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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.

SR_Donate_6.9.14_5

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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Simmaron’s Fifth Anniversary Event Updates ME/CFS Community on Dynamic Research Underway

5th-birthday-258x300

Simmaron recently held a patient update session with its Scientific Advisory Board and key collaborators in Incline Village, Nevada. The event celebrated the Simmaron Research Foundation’s fifth year anniversary.  I don’t know if anyone would have predicted five years ago that patients would be hearing from the likes of Mady Hornig, Maureen Hanson, Konstance Knox and Elizabeth Unger but here they were in little Incline Village talking about their work.

CDC Collaboration

The surprise guest at the event was Elizabeth Unger. Dr. Unger was a fitting guest at the Simmaron’s 5th year anniversary meeting; it’s been, after all, just over five years since she took over the helm of CDC’s Chronic Fatigue Syndrome (ME/CFS) program.  Who would have thought five years ago that the head of CDC’s CFS program would show up at a Simmaron information meeting.

Certainly not Dr. Peterson. About five years ago I asked him if the CDC  had ever shown interest in his work,  and he just laughed.  His relationship with the CDC was frosty to say the least. That’s not true any longer.Dr. Elizabeth Unger

Under Dr. Reeves, the CDC developed a definition in-house that received zero support from researchers (and patients). Under Dr. Unger, the CDC has made ME/CFS experts a core feature of its work, is meeting with patient groups, has worked with CFSAC on its website, and is engaging with patients and experts in its educational materials.

Instead of a stumbling block, Dr. Unger turned out to be a collaborator who’s committed an enormous amount of time, energy and her (limited) budget to learning about ME/CFS doctors and their patients.  What a shift that has been.

Dr. Unger threw all the definitions out the window in the multisite ME/CFS expert study. Realizing that doctors, most of whom had decades of experience in this disease, were a better source of what ME/CFS was than any definition, she cleared the decks; anyone the expert doctors believed had ME/CFS, whether they met x or y definition or not, she would study. They were, by default, ME/CFS patients. Dr. Peterson thought it was a brilliant move.

At Dr. Peterson’s invitation, Dr. Unger stayed following a routine site visit to hear the presentations from Simmaron’s Scientific Board and attend the patient gathering.  At the patient meeting she had some good news; the first paper from the ME/CFS experts multisite study was finally under review for publication.

It had been a long time coming. Simmaron and Dr. Peterson are already deeply immersed in the greatly expanded second phase of the trial, and had just gotten a contract for the third phase of the study. The study was already slated to continue at least into 2017 and now will continue further.

This now immense study involving over 800 patients and controls will surely supplant the infamous PACE trial as the largest and longest ME/CFS study ever done. With a third phase slated to begin shortly, it’s going to provide an unprecedented look at a very large group of ME/CFS patients, and how they are tested and treated by doctors over time.

Dr. Unger quickly went over a few of the highlights; the greatest heterogeneity, surprisingly, was found within the ME/CFS expert’s sites, not between them. By and large, the practitioners are not seeing different kinds of patients; instead each is seeing a similarly wide variety of patients. How wide? The standard functional tests being done, for instance, indicate that some people with ME/CFS experience high rates of pain while others experience no pain at all.

The constant is that ME/CFS is producing high reductions in vitality and physical functioning but has relatively little effect on mental or emotional functioning.  Dr. Unger said the multisite studies will go a long way to helping the public understand how severe a disease ME/CFS is.

Konstance Knox  

Konstance Knox, PhD, is collaborating with Simmaron on her insect infection study at Coppe Healthcare. She posited the interesting idea of ME/CFS having a similar trajectory to Lyme Disease. Lyme Disease,she noted, first showed up in pediatrician’s offices in children with arthritis in Old Lyme, Connecticut in the 1970’s.  Eventually the children were found to be infected with bacteria carried by ticks.

