma -2, pancreatic-1)
  • Infections – 2 (West Nile Virus encephalitis – 1; Unspecified viral encephalitis – 1)
  • Illness during foreign travel – 2
  • Illness after blood transfusion – 1
  • Seizure disorder – 6
  • Gulf War Illness – 1

Immune “Exhaustion”?

This “broadly based” immune study compared 51 cytokines and other immune factors in the cerebral spinal fluid of 32 typical and 19 atypical ME/CFS patients. These numbers at first glance may seem small but they’re actually quite large for spinal fluid studies.

The Simmaron Research Foundation/Center for Infection and Immunity’s prior studies suggested that typical ME/CFS patients’ immune systems went on high alert for the first couple of years of illness but then went into slumber mode. In fact, it was more than slumber mode: their immune activity essentially tanked – leading to the hypothesis that frantic activity of the first couple of years might have left their immune systems depleted.

autoimmune diseases

Autoimmune diseases were amongst the unusual comorbidities found in the atypical subset.

This study suggests that the “Peterson Subset” follows a markedly different pattern. The major burst of immune activity early on followed by equally dramatic downturns found in the typical patients is gone. Instead the study suggests that the immune systems of the atypical patients essentially started off low and stayed low.

Almost half the immune factors tested (IL1β, IL5, IL7, IL13, IL17A, IFNα2, IFNγ, TNFα, TRAIL (TNFSF10), CCL2, CCL7, CXCL5, CXCL9, CSF3 (GCSF), βNGF, resistin, serpin E1) were lower early in the illness in the atypical group.

As the illness proceeded, though, the pattern changed again: the atypical groups’ immune system actually revved up again.

When I asked if immune exhaustion was bringing the immune system down early in the atypical group, Mady Hornig replied:

 “We don’t know yet. Our additional finding of an interaction of diagnostic subset with duration of illness – wherein the atypical group showed a pattern of increased levels of immune molecules with longer duration of illness, as opposed to the dampened immune profiles in the classical group with longer illness duration compared to classical ME/CFS in the early stages of disease  (as we had seen in the immune profiling work based on plasma samples) – suggests that the response tends to be more suppressed at the onset of ME/CFS in the atypical group.”

Could that dampened immune response early in their illness be contributing to the illnesses the atypical group experienced later? Dr. Hornig again cautioned about the need to replicate the study but suggested it might.  A viral trigger could have blasted their immune systems or vice versa – a problematic immune system could have allowed a virus in …

 “However, dampening of inflammatory (so-called Th1/Th17-type) responses might be expected to restrict an individual’s ability to keep problematic microbes from replicating. Certain viruses – even common ones implicated in ME/CFS in some studies, such as Epstein-Barr Virus (EBV) – are well-known to be associated with development of certain cancers; however, only a fraction of those infected with EBV develop cancers.

It is a bit of a chicken-egg conundrum: EBV could alter immune responses of T/NK cells to increase cancer risk, or altered T/NK responses at the time of EBV infection could be the critical factor. Alternatively, reduced Th1/Th17-type immune profiles after infection – along with reduced T regulatory cell responses – might skew some individuals toward autoimmunity, raising the risk for more severe autoimmune diseases, including atypical multiple sclerosis or even autoimmune-mediated epileptiform disorders. But at this early juncture this remains only speculation.”

Epstein-Barr Virus (EBV) brings up the age and exposure question. It’s much more difficult for the immune system to corral or ward off EBV if EBV is encountered for the first time at a later age (during or after adolescence). That difficulty shows up as the months long fight to beat EBV called infectious mononucleosis.

A meta-analysis of studies examining many environmental risk factors for multiple sclerosis (including vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to environmental agents, and biochemical, infectious, and musculoskeletal biomarkers) found that only three were associated with an increased risk of coming down with MS. Two of those concerned EBV (having had infectious mononucleosis, IgG seropositivity to EBNA). (The last significant factor was smoking).

Could a later exposure to EBV which resulted in infectious mononucleosis be the straw, so to speak, that ultimately broke the camel’s back for some of the atypical patients?

Dr. Hornig agreed that a study parsing out the rates of infectious mononucleosis in ME/CFS could be helpful but said it was hard to know at this point if IM played a role. She said that the CII group was investigating EBV further:

 “Hard to know (if late exposure to EBV is involved)- we are looking for clues suggesting greater risk for autoantibody-mediated disease in EBV and other virally-exposed subsets of ME/CFS. We do know that females have higher risk for autoimmune disease, but the sex skew only begins after puberty (when females might have come down with IM [Infectious Mononucleosis]).”

