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The Evolution of a Chronic Fatigue Syndrome (ME/CFS) Researcher? CBT Proponent Calls for More Herpesvirus Research

At times Dr. Wyller of Oslo University has seemed more like a Norwegian version of Simon Wessely than anything else. He’s shown that biological issues were present in ME/CFS, but always manages to come back to the psychological or behavioral elements he believes are perpetuating the disease. His new research, however, is taking him in another direction.


Wyller appears to believe that the fatigue in ME/CFS is the result of a false alarm in the same way that pain is in fibromyalgia

Wyller’s research group has highlighted sympathetic nervous activation and inflammation in chronic fatigue syndrome (ME/CFS) adolescents. His “sustained arousal” hypothesis, however, is a mishmash of physiological (infections, genetics) and psychological components (psychosocial challenges, illness perceptions, poor control over symptoms, “inappropriate learning processes”, personality traits, etc.).

That hypothesis posits that a “false-fatigue alarm” state exists in ME/CFS which is largely held in place by classical and/or operant conditioning. That conditioning can be ameliorated by behavioral techniques which tamp down the “alarm” and the sympathetic nervous system activation.

Wyller’s belief that ME/CFS is an infection/stress triggered disease of sympathetic nervous system (SNS) activation, however, took a hit when clonidine – an SNS inhibitor – actually made ME/CFS adolescents worse. Since SNS activation is arguably present and would certainly contribute to the inflammation in ME/CFS, that result probably shocked just about everyone. It suggested, though, that just as in some cases of POTS, the sympathetic nervous system activation found might be a compensatory, not pathological, response to the illness.

Wyller  admits that that CBT’s “effect size” is “modest” and that there is little evidence that it helps sicker patients, but asserts that the evidence-base is “so-solid” that it should be attempted in every patient.

“We believe the evidence base for cognitive behavioural therapy is so solid that all patients with chronic fatigue syndrome/myalgic encephalomyelitis should be offered this treatment.” Wyller et. al.

Wyller 2017: the Evolution of an ME/CFS Researcher?

Wyller may be a CBT/GET apologist, but he’s mostly done physiological research, and whatever his CBT/GET beliefs, it’s difficult to pigeonhole him. His failed Clonidine trial constituted a biological approach to ME/CFS plus his 2016 followup study suggested that a genetic polymorphism in the COMT gene may be responsible for reduced physical activity and impaired sleep and quality of life in some ME/CFS patients.

It’s Wyller’s latest study, however, that takes him into entirely new ground. To his credit, he’s allowing the data to lead him where it will.

Wyller is clearly heavily invested in CBT/GET, while his Norwegian counterparts, Drs. Fluge and Mella, eschew CBT/GET and focus on Rituximab and immune modulation. Wyller mentioned Rituximab in his 2015 overview, but not surprisingly gave it short shrift because of the lack, what else, of follow up studies. But here’s Wyller in 2017 with a study that’s pointing an arrow right at the B-cells in ME/CFS and perhaps even Rituximab.

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival. Chinh Bkrong Nguyen,1,2 Lene Alsøe,3 Jessica M. Lindvall,4 Dag Sulheim,5 Even Fagermoen,6 Anette Winger,7 Mari Kaarbø,8 Hilde Nilsen,3 and Vegard Bruun Wyller. J Transl Med. 2017; 15: 102. Published online 2017 May 11. doi:  10.1186/s12967-017-1201-0

Using his own definition of ME/CFS, Wyller and his research team took a deep look at gene expression using a technology called high throughput sequencing (HTS) which has not been used before in ME/CFS. You never know what exploratory studies like this will turn up.

The 176 genes whose expression was highlighted in the ME/CFS group most prominently featured a down-regulation of genes involved in B-cell differentiation. The activity of five genes involved in B-cell development, proliferation, migration and survival were significantly reduced in Wyller’s ME/CFS adolescents.

Wyller chronic fatigue syndrome

Wyller’s research is leading him into some unexpected areas

This finding, Wyller reported, jived with findings from the Australians of decreased levels of some B-cells and increased levels of others. (Decreases in the gene expression of genes regulating B-cell proliferation could result in either reductions or increases in different types of B-cells).

