Sci Rep. 2018 Jul 3;8(1):10056. doi: 10.1038/s41598-018-28477-9.Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics.  Nagy-Szakal D1, Barupal DK2, Lee B1, Che X1, Williams BL1, Kahn EJR1, Ukaigwe JE1, Bateman L3, Klimas NG4,5, Komaroff AL6, Levine S7, Montoya JG8, Peterson DL9, Levin B10, Hornig M1, Fiehn O11, Lipkin WI12.
After striking that rich vein, the Lipkin group expanded their research effort – incorporating metabolomics for the first time into their studies. (Lipkin and the Simmaron Research Foundation are also currently engaged in the first metabolomics spinal fluid study.) Once again incorporating a wide variety of doctors from different locations (Peterson, Bateman, Klimas, Levine, Montoya) and using a fairly large sample set (n=100) Nagy-Szakal/Lipkin, the Lipkin group fused together blood metabolomic, fecal bacterial metagenomic, and clinical data to paint a new picture of ME/CFS.
The study represented the first attempt to meld two potentially important fields in ME/CFS – metabolomics and gut microbiome findings- together.  Lipkin and Hornig have proposed that the gut issues play an important role in ME/CFS, and several studies have found evidence of dysbiosis (pro-inflammatory gut bacteria) in ME/CFS.  Unutmaz is chasing down a T-cell gut connection, and past studies have suggested that bacterial leakage from the gut could help explain at least some of the post-exertional malaise present.
Given the group’s past gut findings – that significant differences in gut bacteria, immune profiles and possibly energy production exist between ME/CFS + IBS patients and ME/CFS patients without IBS, it made sense for the Lipkin group to once again split the ME/CFS group into subsets with and without IBS and analyze the heck out of them.
Study Results
Energy Production Problems Highlighted
The study confirmed past general findings of decreased levels of phospholipids and sphingomyelins – two important findings by Naviaux- and increased levels of triglycerides (TG’s). (Triglycerides have been associated with metabolic problems and hypothyroidism.)
That both the ME/CFS + IBS group and the ME/CFS without IBS group had reduced levels of metabolites associated with the choline-carnitine energy pathway suggested that both groups had similar core metabolic problems.  (Carnitine participates in the TCA cycle, ATP production and energy metabolism).
More Was Better
The Lipkin group’s decision to integrate metabolomics, microbiome and clinical data worked. Not only did incorporating all this data together illuminate a possibly important subset – the ME/CFS IBS subset – but it also allowed the group to better differentiate ME/CFS patients from controls. It suggested that studies which combine multisystemic data together will do a better job in describing this multisystemic disease.
As with the 2017 study, having or not having IBS was the biggest driver in determining the kind of bacterial profile (and bacterial metabolic pathways) present. This time the study found that the metabolomics of the ME/CFS + IBS group were significantly different from the ME/CFS only group as well. That suggested these two subsets of ME/CFS patients might be quite different indeed.
In contrast to Naviaux, the study did not find a “consistent decrease” in ceramide metabolites – the most commonly disrupted metabolite Naviaux found in his ME/CFS group.  When Lipkin controlled for IBS, he found increased levels of ceramides in the ME/CFS plus IBS group but decreased levels of ceramides in the ME/CFS only group. That suggested that key metabolites in ME/CFS might be different in these two ME/CFS subsets.
Bacterial Toxins Highlighted
Nagy/Lipkin suggested that increased levels of bacterial toxins (IBS connection) in ME/CFS may be triggering an enzyme called sphingomyelinase to produce the ceramides which then may damage the gut lining and possibly interfere with energy production.
Ceramides are waxy fats that figure in a number of processes that may be important in ME/CFS. Not only can they produce many free radicals (reactive oxygen species) that can damage the gut lining (the IBS connection), they can also interfere with electron transport (the energy connection) as well as contribute to insulin and leptin resistance (metabolism issues).
The authors also proposed that the higher mannitol levels found in the ME/CFS could reflect the breakdown of two important barriers in the body: the gut barrier and the blood-brain barrier.
Several studies suggest a breach in the gut barrier could be contributing to systemic inflammation in ME/CFS, and one suggests that exercise may further widen that breach. Several researchers, including Jarred Younger and Avindra Nath, have also postulated that the suspected neuroinflammation in ME/CFS results from immune cells entering the brain through a weakened blood-brain barrier.
The Gut Shines in Distinguishing ME/CFS Patients From Healthy Controls
Interestingly, for all the focus on metabolomics, a network analysis using differences in gut bacterial abundance was better able to distinguish ME/CFS patients from healthy controls than did metabolomic results.
That suggested that gut bacterial differences may be more prominent than metabolomics differences in ME/CFS patients. That was a surprise, and we’ll see how this all turns out. It stands to reason that the closer we get to the core of the problem, the more striking the differences we’ll see between healthy people and people with ME/CFS.  (Will the gut play a bigger role than we thought?)
Possible Treatment Options
The group suggested that their findings, if validated, could present some possible treatment options. They included using SMAse blockers to reduce ceramide levels and giving carnitine supplementation to increase the low levels of metabolites in the choline-carnitine pathway.  One open-label study found that carnitine supplementation helped over half of ME/CFS patients.
Given the unrevealing cytokine data from Lipkin’s cytokine data and his recent turn to metabolomics I asked Lipkin how important a role cytokines were likely to play in future ME/CFS research and treatment. Lipkin felt they may yet play an important role in ME/CFS indeed:
“Cytokine disturbances can result in fatigue, cognitive and other disturbances. The observation that other biomarkers such as metagenomic or metabolomic profiles are highly associated with disease does not diminish their (cytokines) importance. There may be people who would benefit from drugs, including antibody therapies, that modulate cytokine responses.”
Scheibenbogen is pursuing antibody therapies in ME/CFS, and Nancy Klimas is reportedly using Enbrel (etanercept) – a cytokine (TNF) blocker – plus mifepristone in her Gulf War Illness trial. Other biologics are available and more are coming on the market.  Recent findings in POTS suggest that antibody drugs will probably play an important role in that disease as well.
Since the study also found that taking Vit. B supplements was associated with higher levels of pantothenic acid and lower fatigue scores, taking Vit. B supplements may be a good idea.
The 5-MT Question
Decreased levels of 5-MT, a metabolite associated with tryptophan, serotonin and melatonin metabolism could reflect problems with serotonin/melatonin conversion. This finding, however, was confounded by the high use of antidepressants (50% of the ME/CFS group) which could have produced the decrease.
Correlation studies do suggest, though, that low 5-MT levels could contribute to problems with cognition, sleep and fatigue. Larger studies are needed to determine if the low 5-MT levels are associated with those symptoms in ME/CFS – and if they are – if it might be beneficial to modulate that pathway using drugs in ME/CFS.
Next Up for the Simmaron Research Foundation and Ian Lipkin
The next phase in the Simmaron Research Foundation’s ongoing collaboration with Ian Lipkin is an expanded study which will, for the first time in ME/CFS, analyze the metabolomics of ME/CFS patients cerebral spinal fluid. The study, which will also include immune analyses is the third Simmaron/Lipkin CSF study to date. The first two studies found dramatic evidence of immune activation and the presence of a potential new subset.
Lipkin also reported rapid progress from his new NIH research center and a new collaborative effort with ME/CFS researcher and NIH ME/CFS research center leader Derya Unutmaz. The idea of two top labs in the country collaborating in a complementary fashion is an exciting one – one we will hopefully see much more of in this field.