Poor Networking

Not only was less immune activation present earlier in the atypical groups but a network analysis indicated a weaker immune network was present as well. These network analyses assess the “wiring” present in the complex immune system.

Immune mediators called cytokines (and other immune factors) form these networks when they communicate with each other to drive an effective immune response.  While a central immune network was found in the typical patients, no such network connection was found in the atypical group.  That suggested a less robust immune response was occurring.

Pro-inflammatory Markers Down

pathogen

A less than robust immune response to an infection could play a role in the atypical group.

Surprisingly, the atypical group’s spinal fluid had lower levels of two pro-inflammatory cytokines, IL17A and CXCL9.  Given the atypical group’s increased neurological and cognitive problems one would have expected the opposite.

That suggested that the atypical patients might be more than different in degree; they might be different in kind. The TH17 pathway that underlies many autoimmune and inflammatory diseases, and which the authors believes may be contributing to the typical ME/CFS group, doesn’t appear to be in play in the atypical group. In fact, the authors suggested the researchers vigorously pursue “alternate, nonimmune mechanisms of pathogenesis in more complex, atypical patients with ME/CFS.”

Dr. Hornig suggested genetics might play a role or that a different kind of immune response; one that was a bit too weak early on to knock off a pathogen, was another possibility.

“I think it may rather be the kind of immune response (inadequate inflammatory responses that might serve to contain an infectious agent upon first exposure, with skew towards autoimmunity or permissiveness to later uncontrolled growth of abnormal cells – i.e., neoplasia) and its timing (too little early on, with some limited immune escape at later time points, allowing for some inappropriate inflammatory type responses after the infectious agent has already had an opportunity to set destructive processes in motion – but too little and too late to contain or eradicate the pathogen).”

That could set up what Dr. Hornig called a “smoldering inflammatory process”.

Cause(s)

What might be causing the immune systems of the atypical group to act so differently early on? Dr. Hornig warned that it was essential that the study results be confirmed by a larger study but suggested that different triggers (unusual infections) or genetic vulnerabilities  (environmental susceptibility, immune response, autoimmunity genes) or even one’s age at exposure could play a role.

Results Suggest Atypical ME/CFS Patients Should Be Screened for Cancer and other Diseases

As with any single study the results need to be validated in studies by other labs using other patients to be validated. If they are, though, they could help doctors and patients. Dr. Peterson said:

 “Early identification of patients who meet the usual clinical criteria when first diagnosed but then go on to develop atypical features would help clinicians like myself identify and treat these complex cases and even prevent fatal outcomes.”

Hornig and Lipkin suggested that atypical ME/CFS patients should be screened for cancer just as patients with paraneoplastic syndromes are. Paraneoplastic syndrome occurs when an immune response against cancer affects other parts of the body, often before a diagnosis of cancer is made.

How Common are Atypical Patients?

How many patients are “atypical”? In her answer to that question Mady Hornig called for more comprehensive studies to fully understand ME/CFS.

 “Though we know comorbidity rates in ME/CFS are thought to be high for quite a number of conditions (allergies, gastrointestinal problems), few studies have addressed this issue in a systematic manner.

It is rare to find physicians who specialize in this disorder, let alone follow the same individuals over time. Given the finding that prior to the development of these other serious comorbidities, all members of this subset met research diagnostic criteria for ME/CFS and would only later qualify as “atypical” based on subsequently developing comorbidities (over many years), we desperately need longitudinal studies that monitor for such issues.

The bottom line is that we don’t know what percentage of ME/CFS patients are “atypical”.”

It’s not clear what percentage of ME/CFS patients are atypical but they may  have already had a dramatic impact on ME/CFS research and treatment. Dr’s Fluge and Mella started the Rituximab saga in ME/CFS after noticing improvements in the fatigue, etc. of ME/CFS patients who’d come down with cancer; i.e. atypical patients.

Dr. Hornig has called the spinal fluid samples Dr. Peterson has collected over the years a “precious” resource, and she highlighted his persistence in collecting them over the years.

 “There also may be long-term cohorts at some ME/CFS clinical sites that might be available for closer examination, at least with respect to clinical patterns and disease/comorbidity trajectories. But most of these sites are unlikely to have cerebrospinal fluid samples (let alone plasma samples) banked in a repository for years!