KKnox

ME/CFS patients have been showing up in doctor’s offices with unexplained fatigue, post-exertional malaise, pain and debilitating symptoms for years. Could a similar scenario prevail for at least a subset of ME/CFS patients? Knox thinks it might. Her large study, using samples from 300 ME/CFS and healthy controls gathered in the NIH’s XMRV study, is looking for evidence of pathogens that aren’t always tested for in chronic fatigue syndrome (ME/CFS). They include three different kinds of Borrelia bacteria, the Powassan and Dengue viruses, and the most widespread insect borne disease in the U.S., West Nile Virus.

Each demonstrates how rapidly insect borne pathogens can invade a country. Borrelia was identified as the cause of Lyme in 1981, and according to one estimate, is believed to effect 300,000 people a year.  West Nile Virus was first found in New York in 1999 and has spread across the country.  Now the Zika virus is beginning to touch upon our southern shores in Florida as well.

In Dr. Knox’s mind, the Powassan virus is the big mystery. Carried by the same ticks that cause Lyme disease, Powassan is similar to tick-borne encephalitis virus which has long been shown to cause serious illnesses in Eurasia.

Unlike the Lyme bacteria, which needs the tick to be attached for quite some time for the bacteria to get transmitted, the Powassan virus can be transmitted in just 15 minutes. Knox found that 11% of the 2,000 ticks she studied in Wisconsin  carried Lyme disease and 6% carried the Powassan virus.  She found 55% of people infected with Lyme disease also were infected with the Powassan virus.

Dr. Knox’s preliminary data of ME/CFS patients with an acute flu-like onset found a low incidence of Lyme disease (3%) but a pretty high incidence (11%) of people who had antibodies which looked like they might be to TBEV; i.e. the Powassan virus. The NIH samples offer an opportunity to study these infections in well characterized patients and controls from multiple clinical sites.

Dr. Mady Hornig

The Hornig/Lipkin team at Columbia’s Center for Infection and Immunity (CII) isn’t just looking at ME/CFS to understand the disease. It’s mining clues from a wide range of disorders – from autism to narcolepsy – to try to understand the disease processes that are occurring. They believe the “omics” revolution – which attempts to understand diseases in terms of their genomics, proteomics, metabolomics (and probably other “omics”) – holds the key to understanding and finding the subsets present in ME/CFS.

Mady Hornig sits on the Simmaron Research Foundations Board. She and the Simmaron Research Foundation are frequent collaborators. Until they get to a cause, Dr. Hornig is unwilling to rule out any possibilities. ME/CFS could be caused by an immune response to a wide range of pathogens (which may be present or not) or to an as yet undiscovered agent. That statement suggested that Dr. Hornig doesn’t consider the earlier CII study which found little or no evidence of pathogens to be the end of the story.

Of course few researchers have looked in the tissues. Dr Chia believes he’s found enteroviruses and Dr. Duffy herpesviruses in the gut tissues of ME/CFS and/or fibromyalgia patients. Hornig and Lipkin have looked in the blood but they’re also raising money to do analyses of the flora in the stool and saliva over time. (Check out the Microbe Discovery Project  for more.) Plus, as we’ve seen, a Simmaron/Konstance Knox project is looking for evidence of insect borne illnesses that have not been tested for before.

If  pathogens are involved, the heterogeneity in the disease could reflect genetic differences in how each person responded to them, how old the person was when the infection occurred, the state of each person’s microbiome at the time, etc.  The take-away message was that different symptoms don’t necessarily mean different diseases.

The CII is doing a lot, but Dr. Hornig started out by focusing on a hot topic these days – metabolomics.  The CII team believes that metabolomics may provide the link between what’s happening in the microbiome and the rest of the body. Metabolomics uncovers the breakdown products of metabolism. If a substance, say tryptophan is not being metabolized properly in the gut, it can leave a metabolic signature in the blood that can be picked by metabolomics tests.  From the blood it’s apparently a pretty straight shot to the brain.

Marrying gut (microbiome) and blood (metabolomics) data would be the cat’s meow, and it’s begun to happen. Several small studies have been able to link altered gut bacteria to the presence of gut metabolites in the blood.  A small Solve ME/CFS Initiative study carried that idea one step forward by adding exercise to the mix. It suggested that exercise could, probably by increasing leaky gut issues, result in increased levels of gut metabolites in the blood.

