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Why has 'persistent enteroviral infection' been dropped as a research strand in ME/CFS? (Jen Brea asking)

Discussion in 'General ME/CFS News' started by Sasha, Jul 11, 2018.

  1. chrisb

    chrisb Senior Member (Voting Rights)

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    I was struck by Jen's description of right sided weakness which apparently made her think of atypical polio. This symptom has been referred to by a number of people, including me. I was at one time noting whom but have of course forgotten. Some have referred to left sided weakness. It is a strange symptom.

    Are we entirely certain that Ramsey did not make careful clinical assessments. It seems to me that someone who picked up on the detail of thee pallor which sometimes proceeds relapses was not short of observational skills.
     
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  2. Alvin

    Alvin Senior Member (Voting Rights)

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    This makes me think stroke. Please not be the case though :(
     
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  3. chrisb

    chrisb Senior Member (Voting Rights)

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    No, I don't think it is that, although it may, temporarily, look similar.
     
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  4. Trish

    Trish Moderator Staff Member

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    On the subject of PEM resembling an infection, I would not say that is particularly true for me - I don't get a fever or sweating or sore throat or swollen glands during PEM (or herpes sores since as far as I know I don't have herpes).

    What I do get is accentuation of my ME symptoms that are there all the time to the extent that I can't eat, stand upright, or think concentrate on anything and the pain becomes much worse. With sometimes the addition of a severe headache, vomiting and fainting. In other words, a crash into the almost unbearable end of the symptoms that are always there. Like a temporary shift from the severe category to the very severe category of ME.

    It is possible that those with a persistent virus like herpes will also get a flare up or the herpes in the form of sores and other infectious flare symptoms as part of their PEM, but it could be the cause or the effect of the PEM.

    I have no idea whether the explanation of the sort of PEM I describe could be that through exceeding the physical energy envelope the cells all over the body are put in such a state of energy deficit that the gut, muscles and brain function becomes a whole lot more limited for the duration of the PEM, until the cells can replenish their energy stores sufficiently to return to their normal (low) level of functioning. A bit like the almost complete shutting down in hibernation.

    Or is it, as others suggest, that the extra exertion beyond the envelope triggers a response in the immune system that sets off all these symptoms. I have no idea.

    I think there are some studies taking blood samples during PEM which could reveal a whole lot more about what is going on, including whether the cells are less able to produce energy, whether there are signs of the immune system activating as in flares in autoimmune conditions and whether there is active infection.
     
  5. Alvin

    Alvin Senior Member (Voting Rights)

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    Anyone can have a stroke at any age, i have read of more then a few cases of people in their 20s or 30s having strokes :cry:
    That said i sincerely hope that is not the case and the likelihood is low but not zero.
     
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  6. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Ramsay made detailed assessments and correctly identified a number of features of the syndrome of ME in the longer term time course. But what I have seen of his account of the neuromuscular function is limited to fatiguability of muscle. That does not fit with a viral lesion like polio at all. I very much get the feeling that Acheson over-egged the neurology.

    One sided weakness occurs in some migraine attacks, where, as for ME, it is fluctuating. Nobody is suggesting that migraine is due to a virus. In conditions where repeated attacks of central nervous system damage occur, such as MS, the symptoms are usually different each time, as the process affects new areas. In situations where the same pattern of symptoms recurs it is much more likely that there is some temporary physiological disturbance that switches on and off without any structural change.
     
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  7. chrisb

    chrisb Senior Member (Voting Rights)

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    That is certainly how it felt. The further point arises when the switching appears to follow a particular pattern rather than being entirely random. If switching is random one can believe in an unstable system, but when the switching appears to be regular does not the switching have to be a feature of the system and give clues as to the nature of the problem?
     
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  8. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    It might I guess. The problem might be in demarcating a 'system'. The whole organism and its environment often does not respect our ideas of 'systems'. It just all interacts. But there might certainly be clues to key pathways and locations for those.
     
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  9. duncan

    duncan Senior Member (Voting Rights)

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    The problem is, IgG titres also represent current infection. You have IgM's associated with most acute infections, but, generally speaking, after roughly 30 days, IgM converts to IgG. If the disease is unresolved, you can test positive based on IgG readings, as you should, if the metric is calibrated correctly. But this little tidbit gets lost at the door to most clinicans' offices these days.

    On paper, PCR is the way to go to resolve the dilemma, however, PCR can be notoriously unresponsive, especially when you are dealing with a pathogen that has a tropism for tissue. If the pathogen or its DNA is not in the blood, PCR likely will fail, unless tissue samples are deliberately sought out where there are pathogen reservoirs. This, too, can be a difficult hit-or-miss process without signs like swelling or overt damage.
     
  10. Hip

    Hip Senior Member (Voting Rights)

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    What's more painful are the mistakes such researchers constantly make when looking for enteroviruses. The testing methods they use would not be able to detect enterovirus. So when they get negative results, it does not mean anything, if their methods are "blind" to enterovirus.

    When Prof Ian Lipkin a few years ago used the latest molecular methods available (namely high-throughput sequencing) to search for viruses in the blood and CSF of ME/CFS patients, he reported that he did not find enterovirus.

    But when I emailed him, asking whether his high-throughput sequencing technique on blood and CSF samples would be able to detect the enterovirus infections in the tissues (many ME/CFS studies have shown enterovirus are hidden in the tissues), he told me that his technique would not be able to detect such tissue infections.

    So for me it's painful that researchers are still looking in the blood for these viruses, when all the evidence we have shows enterovirus is not in the blood, but living in the tissues.



    I wish some enterprising researcher would invent some sort of MRI scan or similar which would be able to detect infections hidden in the body tissues and organs, and highlight such infections in bright red on the 3D scan.