The suggestion that biological pathways in the CNS already look different even before the onset of these comorbidities implies not only that screening and surveillance are likely to be important to ensure better long term care for individuals with ME/CFS, but also that treatment might need to be tailored differently in classical vs. atypical subsets.”

 Similar Issues Showing Up in Other Neurological Diseases

subsets chronic fatigue

Subsets are common in neurological diseases.

Gunnar Gottschalk, a co-author of the study and medical student is a former research manager for Simmaron Research Foundation. He’s been deeply immersed in ME/CFS research for several years and continues as a Trustee of the Foundation.  Gunnar noted that the neuroscience lab he is working in is studying similar issues in Parkinson’s, Alzheimer’s and other neurodegenerative diseases. It’s not that the same findings are present but that highly abnormal spinal fluid cytokine findings are showing up in all these diseases –  including ME/CFS.

Nor is this study’s general finding – that atypical patients can be differentiated from typical patients in ME/CFS – unusual in the neuroscience field.  Virtually every neurological disease, Gunnar said, appears to be studded with subsets. Different types of multiple sclerosis, for instance, have been identified using similar kinds of spinal fluid analyses.

Noting that developing animal models are critical to understand what’s happening in the brain, Gunnar said he wouldn’t be surprised at all if some animal models which have been developed at great cost for other diseases wouldn’t eventually be helpful in some ways for ME/CFS.

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Next Steps

This is not it for the spinal fluid and the atypical patients. Metabolomics and proteomics studies are next in Phase 2 of the study, which is being funded by Simmaron.  Gunnar noted that the cytokine studies can identify important pathways, but the metabolomics studies can provide more detailed results and he’s eager to see how they turn out.

Dr. Hornig has a long, long list of studies she’d love to do in ME/CFS. This is a disease, she feels, that is calling out for comprehensive studies. She wants to analyze blood, fecal and spinal fluid samples collected at the same time to assess what infection or environmental insult the patient is reacting to.

Comparing immune profiles in the blood and spinal fluid could, for instance, help tell her whether powerful immune cells are squeezing though the blood-brain barrier and wreaking havoc in the brain. Determining that immune cells from the periphery are in the brain would open an entirely new window on ME/CFS.

The gut is another area primed for research. Dr. Hornig pointed out that it’s clear that the bacterial communities in our gut shape our immune response. The TH17 profile found in some patients that tilts the immune system towards inflammation could derive from danger signals produced in the gut. Similarly the TH2 profile found in other patients that tilts them towards autoimmunity could come from the gut as well.

What Dr. Hornig wants is “system-biology” work that ties all these systems into a coherent whole. A gut level disturbance could, for instance, end up impacting virtually every system involved in ME/CFS – including the central nervous system.

“Further systems biology-type work will help us delineate how altered gut microbiota might translate into faulty signals – ranging from bacterial or human metabolites, including a range of immunity-modifying and neuroactive molecules, to immune molecules, to autonomic/vagal nerve axis effects – that then access the CNS (perhaps involving damage to the integrity of the blood-brain barrier to allow entrance of these aberrant signaling molecules) and disrupt brain function.”

In fact, Mady Hornig and Ian Lipkin do have most of the samples they need to begin this work. In what must have been one of the stranger NIH grant awards ever, however, the NIH funded the collection of an enormous amount of samples taken at four points over a year in 250 ME/CFS and healthy controls, but has not funded the analysis of these very same samples.

“In the more recent longitudinal NIH study we have no funding at all for laboratory studies, but have a unique banked set of well-characterized samples (oral, fecal and blood).” (bold added)

Having so many samples just sitting there is astonishing, and hopefully the second half of the study will get funded.

When I asked Dr. Hornig about funding the metabolomics and proteomics work she said that the metabolomics and proteomics assays had been run – but only for a subset of patients.  The CII, she said had funding:

 “Only for analysis of a subset of the Chronic Fatigue Initiative main study cohort samples (and this assay work is completed with analysis in progress) – not for the latest 125+ cases and 125+ controls based on the 1-year, NIH-funded study with 4 serial sample collections.

We don’t have any funding to follow up on candidates identified, including validation, quantitation and correlation with genetic, epigenetic and RNA-based assays.”

 A Foundational Approach To ME/CFS Proposed

foundational study

Large foundational studies are needed to take ME/CFS to the next level

Dr. Hornig went further, though, and called for a “foundational” approach to chronic fatigue syndrome (ME/CFS) that included national registries which would be able to tease out subsets and determine just what happens as people get ME/CFS.