Lipkin and Unutmaz are merging their respective strengths in a collaboration – something we could use much more of in ME/CFS.
We are completing analysis of saliva, blood, and feces for bacteria, viruses and fungi from ME/CFS and control subjects using powerful new sequencing methods. This will be the largest and most comprehensive study to date on the microbiome in ME/CFS. We will soon begin metabolomic, proteomic, and transcriptomic analyses of ME/CFS and control subjects before and after exercise. We are deeply grateful to the patients who are contributing to this work despite the implications for their health. They are true heroes.
We have begun a new collaboration with Derya Unutmaz and Jackson Laboratories that builds on the complementary expertise of our teams in cellular immunology and molecular microbiology and biochemistry.
Dana March and Tony Komaroff are building an app to help ME/CFS subjects and their caregivers track their status. We have had great support in this effort from people in the community.
Conclusions
In the past three years Lipkin’s identified three potential subsets (early/late duration patients, the “Peterson subset”, ME/CFS + IBS subset) and his explorations into the ME/CFS IBS subset continues to reap dividends.
His metabolomic study found signs of energy production problems in all ME/CFS patients, but when Lipkin separated out the ME/CFS + IBS patients, he found altered, even at times opposite metabolic findings that could suggest a different source of fatigue was present in the ME/CFS + IBS patients. His earlier study suggested more severe energy production problems may be present in ME/CFS patients with IBS.
The importance of the gut bacteria in ME/CFS perhaps rose to a new level of significance when a network analysis found larger differences in gut bacteria than metabolites. Lipkin’s ability to better differentiate ME/CFS patients from healthy controls using gut bacteria, metabolomic and clinical data suggests that large studies which tie together multiple systems will be the most helpful.
In short, the latest study from the Lipkin group indicates that the gut does matter in ME/CFS and that in those with gut problems it may matter more than we think.
The Simmaron Research Foundation and Lipkin are employing metabolomics in the study of cerebral spinal fluid for the first time, and Lipkin has launched a new collaborative ME/CFS effort with fellow NIH ME/CFS Research Center leader Derya Unutmaz.
 ​

Rich Haridy   July 10th, 2018

• A new blood metabolic profile for chronic fatigue syndrome may be a step towards a tool to help diagnose the disorder

 

• In the world of medicine there are still many biological mysteries yet to be solved. Chronic fatigue syndrome (CFS) is one of those big unsolved mysteries but a team from Columbia University is bringing us closer to understanding this elusive disorder, finding a specific metabolic fingerprint for the condition that could lead to a new diagnostic tool for doctors.

 

• Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a controversial condition identified by a variety of symptoms, from severe fatigue and muscle pain, to allergies, depression and impaired memory. Other than targeting specific symptoms, there is no effective treatment for CFS, and despite a growing body of strong physiological evidence, some in the medical community still persist in labeling it a psychological condition.
• Last year, a team of researchers from the Center for Infection and Immunity at Columbia University's Mailman School of Public Health revealed sufferers of CFS displayed microbiome profiles that were unique to the disorder. Compared to a healthy control group, the researchers found that CFS patients could be identified by having abnormally high levels of certain bacteria in the gut.
• Following on from that research the team moved to studying the particular blood metabolite profile of CFS patients and analyzed plasma samples from 50 CFS sufferers compared to 50 healthy control subjects. Over 500 different metabolic biomarkers were examined and the researchers homed in on several that were significantly altered in relation to the healthy control group. 
• When a predictive model was generated to diagnose CFS using these blood biomarkers the researchers reached an accuracy rate of over 80 percent. A comprehensive model was then generated combining the metabolic markers and the previously studied microbiome markers. This model could accurately predict the presence of CFS with 84 percent certainty.
• "This is a strong predictive model that suggests we're getting close to the point where we'll have lab tests that will allow us to say with a high level of certainty who has this disorder," says Dorottya Nagy-Szakal, first author on the new study.
• Other than offering a pathway towards a much-needed diagnostic tool for the disorder, it's hoped this research will lead to a better understanding of what causes this devastating condition. One outcome the researchers suggest is that animal models be developed that simulate these same metabolic and microbiome footprints. If those animals subsequently display CFS symptoms and behaviours it means that those specific parameters are playing a causal role in the disorder. 
• "We're getting close to the point where we can develop animal models that will allow us to test various hypotheses, as well as potential therapies, says W. Ian Lipkin, director of the Center for Infection and Immunity. "For instance, some patients might benefit from probiotics to retune their gastrointestinal microflora or drugs that activate certain neurotransmitter systems."​