Dr. Hornig believes that aberrant tryptophan metabolism in the gut could provide a major clue for ME/CFS patients.  These metabolic by-products have already been associated with several neurological diseases and are known to cause symptoms similar to those found in chronic fatigue syndrome (ME/CFS). If she finds problems with tryptophan metabolism in the gut and then can pick up their metabolic by products in the patient’s blood she can make a strong case for a gut-brain connection in ME/CFS.

While she was at it, she also noted that these bacteria can affect NAD+ and energy production.  To sum up, Dr. Hornig is gathering data on a process that could be affecting cognition, the gut and energy production in ME/CFS.

No Mady Hornig talk it seems is complete without an emotional moment. Every event I’ve seen her at has left her and others in tears at some point, and it happened again. I watched an older gentleman come over and clasp her hands. Five minutes later there they were hugging each other and sobbing away.

Top Poop Crew

Dr. Peterson and Simmaron won the top poop collector award

Dr. Peterson and Simmaron won the top poop collector award

While on the microbiome she noted, with a smile, that of all the groups they were working with, Simmaron was the best poop collector; Dr. Peterson gathered more stool samples (hundreds of them apparently) from more patients than any other doctor they were working with. (Go Simmaron :))

Maureen Hanson

Maureen Hanson, PhD, presented some  interesting news recently when she announced during an SMCI webinar that her small metabolomics had duplicated the Naviaux study’s core finding that ME/CFS was a disorder of reduced metabolism; i.e. it’s a hypometabolic disorder.

Maureen Hanson

That finding helps us understand her Simmaron talk a bit better. Hanson explored the subset question more deeply than anyone I’ve seen before.  Chronic fatigue syndrome (ME/CFS), she said, could be a bunch of different diseases, or one core pathology could be driving it.

Whatever it is, the diversity of symptoms found in the disease has produced a credibility problem because diseases which produce lots of symptoms have long been considered “psychosomatic”. The many different triggers ME/CFS and outbreaks has been associated with, and the many different bodily systems it effects, have been confusing as well.

Hanson thought it was intriguing that the symptom presentations seen in different locales appears to be similar! If ME was the result of different agents producing different diseases in different places then the locales should look very different but they don’t.  Hanson then fished out a bevy of factors which could affect symptom preSimmaron Research | #ShakeTheCFSstigmasentation; the age at which ME/CFS occurred, gender, genetic background, co-infections present, pathogen variations, treatments tried, degree of exercise attempted – all of these could conceivably tweak one disease into producing different symptoms. (Consider what happens to some people who collapse and appear to revert to a different state after overexertion or after using the wrong drug.)

She noted that her mitochondrial DNA study suggested that slight alterations in ME/CFS patients’ mitochondrial DNA could result in different symptoms. That sure presents just the tip of the iceberg with regards to genetics.  (Ron Davis and the Open Medicine Foundation will be attempting to marry genetic data and metabolomics in one of their studies.)

Hanson’s microbiome project was powered by a small NIH grant and took place in a Cornell lab famous for its microbiome work.  The project was a small one but it made a big splash and was picked up by over 50 media outlets.

The study’s finding – a reduced diversity of bacterial species (about 20% less) similar to that found in two potentially devastating gut diseases (Crohn’s and ulcerative colitis) gave Hanson the opportunity to tell the media again and again that ME/CFS is a real disease.  The study also found that ME/CFS patients’ gut bacteria tended to be more dominated by a smaller number of bacteria.

Bacteria of the Ruminococcaceae family –  important in fighting inflammation  – were significantly reduced in ME/CFS.  The representatives of another bacterial family called Enterobacteriaceae – which contains some rather nasty pathogens but hundreds of other species – doubled in ME/CFS patients.

At the genus level, Faecalibacterium prausnitzii, a butyrate bacteria, which produces an anti-inflammatory protein and protects the intestine was reduced in ME/CFS. A similar finding is found in irritable bowel syndrome.

The low butyrate findings in both Hornig and Hanson’s microbiome studies suggest they are both on the right track. That’s actually a big win given how complex (and new) microbiome analysis is, but perhaps it is not surprising given the pedigree of the labs doing the analyses.