“To support this sort of work on a larger scale, fundamental and foundational work is required. National registries of ME/CFS populations could be developed that would have the capacity to identify the range of preceding potential triggers to disease, to define comorbidities at the time of diagnosis, as well as to longitudinally track the new occurrence of comorbidities in ME/CFS populations over time.”

That is the kind of vision this field needs.  That is the kind of vision that should be able to excite NIH and other funders.

The Simmaron Research Foundation’s unique spinal fluid work with the CII has thus far helped to identify two potential subsets in ME/CFS.  Validating the atypical or “Peterson Subset” could lead to a new understanding of how ME/CFS works and open new treatment options for patients.  The SRF looks forward to further collaborations with the Center for Infection and Immunity and Mady Hornig and Ian Lipkin as it works to redefine ME/CFS biologically.

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Poll Note: The poll will only allow one option to be picked. One positive response suggests you may be an atypical patient. Keep in mind, though, that this is early research on subsets and further studies are needed to verify the findings.

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The Shift: Top Science Journal Asserts Shift in Attitude Towards ME/CFS Has Occurred

“Chronic Fatigue Syndrome is a biological disease” Dr. Ian Lipkin’s Center for Infection and Immunity at Columbia University

From NIH Director Francis Collins’ high profile blog “Moving Toward Answers in ME/CFS“, to the New York Times Opinion piece “Getting It Wrong on Chronic Fatigue Syndrome” exposing the failures of the PACE trial, to the coverage of the Australians’ search for a biomarker, the chronic fatigue syndrome (ME/CFS) community has been treated to some excellent press lately.

difference-maker

Influential journal suggests a shift is occurring in how researchers are viewing ME/CFS

Now comes a piece “Biological underpinnings of chronic fatigue syndrome begin to emerge” from the news section of Nature, one of the world’s most read and most prestigious scientific journals. The article, written by Amy Maxmen, proclaims that a “shift” from viewing ME/CFS as psychosomatic to viewing it as a real disorder has occurred.

The article is a far cry from some of sentiments of the “Life After XMRV” piece Nature did in 2011 in which Simon Wessely asserted that the patients’ reactions to that finding would lead another generation of researchers to avoid ME/CFS research.  (He rather memorably suggested that researchers would rather “work on images of Mohammed” than study it.) Even advocates for the disease, though, worried that the controversy would turn off researchers.  Others, however, felt that the XMRV finding would galvanize researchers to use new technologies to understand ME/CFS.

They were right. Wessely, it appears, was wrong.

World-Class Researchers Beginning to Take ME/CFS On

The Nature article makes it clear that a major cause for the shift occurring is the presence, for the first time ever, of world-class researchers willing to take ME/CFS on.

Dr. Ian Lipkin, an immunologist with an unmatched resume, has not only lent his name and prestige to this disease, but his Columbia team’s published findings  – two of which have outlined dramatic changes in immune functioning in ME/CFS –  have been at the center of this shift. The Columbia team’s findings have been built on collaborations with expert clinicians, including Dr. Daniel Peterson and the Simmaron Research Foundation he advises. (Check out the slideshow that dominates the website for Lipkin’s Center for Infection and Immunity (CII): one of the slides simply says, “Chronic Fatigue Syndrome is a biological disease”.)

Ron Davis, with his many awards and the stunning story of his son’s illness, is also reaching deep into the scientific world to find answers. The stunning picture of Davis holding the printed circuit he’s using to decipher ME/CFS could be a metaphor for the search for the answer to ME/CFS itself.  The answer is there in that maze somewhere, and it’s going to be technology – probably new technology – that uncovers it.

These two men, with their willingness to publicly take bold stands for this disease, have been at the forefront of the “shift” that appears to be occurring. Both men have had the ear of the NIH Director, Francis Collin.  Their credibility has gone far in helping the National Institutes of Health, the largest funder of biomedical research in the country, take a reinvigorated approach to ME/CFS.

Dr. Avi Nath

Dr. Avi Nath, National Clinical Center, NIH

Next, Nature cites the conclusion from the IOM report’s “expert panel” that  chronic fatigue syndrome is an under-studied physiological illness. Then comes mention of the intramural study led by Avindra Nath, the widely published and respected clinical director for the National Institute of Neurological Disorders (NINDS). An infectious neurologist, Dr. Nath is conducting the first intramural study in ME/CFS in decades at the National Institutes of Health Clinical Center. Dr. Lipkin and Dr. Peterson are advisers on this intramural study.