​The Immune System and Sleep
August 29th, 2017, Cort Johnson Source: http://simmaronresearch.com/2017/08/ sleep-reduced-immunity-vicious-circle-mecfsfibromyalgia/
Ed note: This article was sourced from ANZMES Meeting Place 130 (Summer 2017) and has been abridged.
The immune system is vast and incredibly complex and has its own extensive set of regulatory factors, but it itself is regulated by two other systems, the HPA axis and the sympathetic nervous system. Both are involved in the stress response, and both are affected in ME/CFS and fibromyalgia (FM). One – the HPA axis – is blunted in ME/CFS while the other – the sympathetic nervous system – is over-activated.
Poor sleep, it turns out, activates both systems. The HPA axis is generally thought to be blunted, not activated, in the morning in ME/CFS patients, but the sympathetic nervous system (SNS), on the other hand, is whirring away at night (when it should be relaxing) in both ME/CFS and FM. Having our ‘fight or flight’ system acting up at night is probably not the best recipe for sleep!
Sympathetic nervous system activation, in fact, was the only factor in one Australian study which explained the poor sleep in ME/CFS. The authors of a recent FM/autonomic nervous system study went so far as to suggest that going to sleep with FM was equivalent to undergoing a stress test!
Heart rates, muscle sympathetic nervous activation, and other evidence of an activated sympathetic nervous system response made sleep anything but restful for FM patients. In fact, the authors proposed sleep problems could be at the heart of FM.
Many questions have involved the roles
pathogens play in ME/CFS and FM. That’s intriguing given the almost universally poor sleep found in the disorders, and the role recent studies indicate that sleep plays in priming the immune system’s pump to fight off invaders. During sleep, pathogen-fighting immune cells move to the lymph nodes where they search for evidence of pathogens. If pathogens are present, those immune cells mount a furious (and metabolically expensive) immune response.
Metabolism is a big issue in ME/CFS right now, but guess what? Poor sleep also appears to interfere with producing the metabolic reserves our immune cells need to fight off infections.
We often think of inflammation in negative terms, but the pro-inflammatory cytokines our immune cells produce are necessary to fight off invaders. Reductions of a key pro-inflammatory cytokine called IL-6 during poor sleep hampers our immune system’s ability to destroy pathogens.
Disrupted circadian rhythms (sleep/wake cycles) aren’t doing you any good either. Having insomnia or altered sleep patterns (e.g. very late bedtimes) appears to cause deficits in two hormones (growth hormone (GH) and prolactin) produced during early sleep, which enhance T-cell activity and promote pathogen defence. That suggests that anyone with an altered circadian rhythm might want to do their best to get to bed earlier.
While pro-inflammatory cytokine production at night primes the immune system to fight off pathogens, the daytime is a different story. Chronic sleep deprivation is associated with increased daytime levels of several immune and endothelial factors (IL-6, TNF) and endothelial markers (E-selectin, sICAM-1) that are associated with chronic inflammation.
One study found IL-6 levels actually became flipped in sleep-deprived people; they were low at night (thereby hampering their pathogenfighting ability) and high during the day (adding to inflammation). The situation may be even worse if a sleep-deprived person is fighting off an infection.
One study found skyrocketing levels of damaging pro-inflammatory cytokines when sleep-deprived people were given a toxin (LPS) associated with infections. Those damaging cytokines did not show up in healthy people. That suggested that, besides the infection they
6
probably weren’t doing too well at fighting off, sleep-deprived people now had inflammation to deal with.
As often happens, women seem to be more affected by immune issues, and it’s no different with sleep. Women appear to be more susceptible than men to inflammation that occurs as a result of poor sleep; women show elevations of pro-inflammatory cytokines the day after getting less than 8 hours of sleep; men show elevations of pro-inflammatory cytokines after getting less than 6 hours of sleep.
Many people with ME/CFS/FM get too little sleep but sleeping more than normal, it turns out, is not good either. People sleeping much longer than normal tend to show the same kinds of elevations of pro-inflammatory cytokines as do people who get too little sleep. The C-Reactive Protein, Sleep, ME/CFS and Fibromyalgia Connection
CRP is associated with a variety of inflammatory states resulting from infection, cancer and stress. Increased levels of the inflammatory marker, C-reactive protein (CRP), are increasingly being associated with sleep disturbance. The CRP- sleep connection is intriguing given Jarred Younger’s preliminary finding of increased CRP levels in a subset of ME/CFS patients, and a recent finding of increased CRP in fibromyalgia (FM).
Those findings might not be so surprising. Ten days or so of partial sleep deprivation in healthy controls caused ‘robust’ increases in CRP levels. In fact, the CRP – poor sleep connection is so robust that simply scoring above 5 on the Pittsburgh Sleep Quality Index (PSQI) strongly suggests that your CRP levels are elevated.
The PSQI is a 19-item self-report questionnaire that evaluates 7 clinically derived domains of sleep difficulties, i.e. quality, latency, duration, habitual efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. A huge nurses study (n=10,908) found that nonrestorative sleep – probably the most common sleep issue in ME/CFS/FM – was associated with increased CRP levels, even in these healthy individuals.
The early or innate immune response has long been thought to play a special role in
ME/CFS. This immune response involving NK cells, neutrophils, macrophages and others constitutes the immune system’s first defence against pathogens.
NK cell activity normally hits a low during sleep but then begins to rise. This rise is blunted in sleepdeprived ME/CFS/FM people. Immune cells called monocytes/macrophages, also involved in the early immune response, play a key role in producing chronic inflammation.
ME/CFS isn’t the only condition associated with NK cell problems; depression is as well, and having poor sleep increases your risk of being depressed two-fold. Plus, for reasons not yet understood, if you are having poor sleep and are under considerable stress or are depressed, it’s likely that your NK cells will be considerably less effective when called on to defend the body from invaders.
We know that having a chronic illness increases one’s chances of becoming depressed markedly, but so does poor sleep. In fact Michael Irwin* reports that having insomnia for over a year increases your risk of becoming depressed 14-fold.
That finding is leading some of the more progressive psychologists to focus on preventing or ameliorating sleep problems.
Sleep disturbance also indicates a shift towards a type-2 immune response often seen in ME/CFS and in allergic and autoimmune diseases. Just one poor night’s sleep the night before a person is given a vaccine is enough to markedly reduce the effectiveness of that vaccine. Studies also suggest that poor and fragmented sleep – which is common in ME/CFS/FM – significantly
7
increases one’s susceptibility to the common cold. If you’re catching a lot of colds, or if they linger for some time, poor sleep could be one reason why. What To Do?
So poor sleep has a major effect on our immune system’s effectiveness. No studies, unfortunately, have examined the effect of sleep drugs on immune factors.
However, several studies have assessed the efficacy of stress reduction therapies. Dr Irwin notes reports that practices such as cognitive behavioural therapy, Tai Chi and yoga, which dampen down sympathetic nervous system hyper-arousal, can help improve immune function. Tai Chi has even been found to improve vaccine effectiveness and reduce inflammation.
Other studies point to the ability of mindfulness based meditations and/or yoga to reduce the cytokine levels and pro-inflammatory gene expression caused by poor sleep. One remarkable study showed a 50% reduction in CRP levels in insomnia patients after a year of cognitive behavioural therapy.
Poor sleep therefore doesn’t just make you feel tired and irritable; it hits your immune system as well.
Getting better sleep through improved sleep hygiene, supplements (melatonin), calming botanicals (valerian root, L-theanine, passiflora, melissa, scutellaria etc), stress reduction techniques (meditation, mindfulness), and sleep medications might just give your immune system a boost.
* Michael R. Irwin. Annu Rev Psychol. 2015January 3;66:143-172.doi:10.1146/