As did a Solve ME/CFS Initiative study, Hanson also found evidence that gut materials were leaking into the blood of ME/CFS patients – a process that could spark an inflammatory process that makes its way all the way up to the brain.

[Butyrate – One neurobiologist calls butyric acid – which is produced by butyrate bacteria – “an ancient controller of metabolism and inflammation”. He reports that butyrate is the primary source of energy for the lining of the large intestine. Butyrate is such an effective anti-inflammatory that butyrate enemas (which reportedly smell horrible) and oral supplements are being used to combat inflammatory bowel diseases like Crohn’s and ulcerative colitis.  Butyrate also appears to reduce intestinal permeability – which Hornig’s/Lipkin’s and Hanson’s studies suggest many be happening in some people with ME/CFS.

Butyrate may also increase the levels of T regulatory cells which help reduce inflammation and autoimmune processes.

Hanson is a careful researcher and she spoke carefully regarding treatment. She noted that the inability of researchers at this point to clearly determine which gut species are present hampers them from recommending treatments. They can determine which families are present but because bacterial families can contain many different kinds of gut species -some of which have opposite functions – the study’s impact on treatment recommendations is not clear.

Atypical vs Typical Patients – the Peterson Subset

For many years Dr. Peterson has speculated about what he calls typical vs atypical ME/CFS patients. It’s not clear to me what the groups consist of but my sense is that  typical ME/CFS patients tend to plateau over time and they tend to have familiar co-morbid disorders such as fibromyalgia, migraine, IBS, etc. Atypical ME/CFS patients, on the other hand, tend to have other serious disorders and/or have really serious cases of ME/CFS. Whitney Dafoe and Corinne Blandino are two examples of atypical patients; Whitney because he’s so ill and Corinne Blandino because she has a strange spinal lesion.

Dr. Peterson

Dr. Hornig reported earlier that a cerebral spinal fluid (CSF) tests results had found dramatically different results.

At another event, Mady Hornig talked about the dramatic differences found in the CSF of classical versus atypical patients. Virtually all the immune factors tested were higher in the complex atypical vs the classical patients. In fact, the findings in the two subsets were so different that the atypical patients had to be removed from a study comparing healthy controls and ME/CFS patients. Simmaron and the Center for Infection and Immunity have taken a deeper look at the cerebrospinal fluid in these two types of patients.

I asked Dr. Hornig if she thought the atypical patients had a different disease or were an offshoot of more typical patients? She simply said that she thought that the atypical patients needed to be more closely watched.  Later Dr. Peterson suggested, however, that they may be profoundly different biologically.

We should know more about the similarities and differences between these two subsets soon. A Simmaron/CII spinal fluid study comparing the two in greater detail has wrapped up. The metabolomics data from the Ron Davis/Open Medicine Foundation severely ill patient study and the Naviaux study examining more typical ME/CFS patients will give us some guidance as well. Plus, the CDC will be comparing the test results of severely ill patients and healthy controls in the third phase of its multisite study.

A talk with Dr. Peterson found him in a more optimistic frame of mind than I’d seen before. While the promised funding package at the NIH hasn’t shown up yet, he was clearly impressed by the Nath Intramural study, the continuing work of the CDC, and the work Ron Davis is doing at the Open Medicine Foundation.

We didn’t talk about Ampligen and Rituximab but advances with both those drugs may make his job easier. Peterson’s stated that his patients have about a 70% response rate to Ampligen. That high percentage probably reflects two things: Dr. Peterson’s feel for who will respond to the drug, and his ability to dose this drug optimally for each patient.

At the IACFS/ME Conference, Hemispherx Biopharma will report a breakthrough in their understanding of the drug effects in ME/CFS. It appears that they’ve found a way to identify which ME/CFS patients respond to Ampligen – a finding that should help doctors and patients decide whether to try the drug, and make their next clinical trial that much easier. Dr. Patrick of Canada appears to have done the same with Rituximab – a very expensive powerful drug that many doctors are probably leery of trying in their patients without more guidance.