Others could have been mentioned: Mark Davis of Stanford, Derya Unutmaz of the Jackson Laboratory, Lasker Award winner Michael Houghton of the University of Alberta, Patrick McGowan of the University of Toronto and others new to the field.  As the names line up, you do get the idea that, as Dr. Nath told Nature, “Researchers are thinking deeply about how to build the field.”

Building the field, of course, is what the NIH’s recent decision to fund three ME/CFS research centers is all about. Yes, much more is needed, but this article, showing up in a highly cited journal, suggests that the tide may be slowing turning where it needs to turn the most – in the research community.

Ian Lipkin and the Center for Infection and Immunity Step Forward

 Ian Lipkin is featured twice in the article, first stating:

“We now have a great deal of evidence to support that this is not only real, but a complex set of disorders. We are gathering clues that will lead to controlled clinical trials.”

Lipkin has been a vocal advocate for ME/CFS

Lipkin has been a vocal advocate for ME/CFS

Three studies from Lipkin and Hornig at Columbia are expected to be published shortly with one to be published next week. Don’t be surprised if, based on Lipkin’s comments, the CII lays the groundwork for something the chronic fatigue syndrome (ME/CFS) community has been waiting for a long time: evidence of biologically determined subsets, or in Lipkin’s words, direct evidence that ME/CFS is made up of a “complex set of disorders”.

The Simmaron Research Institute / Center For Infection and Immunity Collaboration

Simmaron CII partnership

Simmaron and the Center for Infection and Immunity: working together to understand ME/CFS

In its efforts to scientifically redefine ME/CFS, the Simmaron Research Foundation regularly partners with Dr. Lipkin’s Center for Infection and Immunity. Recent efforts included the spinal fluid study which showed dramatic alterations in immune functioning in the brain, the immune study which differentiated short from long duration ME/CFS patients, and the gut study about to be published. Simmaron is currently collaborating with the CII on additional phases of spinal fluid research and more.

Stay tuned for a Simmaron/CII study that will help to reshape our understanding of what ME/CFS is and how it should be treated.

Simmaron

The Gut and ME/CFS

The gut with its immense effect on the immune system is proving to be a fertile area of research on ME/CFS (see below). Perhaps no other team has pushed the ME/CFS gut connection more effectively recently than Ian Lipkin and Mady Hornig at the CII.

The Nature piece tantalized us a bit with news from Ian Lipkin that one of those studies showing an unusual pattern of gut flora in people with ME/CFS and IBS will be published soon.

A quick look at what studies have told us (see below) about the gut and chronic fatigue syndrome (ME/CFS) suggests that reduced gut floral diversity, possibly characterized by increased numbers of inflammatory bacteria may be common in ME/CFS.

Importantly, every study that has looked for leaky gut – which involves the translocation of gut bacteria into the blood – where it could spark an immune response causing fatigue, pain and other symptoms – has found it.  Most intriguingly, the research suggesting that exercise may negatively affect ME/CFS patients’ gut flora and increase their leaky gut issues could help explain post-exertional malaise.

The Gut and ME/CFS – Recent Findings

  •  Exercise in ME/CFS produces changes in gut flora, leaky gut and Inflammation  – Shukla’s 2015 study suggests that exercise not only changes the composition of the gut flora in people with ME/CFS but results in increased levels of gut bacteria leaking into the blood (possibly causing inflammation and post-exertional malaise.) The fun didn’t stop there. The ME/CFS patients also had more trouble clearing the gut bacteria from their blood than the healthy controls.
  • People with ME/CFS have reduced gut flora diversity and leaky gut – Gilotreaux’s 2016 study suggests more pro-inflammatory and fewer anti-inflammatory gut species are present in ME/CFS, and provides more evidence of bacteria sneaking through the gut lining and ending up in the blood.
  • Gut bacteria/viruses are infectious triggers in ME/CFSNavaneetharaja’s 2016 review paper suggests that gut bacteria and/or viruses have been overlooked in the search for an infectious trigger in ME/CFS.
  • ME/CFS is associated with reduced gut microbiome diversity and increased gut viral activity – Gilotreaux’s 2016 case report of twins found reduced VO2 max, decreased gut bacterial diversity and increased gut viral activity in the sick ME/CFS twin.
  • Antibiotics can improve gut flora and sleep in some ME/CFS patientsJackson’s 2015 Australian study suggests that erythromycin improved the gut flora and sleep in about a third of ME/CFS patients but not in the rest.
  • Altered gut flora diversityFremont’s 2013 study shows increased abundance of the same bacterial family (Firmicuties) in ME/CFS as found in Shukla’s 2015 study.
  • Leaky gut is associated with an autoimmune processMaes 2013 study suggests that increased bacterial translocation (leaky gut) is associated with high levels of antibodies targeting serotonin. Patients with these antibodies had evidence of increased inflammation.
  • Leaky gut is associated with inflammation and symptom severityMaes 2012 study suggests ME/CFS patients are mounting a very strong immune response to intestinal bacteria found in the blood that is leading to increased inflammation.
  • IBS/leaky gut subset is present in ME/CFSMaes 2012 study shows one subset of ME/CFS patients (60%) has leaky gut and IBS while another subset does not.
  • Treating leaky gut in ME/CFS can reduce symptomsMaes 2008 study shows that treating leaky gut with natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc in conjunction with a leaky gut diet can significantly improve symptoms in ME/CFS