At the same time the B-cells in his ME/CFS adolescents were taking a hit, the expression of their innate immune system genes were being upregulated. Interestingly, given the idea that a pathogen is whacking the B-cells in ME/CFS, the expression of several genes associated with pathogen defense were increased in ME/CFS. (Wyller, in fact, reported this was the first time that increased expression of genes associated with innate antiviral responses has been seen in ME/CFS.)

Then, remarkably, Wyller – who recently criticized antivirals as he argued that CBT/GET should be the treatment of choice in ME/CFS – asserted that this finding could reflect problems his ME/CFS adolescents were having with clearing latent herpesviruses.

They “might suggest less efficient viral clearance or reactivation of latent viruses such as members of the herpes virus family, in the CFS group” Study Authors.

Then Wyller suggested that “inefficient viral clearance or reactivation” or chronic viral infection-triggered immune dysfunction warrants further study in ME/CFS.

Then he referred to a remarkable 2014 German study which suggested that a deficient B- and T-cell memory response to EBV may be making it difficult for ME/CFS patients to control EBV infections. That’s really no surprise to the ME/CFS community; it’s long been clear that infectious mononucleosis is a common trigger for people with ME/CFS and FM – but it’s for a CBT proponent to make the connection.

Herpes viruses continue to show up ME/CFS research

Herpes viruses continue to show up ME/CFS research

Finally, Wyller’s study suggested that neither inactivity nor mood disorders had any effect on the biological findings presented. (One of his earlier studies discounted the idea that deconditioning was a relevant factor. )

Wyller’s findings are good news, not just because he’s been so committed to his idea that “classical or operant conditioning” perpetuates ME/CFS, or that he’s been such a robust CBT/GET advocate, but because he has shown the ability to get funding.

His next step is to determine how effectively the B cells in ME/CFS are responding to EBV antigens (VCA, EBNA-1) before and after the introduction of stress hormones. If he finds that B-cells are not doing their job with respect to EBV, then both Wyller and the ME/CFS research field are going to have a take a closer look at the role EBV plays in ME/CFS. What a switch that would be!

Wyller isn’t the only one diving back into the herpesviruses.  Two Solve ME/CFS Initiative studies are examining metabolic issues in B-cells and cells infected with HHV-6. Plus studies into B-cell issues in ME/CFS are continuing.

One wonders what further positive results would do to Wyller’s view of the appropriate treatments for ME/CFS. Given the tendency of herpes viruses to reactivate during stressful situations, stress reduction techniques (CBT, meditation, MSBR) might, in fact, be useful, but more importantly, so might antivirals, and immune  modulating drugs like Rituximab or cyclophosphamide.

It’s possible that at some point that researchers on both sides of the ME/CFS divide will someday meet in the middle.


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  • Beth

    June 19, 2017 at 9:46 pm - Reply

    What are your thoughts on an endocrine imbalance or adrenal insufficiencies such as GH or Cortisol levels and the relationship to ME/CFS?

    • Cort Johnson

      June 19, 2017 at 11:26 pm - Reply

      I think cortisol and the HPA axis is potentially a fascinating part of ME/CFS. I wouldn’t be surprised if future research brings up some interesting stuff. Some researchers are looking.

  • Fiona

    June 20, 2017 at 1:39 am - Reply

    “His next step is to determine how effectively the B cells in ME/CFS are responding to EBV antigens (VCA, EBNA-1) before and after the introduction of stress hormones. If he finds that B-cells are not doing their job with respect to EBV, then both Wyller and the ME/CFS research field are going to have a take a closer look at the role EBV plays in ME/CFS.”

    This will be a fascinating study ☺ I guess it’s worth keeping in mind that EBV may not trigger ME/CFS in all cases, but reappear some time later as the body’s wonky immune system can’t control the infection. That seems to be the case with me, anyway.

    I hadn’t heard of this researcher, but if he’s moving away from a BPS model and towards a physical one, more power to him. If only more would do likewise!