  • Dr. Peterson will be co-leading a session with Drs. Fluge and Mella on Rituximab and Emerging Treatments, and will be a panelist on a session devoted to diagnosing difficult cases of ME/CFS, and will be highlighting a fellowship opportunity with Simmaron, at the International IACFS/ME Conference at the end of October.

With groundbreaking spinal fluid publications, more collaborative studies lined up, and additional findings on their way to publication, the Simmaron Research Foundation (SRF) has made pivotal contributions to the rising science of ME/CFS in its first five years. The Simmaron Research Foundation is committed to translational research efforts that produce solid gains for patients. With collaborators like these, the next five years promise much.

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

Infection, Autoimmunity and PANDA’s: Dr. Hornig on Chronic Fatigue Syndrome at Dr. Klimas’ NSU Conference

Quite the Resume

Dr Mady Hornig comes with quite a resume. She and Dr. Ian Lipkin MD direct the Center for Infection and Immunity at Columbia University in New York, and Dr. Hornig is directing the Pathogen Discovery and Pathogenesis Program at the Chronic Fatigue Initiative (CFI).

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

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

An MD and immunologist with a background in neuropsychiatry, Dr. Hornig’s been focused throughout her career on uncovering immune dysfunctions associated with mood and developmental disorders such as autism, PANDA’s, ADHD and schizophrenia. Her current work on the MIND (Microbiology and Immunology of Neuropsychiatric Disorders) Project constitutes the largest examination yet of the role the immune system and viruses play in mood disorders and schizophrenia. She’s currently a lead investigator for  the Autism Birth Cohort study determining how development, genes and environmental factors combine to produce autism.

Dr. Hornig has quickly become a major chronic fatigue syndrome investigator and said she and Dr. Ian Lipkin were using all the tools available to them including gene expression studies, immune and stress markers and proteomics using mass spectroscopy.Check out the ME/CFS studies her lab is or has been involved in….

Chronic Fatigue Syndrome Studies at Dr. Hornig’s Laboratory

  • 200/200 Cases and controls with Chronic Fatigue Initiative  – 18 pathogens identified, then unbiased high throughput sequencing – pretty much tell us anything that is in there
  • 150/150 cases/controls in XMRV study
  • 400/400 cases/controls in huge Montoya Stanford study
  • 60 cases/60 controls Simmaron Spinal Fluid Study

Dr. Hornig focused in on the Simmaron Institute spinal fluid study calling it ‘really intriguing’, calling the number of well-characterized spinal fluid samples  ‘unparalleled’, and stating the study was a ‘unique opportunity’.

We’ll get another chance to see her at the 2013 Invest In ME Conference in May.

The Talk – Infection, Autoimmunity and Illnesses

Placing chronic fatigue syndrome into the category of ‘neuropsychiatric disorders’ (disorders that effect cognition and mood among other things) Dr Hornig started off her talk demonstrating how attacks of insanity seem to have swept over populations, not suggesting that she’s studying a group of insane people, but demonstrating how infections can generate symptoms we don’t generally associate with them.

Mom???

Dr. Hornig believes three factors, timing – a window of opportunity,  a genetic predisposition, and an environmental insult probably come  together to cause chronic fatigue syndrome.  That window of vulnerability could have occurred at any time but Dr. Hornig zeroed in on pregnancy:  a time, it appears, when many chronic disorders are  set into motion.

Mom? The roots of some chronic illnesses appear as far back as pregnancy

Mom? The roots of some chronic illnesses appear as far back as pregnancy

She suggested, but did not say, that chronic fatigue syndrome could be triggered as early as pregnancy and then not show up for 20 or  40 or 50 years until  another window of vulnerability opens up – perhaps during a stressful period, another infection, toxic overexposure. (She noted that the stress response is similar in all these cases).   Indeed, that model of disease, she said,  could apply to outbreaks of autism and ADHD in early life, multiple sclerosis, schizophrenia and ME/CFS in middle life and Parkinson’s and Alzheimer’s disease in later life.