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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.

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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.

 

Major Study Suggests Early Immune Activation May Drive Chronic Fatigue Syndrome

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

big me-cfs study

Big study – big results

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

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

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

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

It’s Biological

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

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

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

Big, Big, Big Study

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

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

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

Different But Not Substantive

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

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

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

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

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

Hit and Run Attack Likely

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

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

chronic fatigue syndrome early immune findings

The key factor for the immune system – was time

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

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

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

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

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

Viral Fighter Stands Out

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

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

infection chronic fatigue syndrome

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

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

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

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

Mady Hornig on the Study

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

THE Pathway???

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

kynurenine pathway chronic fatigue

Could the kynurenine pathway be it for ME/CFS?

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

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

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

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

CD40L

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

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

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

Flipping the Switch

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

Dr. Hornig described a condition of immune system burnout:

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

primed for burnout cfs

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

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

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

Leptin Again

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

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

Hit and Run Again

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

hit and run me/cfs

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

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

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

The High Cytokine- Longer Duration Patients?

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

Conclusion

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

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

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

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

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

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

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

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

Stay tuned!

Foremost Virus Hunter Finds Biomarkers, Few Viruses in Big Chronic Fatigue Syndrome Study

Dr.Ian Lipkin collaborated with Dr. Peterson, Dr. Klimas, Dr. Bateman and others

A Surprise Presentation

We will publish data very soon on biomarkers of cytokines. Our evidence now suggests there is ongoing stimulus to the immune system. Dr. Ian Lipkin

You don’t usually get study results in talks like the one put on by  the CDC yesterday but this time Dr. Ian Lipkin spilled the beans on the results from the big pathogen studies sponsored by the Chronic Fatigue Initiative (n=200) and Dr. Montoya (400).  (From notes taken on the talk)

Virus Study Results Revealed

SR Facebook logo new

The Simmaron Foundation provided a rare resource: sixty cerebral spinal fluid samples

Viruses have always been the elephant in the room in ME/CFS; everybody has wondered about them but until the Chronic Fatigue Initiative came along, few major studies had been done.  This landmark  study, using the one of the top virus hunters in the world and epidemiologist  Mady Hornig, and containing hundreds of patients from ME/CFS specialists (Dr. Peterson, Klimas, Montoya, Levine, etc.) from across the country, sets a benchmark for pathogen research in ME/CFS.

A special feature of the study involved Simmaron Research’s spinal fluid samples. Called a ‘unique resource’ earlier by Dr. Mady Hornig, these samples allowed the researchers to get as close to the brain – long thought to be a key area in chronic fatigue syndrome – as they could.  And the spinal fluid results were spectacular.

The Studies

virus cartoon

This study funded by the CFI, using top labs, and involving hundreds of people with ME/CFS, is a benchmark in ME/CFS research.

The studies looked at both pathogen presence and  the immune response in hundreds of people with chronic fatigue syndrome.