​The Autoimmune Virus? Groundbreaking EBV Finding Could Help Explain ME/CFS
Cort Johnson April 30, 2018
Viral Mystery 
“I’ve been a co-author in almost 500 papers. This one is more important than all of the rest put together. It is a capstone to a career in medical research,” Harley
I sensed some awe in Ron Davis’s voice as he pushed for more understanding of Epstein-Barr Virus’s effects in ME/CFS during a talk at the Brain Science conference.  Davis is not to my knowledge finding much evidence of EBV reactivation in the severe ME/CFS patient study – a surprise – but he is very interested in what happened during that initial EBV infection, which appears to have triggered chronic fatigue syndrome (ME/CFS) in so many people.
 
A large, complex and very common virus, EBV is responsible for infectious mononucleosis and appears to contribute to numerous autoimmune disorders.
He’s not alone in his “admiration” for the virus. Simmaron’s Advisor, Dr. Daniel Peterson, whose clinical practice and research stemmed from an outbreak in the Lake Tahoe region of Chronic Fatigue Syndrome, has tracked EBV in patients for decades, noting very high titers to EBV and other herpes viruses in subsets of patients.
It’s not surprising that these two important figures have had their eyes on EBV. EBV, after all, is kind of in a league of its own.  An invader of B and epithelial cells, the 50th anniversary of its discovery was recently celebrated with numerous reviews.  Epstein-Barr was discovered in 1966 by Anthony Epstein and Yvonne Barr. It was the first human virus shown to cause cancer. The sequencing of its large genome in 1995 helped launch the genomic era.
One of the more massive and complicated viruses, it’s one of the very few viruses that’s able to avoid elimination: once EBV infects your B-cells, it’s in your body to stay. It’s able to effectively hide from the immune system and reactivate just enough so that when the infected B-cells die it can move on to other cells.
We’re well equipped to ward off EBV when we’re young – it usually produces only minor symptoms – but as our immune systems alter as we age, that changes.  Encountering EBV as an adolescent or adult (infectious mononucleosis, glandular fever)  – as increasingly happens in our germ phobic age – often means months of convalescence as our immune systems struggle to ward off this powerful virus.
The problems don’t stop there. We know that infectious mononucleosis (IM) is a common trigger of ME/CFS but coming down with IM/glandular fever in adolescence has also been shown to increase one’s risk of coming down with multiple sclerosis 2-4 fold and lupus by fifty percent.  Because of EBV’s ability to remain latent in the body, EBV reactivations are a huge problem for transplant patients with compromised immune systems.
The big question concerning EBV is how a virus which has essentially been latent for decades could contribute to serious diseases like MS and lupus. We now may have the answer. Last week, what will probably turn out to be a seminal paper in pathogen research directly showed for the first time how EBV appears to be able to trigger autoimmune diseases later in life and could conceivably play a role in ME/CFS.
The rather hum drum title of the paper “Transcription factors operate across disease loci with EBNA2 implicated in autoimmunity” in the Nature Genetics Journal hardly hinted at the possibilities the paper presents.
Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity John B. Harley, Xiaoting Chen, Mario Pujato, Daniel Miller, Avery Maddox, Carmy Forney, Albert F. Magnusen, Arthur Lynch, Kashish Chetal, Masashi Yukawa, Artem Barski, Nathan Salomonis, Kenneth M. Kaufman, Leah C. Kottyan & Matthew T. Weirauch. Nature Genetics (2018) doi:10.1038/s41588-018-0102-3
EBV  consists of several proteins of which EBNA-2 is one. EBNA-2 is EBV’s main viral transactivator; i.e. it’s a transcription factor that turns on genes in an infected cell that help EBV to survive. Essentially EBNA-2 allows EBV to hijack a cell’s genetics and put them to its own use.
The study – produced by researchers at Cinncinnati’s Children Hospital – demonstrated that once EBV infects B-cells, it turns on genes that have been identified as risk factors for a boatload of autoimmune diseases.
It turns out that even though the virus is, so to speak, latent; i.e. it’s not replicating – its transcription factor is still active  – altering the expression of our genes. The genes that it affects just happen to be the same genes that increase the risk of developing lupus, multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes.  Apparently decades of genetic assault from EBV’s transcription factor can set the stage or at least contribute to many autoimmune diseases.
Chronic diseases are usually caused by a variety of genetic and environmental factors. Because not everyone with these transcription factors comes down with a chronic illness, other factors must play a role. The authors believe, though, that the gene expression changes induced by the virus in the B cells could account for a large number of people with lupus and MS who fall ill.
“In lupus and MS, for example, the virus could account for a large percentage of those cases. We do not have a sense of the proportion in which the virus could be important in the other EBNA2-associated diseases,” Harley
Chronic Fatigue Syndrome and EBV/Infectious Mononucleosis – A Short History
Researchers have been trying to figure out – mostly unsuccessfully- what the heck happens to plunge people with infectious mononucleosis into ME/CFS for quite some time.
 