Cannabis triggered schizophrenia during adolescence is an example of the three factors combining in a perfect storm to cause a devastating  disease.  It turns out that bringing together one form of a COMT gene (the COMT gene, oddly enough is implicated in ME/CFS), the tumultuous physiological time of  adolescence, and an environmental factor (cannabis) you get an increased risk of (gulp) schizophrenia.  Basically smoking pot when you’re an adolescent increases your risk of  schizophrenia (it happened to one of the my best friends) but smoking it when you’re an adult – even if you have this particular form of this gene- doesn’t increase your risk at all.

She described an incredible and rather frightening study in which researchers examined pro-inflammatory cytokine levels (IL-6 and IL-1b) in the blood of mothers collected 40-50 years ago. Skipping  forward they found that women whose mothers had high cytokine levels during pregnancy  tended to be depressed and have reduced  brain activation in middle age. This suggested those high levels of pro-inflammatory cytokines changed the circuitry of female fetus’s brain enough to make those women more vulnerable to depression later on.  She noted that some of the same stress-circuitry showing up  in those women is implicated in ME/CFS as well.

The Immune Side of Neuopsychiatric Disorders

Hornig is an immunologist and she  explained that many ‘neuropsychiatric disorders’ may be explained by immune problems; the list  she presented was not a particularly pretty on; besides fibromyalgia and ME/CFS it included Tourette’s syndrome, autism, obsessive compulsive syndrome, ADHD, anorexia nervosa, narcolepsy, major depressive disorder, bipolor disorder and schizophrenia (and probably should have included irritable bowel syndrome, interstitial cystitis and other disorders that co-occur with ME/CFS. ).

There are several  groups in here; the heavy psychiatric disorders – depression, bi-polar disorder, compulsive obssessive disorder and schizophrenia; the CFS-like disorders (ME/CFS, FM….IBS, IC, etc.) and then autism and ADHD.

The Infection Autoimmune Connection

The infection/autoimmune connection is a strong one with many autoimmune disorders showing up shortly after infections…but..(there’s always a but :))  she noted that other autoimmune disorders  can take years to show up making it difficult to determine the trigger.  If it was a pathogen, it could’ve  and may very well have done it’s damage and then disappeared, leaving a chronically disrupted immune system in its wake.

PANDAS – A Possible  Model for ME/CFS

“Several studies suggest autoimmunity may play a role…”

PANDA's - a childhood disorder associated with Streptooccus infection could be a model for ME/CFS

PANDA’s – a childhood disorder associated with Streptooccus infection could be a model for ME/CFS

Hornig  then described an infection triggered neuropsychiatric disorder called PANDAS that could be a model for ME/CFS.  Children with PANDAS don’t eat eucalyptus leaves for lunch, but they do display dramatic changes in behavior including obsessive-compulsive behavior, tics, mood swings and anxiety soon after a staphyloccus infection. They also display the kind  of ‘ vigilance’ and arousal that shows up in some people with chronic fatigue syndrome.

Hornig has become deeply involved in PANDAS. Much is controversial about PANDAS but it’s believed to be an autoimmune disorder that targets the basal ganglia in the brain (which is, yes, also under consideration in ME/CFS…). Working with Dr. Lipkin, Dr. Hornig found that mice injected with strep   engage in obsessive compulsive behaviors (they flip themselves over backwards again and again) and that simply injecting  antibodies to streptococcus  into mice caused problems with learning and memory, coordination, and social interactions.  Then, in a nice Koch-like test, they found that  removing the antibodies from the mice  resulted in the return of  normal behavior.

General Stress Response Affected

That made it pretty clear  it’s the antibodies; eg. the immune response that’s the problem and what they found next confirmed that; they found that the antibodies to strep mistakenly cross-react (ie  target  for destruction) two important parts of  the  immune system; C4 complement and heat shock proteins.

Why would we, with ME/CFS, be interested in these factors?  Because both  appear, Dr. Hornig said, to be general responses to infections and stressors of all sorts, with all its different triggers, chronic fatigue syndrome could be associated with a basic derangement of the stress response (to  infection, trauma, etc.).