Pathogens

  • First Phase – Screens for 18 specific pathogens already implicated in ME/CFS (herpesviruses, HTLV, enteroviruses, West Nile Virus, etc.) were done on blood from Montoya’s patients and the CFI’s group (Dr’s Peterson, Klimas, Bateman, Levine, etc.).  Dr. Lipkin was looking for the virus, not a indication it was present, but the virus itself. Any finding of a virus in the blood would indicate it was active.  The same screen was done on Dr. Peterson’s sixty spinal fluid samples.
  • Second Phase – The second phase involved sequencing all the DNA/RNA in the blood to identify  known and unknown viruses. Dr. Lipkin’s lab has been able to identify hundreds of novel viruses using this technique.
  • Third Phase – Any finds in the second phase are confirmed/denied by more accurate testing.

Immune Response

A ‘multiplexed immunoassay’ looked at 50 proteins associated with immune activation/inflammation and oxidative stress.

Active Viruses Strike Out

Four of the 285 ME/CFS blood  samples tested positive for HHV-6B.  One of the sixty spinal fluid samples tested positive for a virus (HHV-6B).  None of the other viruses commonly associated with ME/CFS (Epstein Barr-Virus, enteroviruses, the cytomegalovirus, etc.) commonly associated with ME/CFS showed up in the first pathogen screen.

The high throughput screening designed to look for any viruses including novel viruses drew a blank as well. Dr. Lipkin was confident in his results stating his lab had found over 500 new viruses using this technique.

Infections

Lipkin’s search for 18 viruses and for novel viruses in hundreds of people with chronic fatigue syndrome largely turned up empty

The  news – that fewer than 2% of patients  with infectious onset – tested positive for viruses in the blood was stunning but not without precedent.  Dr. Unger reported earlier that  the first stage of the CDC’s BSRI pathogen study  drew a blank.  A spinal fluid study also turned up no viruses, and PCR analyses done by the Dubbo group were unable to find evidence of a virus in their post-infectious cohort.

With two large sample sets turning up negative in the lab of one of  most acclaimed virus hunters on the planet, it’s probably safe to say that the hunt for an virus in the blood of people with ME/CFS is over.

(Lipkin did report 85% of pooled samples possibly showed evidence of a retrovirus but believes they will not be related to CFS. He also dismissed earlier rumors that a novel infectious agent had been found.)

Infectious Agent Still Proposed

That doesn’t mean an infectious agent is not involved. In  fact, Dr. Lipkin stated he didn’t doubt that an infectious agent was involved.  He didn’t say where and he didn’t say it was still present.  His allusion to the importance of finding evidence of a past infection (“researching the shadows”) suggested  he could  be leaning to the ‘hit and run’ hypothesis where a pathogen sweeps in, does its damage, and then gets removed by the immune system.

The Dubbo studies’ finding that high cytokine levels early in the infection were strongly associated with getting ME/CFS later on suggested an overactive immune system may have a blown a few fuses somewhere.

On the other hand, Dr. Lipkin specifically alluded to an ‘agent’ driving the immune activation he found in both the blood and spinal fluid of ME/CFS patients (but not the healthy controls).

Localized Infections Still Appear to Be a Possibility

Dr. Lipkin didn’t discuss this possibility. The blood is the most convenient place to search for an virus and active viruses usually do travel through the blood but central nervous system or localized infections may not show up in the blood or the spinal fluid.

Some evidence of localized infections in the gastrointestinal tract has been found in ME/CFS. A De Merileir team found evidence of HHV-6, EBV and parvovirus B-19 in 15-40% of gut biopsies. Eighty-two percent of stomach biopsies tested positive for a protein associated with enteroviruses in Dr. Chia’s 2008 study. Dr. Chia reports enteroviruses are found much more readily in the stomach than the blood (but he is able to find it in the blood). No enterviruses were found in the present study.

Vanelzakker proposes that a localized vagal nerve infection is causing the symptoms in ME/CFS.  It’s not clear what these results mean for Dr. Lerner’s theory that an aborted EBV infection is spilling viral  proteins into the blood that are sparking an immune result.

The Three Year Breakpoint 

Data suggests there may be substantial differences in biomarkers in people with less than 3 years of disease and those with more than 3 years of disease. Dr. Lipkin

subsets

Two recent research findings suggest the immune systems of people with recent onset and longer duration ME.CFS are significantly different.

Echoing similar recent findings from the Broderick/ Klimas team at NSU, Dr. Lipkin stated the immune system in ‘newbies’  (patients with recent onset), and patients with a longer case of  ME/CFS was different.  Dr. Lipkin’s ability to independently differentiate ‘newer’ from ‘older’ patients using  cytokine results is pivotal, and points to the central and progressive role the immune may play in this disorder.