In fact, infectious mononucleosis/glandular fever was probably the first disease associated with ME/CFS. Studies in the mid-1990’s, including one from the CDC, suggested ME/CFS was, at least in part,  “chronic infectious mononucleosis” or “chronic mononucleosis syndrome“.  Even Stephen Straus penned a paper on the “The chronic mononucleosis syndrome“.
Straus’s small 1989 study reporting high rates of psychiatric diagnoses in ME/CFS patients prior to their becoming ill set a theme in motion which was disproved by two Peter White  ME/CFS IM publications.  White found IM/glandular fever to be a particularly strong trigger of ME/CFS which he concluded was probably responsible for about 3,000 new cases of ME/CFS a year in the U.K.
A 1992 Swedish study began a trend of examining people with ME/CFS during infectious mononucleosis and afterwards in order to try and determine what happened. That study concluded that whatever happened was not due to EBV reactivation.
In 2010 Taylor found reduced peak oxygen consumption during exercise in adolescents with ME/CFS after IM compared to IM patients who had recovered. Broderick’s finding of altered cytokine networks associated with Th17 in ME/CFS patients following IM suggested immune dysregulation had occurred.
Glaser’s 2005 study suggested that an EBV encoded enzyme produced by a non-replicating form of EBV could be producing symptoms in ME/CFS.  Lerner’s 2012 study suggested that antibodies to two EBV produced proteins were commonly present in ME/CFS – suggesting that a prolonged immune reaction to EBV might be occurring in ME/CFS as well.
In 2014 Loebel/Scheibenbogen suggested that ME/CFS patients may be having difficulty controlling the early stages of EBV reactivation.   Loebel’s 2017 follow up study suggested that ME/CFS patients’ immune system might be over-reacting to an EBV produced protein and that autoimmunitymight be involved.
Leonard Jason’s large IM college student study will hopefully provide clues why some people never recover from it. He’s completing data analysis of a study examining college students who came down with infectious mononucleosis and then ME/CFS. So far Jason has found that at least 4-5% of college students come down with IM while at school.
Treatment Implications
Interestingly, several drugs that are available can block some of the transcription factors EBV has inserted into B-cells.  (I was unable to determine what they are.) The authors also hope the study will help spur more efforts to produce an EBV vaccine.
Next For ME/CFS and EBV
Now that we have evidence that EBV/IM contributes to many autoimmune diseases, it’s hard to think that ME/CFS is not somehow involved. Chronic fatigue syndrome is different in that infectious mononucleosis (and other infections) immediately triggers ME/CFS in many people. What we don’t know is if bouts of IM also trigger ME/CFS 5, 10, 15 or more years later as occurs in these other disorders.
Opportunities for Collaboration Open Up
The big question awaiting ME/CFS now is if the abnormal transcription factors associated with the autoimmune diseases in the recent paper are present. The good news is that a study determining that appears to be within reach of an ME/CFS researcher with the technical ability and funds. In an unusual move, the Cincinnati researchers are making the computer code they used available to other researchers.
“We are going to great lengths to not only make the computer code available, but all of the data and all of the results. We think it’s an interesting approach that could have implications for many diseases, so we’re contacting experts on the various diseases and sharing the results and seeing if they want to collaborate to follow-up on them.” Weinrauch
“This discovery is probably fundamental enough that it will spur many other scientists around the world to reconsider this virus in these disorders” Harley
 
They believe EBV will be implicated in many more diseases, and there is already some evidence that it is.  Using the same analytical techniques, they’ve already identified 94 other diseases including many non-autoimmune diseases in which EBV may play a role.
This is one of the few studies in which the researchers are so jazzed by their results that they’ve dropped all pretenses to modesty. The study results need to be validated, but because EBV is so common and is potentially linked to so many autoimmune (and other diseases), it has the potential to rewrite our understanding of how autoimmune diseases arise. The authors fully recognize the potential importance of their finding. The lead author of the study, John Harley, said:
“I’ve been a co-author in almost 500 papers. This one is more important than all of the rest put together. It is a capstone to a career in medical research,” Harley
One of the senior authors of the study stated:
“This same cast of characters is a villain in multiple immune-related diseases. They’re playing that role through different ways, and doing it at different places in your genome, but it’s the same sinister characters. So if we could develop therapies to stop them from doing this, then it would help multiple diseases.” Matthew Weirauch
 
 

HEALTH
Queensland Scientists Make Chronic Fatigue Syndrome Research Breakthrough
The condition has been linked to abnormal immune system cells.
 21/02/2017 4:07 PM AEDT | Updated 22/02/2017 8:51 AM AEDT
·         Luke CooperAssociate Editor, HuffPost Australia
 