Dr. Hornig didn’t mention it both C4 and heat shock proteins  have (yes, yes, yes :)) been implicated in chronic fatigue syndrome at one time or the other

Dr Hornig noted that children with  PANDAS can respond to IVIG, antibiotics and other immune agents.  That’s a bit controversial (no surprise there) with  the American Heart Association (AHA)  recommending that strep not be tested for in children with PANDAS or that they attempt IVIG  treatment despite the fact that one preliminary  study has found IVIG effective.

It’s more of the old, we need more studies before we do or recommend anything without providing the money to do them leaving potential helpful treatments on the shelf while patients suffer (sound familiar?). (PANDAS is way down on the NIH’s priority list.

Key Partners – The Stress Hormone-Immune System Interactions

Hornig noted the immune- stress response connection with PANDAS and now she enlarged on it. Proper central nervous system functioning is dependent on having  balanced immune and stress responses; throw those responses in just one part of the system-  tryptophan degredation – into disarray can cause you to not be able to lay down a memory. Tryptophan is a possible candidate with ME/CFS but she was most interested in the biggest bundle of nerves outside the brain – the enteric nervous system or gut….

Getting Down With The Gut

Hornig then directed us out of the brain and downwards into the gut.  On a very, very basic level this makes sense since  everything  that our bodies run on (except for the gases) comes from our food which means we better be able to digest it well. Stopping the flow of anti-oxidants  (selenium, cysteine, glutathione) from our food out of the gut into our body, for instance, results in increased levels of oxidative stress,  pro-inflammatory cytokines and auto-antibodies  (autoimmune reactions).

Get increased auto-antibodies and you can have problems showing up in literally any part of the body. Just to get our attention, Dr. Hornig noted that an  autoantibody attack of folate receptors could show up in problems with  metabolism,  methylation and B-12.

Then she shifted upwards – back to the brain.  So far our dysfunctional gut has left us with low levels of anti-oxidants, high levels of pro-inflammatory cytokines,  and high levels of autoantibodies in our blood.  Send all that stuff up to the precious (and fragile) blood-brain barrier  protecting our brain and….you have the possibility of a rip exposing the brain to all sorts of bad actors. Depending on which part of your brain gets attacked there goes your  sex drive, appetite, motivation, energy levels, etc….and to think it all could have started with bad flora in your gut.

More Floral Than Viral?

Lest we think this is some researcher’s fantasy, Hornig described her work with autistic kids.  Hornig’s group did not find evidence of measles in autistic children but they did find levels of digestive enzymes so low to be almost non-existent. The autistic kids couldn’t break down milk products because they were lacking the enzyme for that but that hardly mattered as their guts were so deficient they couldn’t have gotten the milk protein into their bodies even they could have broken it down.

Not only was their gut flora massively different but they also they harbored a rare bacteria called Sutterella not present at all in the healthy controls.  Sutterella was not just present,  it was flourishing, accounting for up to  7% of all gut bacteria. Usually a very minor component of the gut microbiome, Suttarella was the third most common bacteria found in these kids.  That really raised some eyebrows.

Could ME/CFS be More Floral than Viral? An upcoming CAA study should be revealing. These bacteria were cultured from yogurt

Could ME/CFS be More Floral than Viral? An upcoming CAA study should be revealing. These bacteria were cultured from yogurt

Still, it’s not clear if Sutterella itself is whacking the kids or if its crowding out good gut flora or if its doing nothing but  we do know that Sutterella thrives in low oxygen  environments and has been linked to inflammatory bowel disorder, Crohn’s disease and ulcerative colitis. (It  can also, though, sometimes be found in healthy individuals.) Hornig’s ability to find an antibody to Sutterella in about 50% of the children indicated they had mounted an immune response to it.

Bacterial imbalances in the gut have been observed in gut disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease but its become clear that  bad gut bacteria could wreak havoc far outside the gut. The first non-gut disorder associated with bad bacteria appears to have been arthritis.  (Check out a horrifying and fascinating New York Times story of  young child’s battle with rheumatoid arthritis.)  Cesareans appear to  put children at increased risk for asthma because they prevent children from picking up important gut bacteria as they pass they through the birth canal.   Bacterial imbalances in the gut appear to be associated with increased obesity in people with  type two  diabetes .