With Broderick suggesting that two distinct illnesses emerge over time, and Lipkin proposing treatment options should reflect illness duration, it was clear these changes were significant indeed.

Natelson, on very different track, is finding changes over time as well with more POTS in his adolescents and a different kind of orthostatic intolerance in older patients.  Studies are underway to understand why this might be so.

An Early Allergic Response

Allergy is not usually mentioned in association with ME/CFS but eosinophils and other markers suggested to Dr. Lipkin that  the allergic response was enhanced in ME/CFS early on. The cast of immune characters Lipkin’s biomarker search fleshed out was refreshingly familiar with IL-17, IL-2, IL-8 and TNF-a leading the list.

IL-17

Levels of Il-17 were raised in recent onset ME/CFS patients. Lipkin suggested immunomoculators able to bring IL-17 levels down might be a treatment option at some point.

No mention, interestingly, was made of autoimmunity, but Lipkin, pointing at the high IL-17 levels in the newbies,  embraced the idea (only after further validation) of using immunomodulators in some ME/CFS patients  to turn down the fire in the immune system.  Immunomodulators exist now, he said, that can bring that IL-17 cytokine  down.  (He stressed, however, that there is not enough research to start using them on patients.)

The spinal fluid, interestingly enough, showed a very different pattern. It showed a consistent profile of immunological dysregulation in CFS, regardless of duration of illness. Dr. Lipkin identified increased IL-10 and IL-13 levels suggesting enhanced Th2 activation and increased IL-1B, IL-5 and IL-17 suggesting Th1 (proinflammatory) activation. Dr. Lipkin was obviously intrigued by the differences in cytokine findings between spinal fluid and blood.

A Focus on the Gut

I think the gut microbiome is going to be where the action is (in chronic fatigue syndrome). Dr. Ian Lipkin

Lipkin’s prime focus at this point is the gut and fecal matter. He  believes the gut microbiome is going to play a, perhaps the key role in ME/CFS.

The Hornig/Lipkin team has had considerable experience with the gut microbiome. They’ve been successful  finding gut abnormalities in autism, a disorder that shares some intriguing commonalities with ME/CFS, including low natural killer cell functioning.  Noting that the gut can modulate immune functioning, not just in the gut, but across the body he asserted the gut is going to be ‘where the action is’ in ME/CFS.

gut picture

Lipkin believes ‘the action’ in ME/CFS is going to take place in the gut microbiome (flora)

Unfortunately, the fecal samples originally collected didn’t provide enough material for analysis so they’re restarting that part of the study.

Even more unfortunately, characterizing the bacteria in fecal matter is extremely expensive and with Lipkin, with just 10% of the money needed to do the job, evidenced considerable frustration at having his hands tied  by lack of money.

Stating that he was not pointing fingers, he then proceeded to point  them everywhere:  at federal politics of funding, at NIH budget cuts, and at the paucity of research funding in our field. As at his last public talk, he urged patients to get active and enlist their congressman in  their cause.  Oddly enough, he also said Dr. Fauci, long considered a kind of ME/CFS nemesis by patients, was supportive of more work in this area.

Reiterating his belief that chronic fatigue syndrome has pathophysiological roots, Lipkin noted his history with it. Dr. Lipkin’s 1999 ME/CFS  study did not find the virus he was researching but it did find a great deal of immune (polyclonal B-cell) activation, a pattern that was recently repeated when he didn’t find XMRV but was impressed by the evidence of immune activation he did find.

Next Up

Lipkin, in close collaboration with his ME/CFS experts, Dr. Peterson, Dr. Montoya. Dr. Klimas, Dr. Komaroff, etc. is following these results with deep sequencing of samples, completion of fecal matter analysis and larger studies to confirm and deepen the understanding of cytokines as biomarkers. Protein analysis was not mentioned but it was part of the original project. Tracking down evidence of past infection was also on the agenda.

Conclusion

The Chronic Fatigue Initiative’s pathogen study set a benchmark for rigor and size in the ME/CFS research field, not the least because of Dr. Lipkin’s leadership. Surprisingly few viruses were found in the blood of ME/CFS patients, yet Lipkin asserted that an infectious agent was likely driving the immune activation he found in the blood and spinal samples.  Cytokine analyses of the blood suggested a different pattern of immune dysregulation was present in  newer onset patients (<3 years) and patients with a longer duration of illness.

Dr. Lipkin believes the “primary cause is likely to be an infectious agent” and the gut microbiome is where ‘the action’ will be in ME/CFS.