    • Cort Johnson

      June 20, 2017 at 12:49 pm - Reply

      Good and interesting point…Its possible that the trigger may have done something to the immune system which allows EBV to reactivate. Didn’t think of that 🙂

  • Audrey Brimson

    June 20, 2017 at 2:39 am - Reply

    Chicken pox at 6 months & twice since, many cold sores over the years, vesicles that appear round my hairline with each low fevered ‘crash’. Yes I can well believe from personal observation that herpes viruses play a part in my ME immune dysfunction. But when energy is unavailable and exhaustion rules all the CBT/ GET cannot change a thing. Why? because when energy IS available all the motivation & stimulous is present too.
    King Canute sat on the beach to try to prevent the tide coming in, hopefully the tide is finally turning against the ME skeptics.
    Histamine & cortisol levels? – Chaotic. Anti-viral cream, anti-histamines do help, and reluctantly, steroids when absolutely desperate. Encouraging article – thanks

    • Cort Johnson

      June 20, 2017 at 1:07 pm - Reply

      I agree that CBT and other stress reduction techniques can’t do a darn thing when exhaustion is present, and their impact, at least for me, is more around the edges when energy levels are higher. It’s good to see Wyller do an exploratory study! Anything can happen in a study like that – and it did – Wyller found evidence of herpesvirus reactivation.

      We should not discount herpesviruses including HHV-6. The 2014 German study found evidence of evidence of impaired immune responses to EBV and several studies have been done since then.

  • Gijs

    June 20, 2017 at 9:10 am - Reply

    The idea -EBV reactivation after stress- is not new, but still very plausible! ME is a lytic abortive chronic infection disease activated by stresshomones!

    • Cort Johnson

      June 20, 2017 at 12:52 pm - Reply

      Not it’s not. We clearly need more research into this fascinating virus. The Marshall group in Ohio is studying it in ME/CFS. Given that, at least in my experience, stress has much more of an effect on my than in the past, I wouldn’t at all be surprised if EBV isn’t involved in some ways.

  • KathyTweety

    June 20, 2017 at 5:21 pm - Reply

    Hello part of this is very interesting to me. I’.m very ill but have not been DX for ME, but have been for CFS/and FMS, and AS. and immune dysfunction/ deficiency. I’ve start taking meds for the ID through infusions. My IG, and IGA and IGM are very low. I’ve had an infection in my body which caused UTI’s for over 6 years, and now I’m also on an antibiotic low dose, for the infection which has been working as long as I stay on it. I do not know what the infection is. I just wish that I would have a Dr. that could test me for ME and what the infections are.
    Question: is the meds that I’m taking for the ID help me with the others?

  • Janice

    June 22, 2017 at 6:51 pm - Reply

    I feel this could be good news….I do hope so. I wonder if my energy is being diverted by my immune system to keep the herpes latent viruses at bay. I have had this for a fair few years and it’s always the same, the more I try and do (and so use more energy) the worst all my symptoms become. When I can remain rested and relaxed (…v v difficult) then I gradually feel better. Unfortunately then I start to hope there’s not much wrong with me and so start to try to do more again to be normal and down I go again. So essentially I feel that my disability is in the amount of energy I can produce above what my immune system is using to keep the latent viruses at bay?

    • Cort Johnson

      June 23, 2017 at 5:40 pm - Reply

      Very possible Janice! It’s also possible that the virus has initiated some process that keeps cells in a kind of hibernation state as Dr. Naviaux has proposed. The Simmaron Research Foundation is funding research that blends the immune system with metabolomics to see if immune factors in this disease are affecting energy production 🙂

      • Janice

        June 24, 2017 at 9:24 am - Reply

        Wouldn’t it be great if the new Crick Building near Euston (where they want to get physicists, chemist and biologist collaborating more) could get fascinated by ME/CFS and look at the energy problems in ME/CFS. ? Does anybody have any contacts there? Maybe James Watson ? I feel I need a tool like a continuous glucose monitor which could show me how much energy I had at that moment to help me make better choices in what I do at that moment. Then hopefully I would stand a better chance of not tipping myself into that toxic /poisoned state when I try and do too much? Surely with nano tech there must be a way of tracking our ATP levels? I know I’m just a naive lay person and there will be somebody out there with more brains than me who will sort it. If anybody knows of any research papers in this area I’d love to have a look. Thank you.

        • Ruth

          January 27, 2018 at 1:37 am - Reply

          Great idea Janice. I will see what i can find and get back to you. Ruth


    June 23, 2017 at 1:18 am - Reply

    Wow!!! This is good, someone who was clearly for “its all in your head, just try CBT/GET” is getting it, or at least trying to and thankfully for all those adolescents out there who have basically been told its laziness, or some ‘imagined’ sickness…it’s about time…good news I think.