Researchers have identified three main types of gut composition in humans and they know that diet can influence gut flora. They know that  cutting out sweets and processed foods and using prebiotics and probiotics can help some people reduce or eliminate  inflammation.  Fecal transplants may actually be more effective because they contain more of the bacteria that’s actually populating our guts.

Hornig noted how  important the small intestine is for so many different type of phenomena – for cognition, anxiety and even for sleep. Did you know that if you’re not getting peristalsis (small gut movements pushing the food along)  during the night then you’re missing some sleep enhancing molecules.

Major Chronic Fatigue Syndrome Gut Study Out This Year

The Shukla CFIDS Association gut metagenome study is looking more exciting all the time. This study, which study started several years ago and should be published soon, sought to characterize the entire  gut microbriome before and after exercise in people with ME/CFS.

By studying the gastrointestinal microbiome, Shukla’s work will determine if the ratio of normal to pathogenic (illness-causing) bacteria is off-kilter in CFS patients and if exercise causes harmful bacteria to travel into the body from the gut, creating the postexertional symptoms that are such a prominent feature of the illness. The results have the potential to yield microbial biomarkers for CFS as well as targeted treatments aimed at rebalancing the ratio of bacteria. From CFIDS Chronicle Winter 2009

  • Xafaxan: Gut Rebalancer Extraordinaire –  Suffering from gut issues? Check out a new page Health Rising has on Xafaxan, a gut antibiotic used to snuff out small intestine bacterial overgrowth (SIBO) problems. One person with ME/CFS ended six years of gut turmoil with one short course of Xafaxan…

 Q & A Period

Is Chronic Fatigue Syndrome Infectious?

She thought perhaps, but if so probably mostly during the initial stage of the illness, and that it was highly unlikely it was  infectious in later stages of the illness.  Hornig is following the same model as Klimas in her research; she’s  looking for an infectious agent but finding  immune and stress response factors indicative of a pathogenic attack (at some point) is a major focus.

With a kind of immune system hypervigilance twist she stated its possible an initial infection sensitized the system so that further infections, even very mild ones, might be  throwing it  into a tizzy.   If ME/CFS patients have a problem with infection in general; that is, if any infection has the potential to trigger a kind of overwrought immune response, then she felt it was more important the source of that than to look for a specific virus.  With all the known infectious triggers for ME/CFS she believes some genetic susceptibility/immune issue was present.

One reason for Hornig’s interest in ME/CFS may be due to her work in autism. Hornig believes innate immune system problems during maternity may play a role in the development of autism, and the innate immune system  – the early immune response system involving NK cells, dendritic cells and others – is getting more and more attention in ME/CFS.  Interestingly, Hornig found that infection induced inhibition of the same Toll-like receptors (TLR3) Ampligen effects lead problems with sensorimotor gating responses as adult.  Check out this blog for a treatment of sensory gating issues in chronic fatigue syndrome.

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Clin Invest Med. 2008 Dec 1;31(6):E319-27. Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndromepatients and matched healthy controls. Thambirajah AASleigh KStiver HGChow AW.

J Intern Med. 2009 Aug;266(2):196-206. doi: 10.1111/j.1365-2796.2009.02079.x. Epub 2009 May 19.Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. Jammes YSteinberg JGDelliaux SBrégeon F.

Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins. Jammes Y, Steinberg JG, Delliaux S. J Intern Med. 2012 Jul;272(1):74-84. doi: 10.1111/j.1365-2796.2011.02488.x. Epub 2012 Jan 4.

Mol Psychiatry. 2010 Jul;15(7):712-26. doi: 10.1038/mp.2009.77. Epub 2009 Aug 11. Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Yaddanapudi K, Hornig M, Serge R, De Miranda J, Baghban A, Villar G, Lipkin WI.

J Allergy Clin Immunol. 2003 Aug;112(2):397-403. Complement activation in a model of chronic fatigue syndrome. Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, Jones JF.

Mol Med. 2009 Jan-Feb;15(1-2):34-42. doi: 10.2119/molmed.2008.00098. Epub 2008 Nov 10. Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Sorensen B, Jones JF, Vernon SD, Rajeevan MS.