SUPPLIED/NCNED
Researchers at Griffith University have made a Chronic Fatigue Syndrome breakthrough.
Queensland scientists have linked Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME), to a dysfunctional immune system -- proving for the first time that the condition does stem from the body rather than the mind.
Researchers from Griffith University's National Centre for Neuroimmunology and Emerging Diseases (NCNED) told the Huffington Post Australia the breakthrough came through findings that showed abnormalities in immune cell receptors.
NCNED Co-Director, Professor Don Staines, said: "We have discovered and reported for the first time abnormalities of a certain receptor in immune cells of the body and hence it's likely to be in every cell in the body.
"What this is, is a defect in the receptor, which is a change in the gene transcription of these receptors, meaning they no longer function the way they should. What the receptors should do is to be able to transfer calcium from outside the cell to the inside."
According to Staines, the discovery of abnormal calcium immune system cells affects CFS sufferers in three main areas of the body where CFS-related pain usually occurs -- the brain and spinal cord, the pancreas and the stomach.
CFS is a debilitating, flu-like medical condition characterised not only by long-term fatigue but a whole host of other symptoms that limit a person's ability to carry out daily life.
There is no cure or effective treatment for chronic fatigue and a lack of understanding of the disease within the medical community has led to many sufferers being misdiagnosed.
"This is huge because for the first time we have documented the pathology in this illness. Up until now people have not really understood the illness," Staines said.
"This illness is very much under-diagnosed. We think about 1-2% of the population have this illness but it could be higher than that. This is a much more debilitating illness than people have realised."
Queensland Science Minister Leeanne Enoch said the findings are an important breakthrough in understanding CFS and helping those who suffer from it, in a statement released on Tuesday.
"This discovery is great news for all people living with [CFS] and the related [ME], as it confirms what people with these conditions have long known - that it is a 'real' illness - not a psychological issue," she said.
"The Griffith University breakthrough now means we have a target for therapeutic intervention, which is welcome news to the 250,000 Australians believed to be affected by CFS and ME."
Staines told HuffPost Australia researchers have now turned their sights towards creating a test that could identify dysfunctional cells in sufferers and developing future laboratory drug trials that could limit the cost of the condition on families.
"People can go for years of getting different tests and these are very substantial costs to the Australian economy, and also there are big costs for families who have to stay home or be a carer," he said.
"Now there's a lot of scope to develop, design and use different drugs. We can use different samples of drugs in what we call in-vitro, and then we can test them based on predictions that they would be a benefit in this condition."
The costs of CFS and ME diagnosis, treatment and management in Australia is estimated to be around $700 million annually, according to the Queensland Government's statement.
The findings come after NCNED received $1.6 million in research funding from the Queensland Government and a $4 million grant from the Stafford Fox Medical Research Foundation.
Staines believes this breakthrough is now a step forward for sufferers.
"We now know that this is a pronounced dysfunction of a very critical receptor and the critical role that this has, which causes severe problems to cells in the body." he said.
"We don't know that we can necessarily cure the illness but we can help people lead a normal life."
 
​

Metabolic features of chronic fatigue syndromeRobert K. Naviaux, Jane C. Naviaux, Kefeng Li, A. Taylor Bright, William A. Alaynick, Lin Wang, Asha Baxter, Neil Nathan, Wayne Anderson and Eric Gordon
PNAS 2016 September, 113 (37) E5472-E5480. https://doi.org/10.1073/pnas.1607571113

1.     Edited by Ronald W. Davis, Stanford University School of Medicine, Stanford, CA, and approved July 13, 2016 (received for review May 11, 2016)

Significance
Chronic fatigue syndrome is a multisystem disease that causes long-term pain and disability. It is difficult to diagnose because of its protean symptoms and the lack of a diagnostic laboratory test. We report that targeted, broad-spectrum metabolomics of plasma not only revealed a characteristic chemical signature but also revealed an unexpected underlying biology. Metabolomics showed that chronic fatigue syndrome is a highly concerted hypometabolic response to environmental stress that traces to mitochondria and was similar to the classically studied developmental state of dauer. This discovery opens a fresh path for the rational development of new therapeutics and identifies metabolomics as a powerful tool to identify the chemical differences that contribute to health and disease.
Abstract
More than 2 million people in the United States have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We performed targeted, broad-spectrum metabolomics to gain insights into the biology of CFS. We studied a total of 84 subjects using these methods. Forty-five subjects (n = 22 men and 23 women) met diagnostic criteria for ME/CFS by Institute of Medicine, Canadian, and Fukuda criteria. Thirty-nine subjects (n = 18 men and 21 women) were age- and sex-matched normal controls. Males with CFS were 53 (±2.8) y old (mean ± SEM; range, 21–67 y). Females were 52 (±2.5) y old (range, 20–67 y). The Karnofsky performance scores were 62 (±3.2) for males and 54 (±3.3) for females. We targeted 612 metabolites in plasma from 63 biochemical pathways by hydrophilic interaction liquid chromatography, electrospray ionization, and tandem mass spectrometry in a single-injection method. Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism. Area under the receiver operator characteristic curve analysis showed diagnostic accuracies of 94% [95% confidence interval (CI), 84–100%] in males using eight metabolites and 96% (95% CI, 86–100%) in females using 13 metabolites. Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environmental stress known as dauer.

 

Tai Chi Beats Aerobic Exercise for Fibromyalgia
Damian McNamara
March 22, 2018
 
Compared with aerobic exercise, the traditional martial art of tai chi is as good as, or better than, aerobic exercise, for improving the overall severity of fibromyalgia symptoms, new research shows.
Results of a 52-week single-blind trial showed that in addition to fibromyalgia symptom relief, tai chi was associated greater improvements in depression, anxiety, self-efficacy, and the mental component of the Short-Form Health Survey (SF-36) quality-of-life measure.
"Compared with aerobic exercise, the most commonly prescribed non-drug treatment, tai chi appears as effective as or better for managing fibromyalgia," the investigators, led by Chenchen Wang, MD, Tufts University School of Medicine in Boston, Massachusetts, write. "This mind-body approach may be considered a therapeutic option in the multidisciplinary management of fibromyalgia."
The study was published online March 21 in the BMJ.
 
Complex Disorder
A complex disorder, fibromyalgia is characterized by chronic widespread musculoskeletal pain, fatigue, sleep disturbance, and prominent physical and
psychological impairment, the investigators note. Estimates suggest it affects 2% to 4% of the general population aged 18 to 65 years.
 Aerobic exercise is recommended as a standard treatment for fibromyalgia, but many patients find it difficult to exercise because of fluctuations in symptoms. Some trials have suggested that tai chi alleviates pain and improves physical and mental health in patients with fibromyalgia but concluded that larger and more rigorous trials are needed to confirm the results.
In addition, the duration and frequency of tai chi required to achieve optimal benefit are unknown, as is its efficacy compared with that of aerobic exercise in this patient population.
To find out more, the investigators conducted a prospective, randomized, 52-week, single-blind, comparative effectiveness trial.
The study included 226 people with fibromyalgia who were randomly assigned to receive supervised aerobic exercise for 24 weeks, twice weekly (n = 75), or one of four Yang-style supervised tai chi interventions, 12 or 24 weeks once or twice weekly (n = 151).  Participants were followed for 52 weeks. Investigators report adherence was "rigorously" encouraged in person and by telephone.
The study's primary outcome was change in the revised Fibromyalgia Impact Questionnaire (FIQR) scores at 24 weeks compared with baseline. Secondary outcomes included changes of scores in patients' global assessment, anxiety, depression, self-efficacy, coping strategies, physical functional performance, functional limitation, sleep, and health-related quality of life as measured by the Short-Form Health Survey (SF-36).
The mean age of participants was 52 years, 92% were women, the racial/ethnic composition was diverse (61% white), and mean body mass index was 30 kg/m2. The average duration of body pain was 9 years.
Participants had poor health status at enrollment, indicated by an average SF-36 physical score that was about 2 standard deviations below that of the general US population.
Each supervised session lasted 1 hour, and all participants were encouraged to include at least 30 minutes of tai chi or aerobic exercise in their daily routine during the intervention period. The researchers also asked participants to continue their exercise routines for up to the 52-week follow-up.
Research staff blinded to group assignment measured body mass index, treatment expectations, adherence, safety, and physical performance on the 6-minute walk test.
People in the tai chi groups attended 62% of classes vs 40% of participants in the aerobic exercise group.
"Participants assigned to the mind-body therapy maintained higher and more consistent attendance than those assigned to aerobic exercise. Tai chi, which consists of a gentler, low impact meditative sequence of movements with minimal side effects, may be better embraced by patients with fibromyalgia in the long term," the authors write.
FIQR scores improved for participants in all groups compared to baseline at the 12-, 24- and 52-week evaluations. Participants in all five groups demonstrated a similar reduction in use of analgesics, antidepressants, muscle relaxants, and antiepileptic agents over time.
A total of 183 participants (81%) completed the 24-week evaluation. At this time point, improvement in FIQR scores in the combined tai chi groups was significantly greater than in the aerobic exercise group (P = .03).
The duration of tai chi mattered, with people in the 24-week groups reporting greater improvements in FIQR scores compared with those in the 12-week groups. The difference was statically significant (P = .007).
When the investigators looked at the frequency of tai chi, they found no significant difference in effectiveness at 24 weeks between those who participated in tai chi once a week and those participating twice a week, suggesting tai chi once a week may be sufficient to see the reported improvements. 
Secondary outcomes at 24 weeks that also significantly favored the tai chi groups included patient global assessment (P = .005), Hospital Anxiety and Depression Scale anxiety scores (P = .006), self-efficacy (P = .004), and coping strategies (P = .005).
A total of 154 adverse events (AEs) were reported in the study. This included 117 AEs among 115 participants assigned to tai chi and 37 among 75 participants in the aerobic exercise group. Most were minor musculoskeletal events, the authors noted, but 8 AEs in the tai chi group and 4 in the aerobic exercise group were considered related to the interventions.
Rethinking the Standard Treatment"It may be time to rethink what type of exercise is most effective for patients with fibromyalgia," Wang writes in an opinion piece accompanying the study.
"Despite the well-established benefits of aerobic exercise as a core standard treatment for fibromyalgia, patients in our trial had difficulty adhering to the aerobic exercise programme. This may not be surprising — many patients with fibromyalgia find performing and adhering to exercise programs hard. Complaints such as 'the floor is too hard,' 'I cannot stand this,' 'I'm too tired,' or 'I'm in too much pain' were common."
Three instructors taught tai chi in the study. The outcomes were consistent across these instructors, suggesting that the "classic Yang style tai chi can be deployed in other settings in a standardized manner for fibromyalgia," the authors write.
In another accompanying opinion piece, Amy Price, a trauma survivor with chronic pain and a former neurocognitive rehabilitation consultant, notes that her "balance was poor from brain and spinal damage, and I could only see the depressing future of being a patient with chronic pain. I didn't expect tai chi to work, but thought I'd give it a chance."
"Initially, I could only do ten minutes, three times a week, with constant supervision, because of memory and balance problems. Gradually, over about six weeks, my balance improved and this reduced anxiety and increased strength in my broken body," she writes. She would generally recommend tai chi for others with fibromyalgia but recommended patients discuss the option with their physician first, that they stop and speak up if they feel any pain, and that the quality of the instructor matters.
The National Institutes of Health National Center for Complementary and Integrative Health, the National Center for Research Resources, and the National Center for Advancing Translational Sciences funded the study. Wang has disclosed no relevant financial relationships. Price is The BMJ Patient Editor for Research and Evaluation and serves on the BMJ Patient Panel. She has disclosed no relevant financial relationships.
BMJ. Published online March 21, 2018. Abstract
 
 
​

​Miriam E Tucker  March 29, 2018
 
Some people with the condition known as chronic fatigue syndrome (CFS) have low circulating levels of the thyroid hormone triiodothyronine (T3) and normal levels of thyroid-stimulating hormone (TSH), new research shows. The results suggest these patients may be in a hypometabolic state, but one expert thinks the low levels are more likely a consequence, rather than a cause, of CFS.
The findings, based on 98 patients with CFS and 99 age- and sex-matched controls, were published online March 20 in Frontiers in Endocrinology by Begoña Ruiz-Núñez, a PhD student at the University of Groningen, the Netherlands, and colleagues.
Several CFS symptoms resemble those of hypothyroidism but without the marked increase in TSH. This is also the case, the authors point out, in the so-called low T3 syndrome. Low T3 syndrome, also known as euthyroid sick syndrome, is characterized by decreased serum T3 and/or thyroxin (T4) levels, increased reverse T3 (rT3), and no significant increase in TSH.
This low T3 syndrome might be in line with recent metabolomic studies that point to a hypometabolic state (Proc Natl Acad Sci U S A.2016;113:E5472-E5480), and if confirmed, T3 and iodide supplements may be indicated as treatments, say Núñez and colleagues.
But endocrinologist Willard H Dere, MD, professor of internal medicine at the University of Utah, Salt Lake City, isn't convinced.
"The limited data are consistent with what is seen in other inflammatory and chronic disease states. There is no current evidence that thyroxine or tri-iodothyronine replacement in those with low T3 syndrome is beneficial. Furthermore, in hypothyroid patients on thyroxine replacement, the use of tri-iodothyronine, along with L-thyroxine, is thought by some experts to be beneficial, but this view is not a consensus," he told Medscape Medical News.
Differences Seen in Thyroid Hormones, Inflammatory Markers
The patients were recruited from a single clinic in Amsterdam, and all had been diagnosed with CFS based on 1994 criteria. However, those criteria differ in several ways from more recent definitions of what is now termed myalgic encephalomyelitis (ME)/CFS, including those published by the US Institute of Medicine (IOM) in 2015.
Both definitions include disabling fatigue that lasts more than 6 months and does not improve with rest, and cognitive impairment. However, the IOM criteria place post-exertional malaise as central to the diagnosis, whereas it's not required in older definitions. Moreover, the IOM criteria don't require that other potentially fatiguing illnesses be ruled out before making the diagnosis, whereas the older definition does.
In the current study, the 21 men and 77 women with CFS had a mean age of 43 years and body mass index (BMI) of 22 kg/m2. The 23 men and 76 women who were control participants had a mean age of 39 years and BMI of 23 kg/m2, which were not significantly different from the CFS group.
Compared with controls, the CFS group had lower levels of free triiodothyronine (FT3), total T4 (TT4), total T3 (TT3), percent TT3, sum activity of peripheral deiodinases (SPINA-GD), and secretory capacity of the thyroid gland (SPINA-GT), as well as lower ratios of TT3/TT4, FT3/FT4, TT3/FT3, and TT4/FT4, and higher percent rT3 and rT3/TT3 ratio.
There were no differences between groups in other thyroid hormone parameters, notably TSH, FT4, rT3, and percent TT4.
FT3 levels below the reference range were more frequent in the CFS group (16/98) compared with controls (7/99; P = .035), with an odds ratio of 2.56 (95% CI, 1.00 - 6.54).
However, Dere commented, "The subset of patients with the low T3 syndrome is relatively small, and their laboratory values don't vary substantively from that of the control group. Overall, I think the probability of a low T3 syndrome causing ME/CFS is low."
In measures of metabolic inflammation, no significant differences were found in white blood count, high-sensitivity C-reactive protein (hsCRP), tryptophan/kynurenine ratio, or urinary isoprostanes, but the CFS group did have lower kynurenine and tryptophan levels than controls.
Ferritin was higher and HDL-cholesterol was lower in patients with CFS. Zonulin, a parameter of intestinal permeability, was also lower in patients with CFS compared with controls.
Measures of nutritional factors influencing thyroid function and inflammation that differed between the groups included 24-hour urinary iodine output, a proxy of iodine status, which was lower in patients with CFS. Plasma selenium was similar, but intracellular selenium was higher in patients with CFS. Vitamin D [25(OH)D] status of patients with CFS was higher, but 59% of patients with CFS and 83% of controls presented with 25(OH)D levels below the optimal cutoff of 80 nmol/L, Ruiz-Núñez and colleagues report.
In two sensitivity analyses that excluded patients with the highest levels of inflammatory markers, all the prior findings remained significant except FT3, which was no longer significantly lower in the CFS group.
Markers of Inflammation: Cause or Consequence?
Overall in both groups, FT3, TT3, TT4, and rT3 were positively related with hsCRP.
"The limited data from this study correlates other markers of inflammation with the presence of low T3 and high reverse T3, and are consistent with what is seen with other inflammatory and chronic disease states," Dere noted.
He added that the low T3 state "seems to be the result, not the cause, of a systemic or localized inflammatory or chronic disease state. During caloric deprivation, the fall in T3 is believed to be an adaptive response directed to saving energy and protein for enduring this acute stress. Thus one can speculate that with some chronic disorders, the diminished plasma T3 helps to preserve caloric expenditure."
Overall, Dere said he wouldn't change clinical practice based on these findings. "A serum TSH is a good screening test to rule out primary thyroidal disorders."
 
Front Endocrinol. Published March 20, 2018. 
Medscape Medical News © 2018 WebMD, LLC