    We would then almost certainly find that ME/CFS patients' lit up in bright red, with their tissues riddled with enterovirus, from the guts, to the muscles, to the brain.
     
    Last edited: Jul 17, 2018
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  11. Hip

    Hip Senior Member (Voting Rights)

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    Can you name any area of ME/CFS research which has a better evidence base, and where the basics are more advanced?


    By the way, those who are skeptical of enterovirus etiologies of ME/CFS: do you know what a non-cytolytic (defective) enterovirus infection is? That's the basis of understanding the enterovirus theory of ME/CFS.

    Talking about enterovirus but not knowing what non-cytolytic enterovirus is would like claiming to understand physics, but not knowing what a proton is.
     
    Last edited: Jul 17, 2018
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  12. Trish

    Trish Moderator Staff Member

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    Perhaps it would help us to 'know what non-cytolytic enterovirus is' if you were to point us in the direction of some research papers or other document that explain what it is. I apologise if you have already done so - I'm having trouble keeping up with this thread.
     
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  13. Hip

    Hip Senior Member (Voting Rights)

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    Sure, measuring IgG titers is not the ideal way of detecting enterovirus, as you will find the occasional healthy control with elevated titers, as well as lots of ME/CFS patients with high titers, as the presentation slide below demonstrates (each dot represents either a patient or healthy control):

    Enterovirus antibody titers of ME/CFS patients (black dots on right) versus healthy controls (hollow dots on left)
    Dr Chia Invest in Me 2009 Conference- Antibody Titers.png
    Source: Dr John Chia, Invest in ME London Conference 2009​

    You can clearly see on this slide that once you get to titer levels of 1:320 and higher (the red horizontal line), there are almost no healthy controls with titers of 1:320 or greater. That is why Chia uses titers of 1:320 and higher as the threshold for diagnosing active enterovirus infection in ME/CFS. In fact you can see that just 2 healthy controls out of 150 have titers of 1:320 and higher.

    (I added a red horizontal line on the above slide to indicate the 1:320 titer level).


    Note that such antibody testing is not done in isolation, but in context with the symptoms presented. If you present with ME/CFS symptoms and have high titers to enterovirus, that's when it is suspected that chronic active enterovirus may be the cause of your ME/CFS.
     
    Last edited: Jul 17, 2018
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  14. Hip

    Hip Senior Member (Voting Rights)

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    Very happy to, Trish.

    As you know, viral particles normally come in spherical shells (called capsids), which break into human cells, then once inside, crack open their shells to release their genetic payload, and these viral genes then start replicating in the cell, in order to construct thousands more viral particles. Those thousands of viral particles made in the cell then eventually break out of the cell, and float off to try to infect more cells. This is normal viral replication.

    Some viruses, like the herpesviruses, have a way of entering a cell, and going to sleep, so that they can hide from the immune system inside the cell, undetected for months or years, waiting to return back to life at a later date. That's called latency. Latency is the basis of the chronic presence of a virus in the body. All these viruses like EBV, HHV-6 and cytomegalovirus that are found as a chronic presence in most of the adult population are able to survive long-term in the body because of latency.

    You never find a virus like rhinovirus (cold virus) taking up long-term residence in the body, as rhinovirus is not capable of latency, so it cannot hide away from the immune system inside cells, and thus the immune system will completely wipe out any rhinovirus infection, leaving no trace of the virus in the body once the acute infection is over. It's totally eradicated by the immune system.

    The typical way a virus maintains a chronic presence in the body is by going into latency (hiding from the immune system). So if a virus is incapable of latency, it may not be able to exist in the body on long-term chronic basis, because the immune system will wipe it out.


    Now enteroviruses are not capable of forming latency states, so it is hard to see how you can have a chronic enterovirus infection, ie, a chronic presence of enterovirus in the body.

    Thus it was always a puzzle why in conditions such as chronic coxsackievirus B myocarditis, enterovirus was able to produce a chronic infection of the heart muscle lasting years. If enterovirus cannot form latency in order to hide away from the immune system, then you might expect the adaptive immune response to completely wipe out any enterovirus infection of the heart in a matter of days or weeks. But the research showed that enterovirus RNA could be detected in the heart muscle in chronic coxsackievirus B myocarditis even years after the initial acute infection was over.

    For decades, that paradox had researchers scratching their heads, until finally, about 20 years ago, it was realized that although coxsackievirus B cannot form latency states, at can form something similar, called a non-cytolytic infection.

    A non-cytolytic enterovirus infection is where the naked genetic material of the virus, its RNA, lives inside human cells on a long-term basis, in such a way that the immune system has a hard time trying to kill it. In these non-cytolytic infections, enterovirus no longer lives as the usual spherical viral particle, but rather as strands of naked RNA within cells.

    But unlike latency, where the virus usually has gone to sleep, in non-cytolytic enterovirus infections, these strands of RNA are not sleeping, they are actively replicating, albeit at a low-level of activity (ie, they are not prolifically replicating like in the fierce acute infection, but more like a slow, smoldering infection). But even though the non-cytolytic infection is slow and smoldering, the immune system often cannot clear it.

    So that is the basis of a non-cytolytic enterovirus infection: it's a smoldering intracellular infection comprising naked strands of RNA that replicate inside our cells. And it is found in ME/CFS.
     
    Last edited: Jul 30, 2018
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  15. Trish

    Trish Moderator Staff Member

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    Thanks for the explanation, @Hip. Do you have any links for research that provides evidence of this being present in ME/CFS?
     
  16. Mij

    Mij Senior Member (Voting Rights)

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    That is exactly it.

    I have recurrent herpes virus and this past week has been very severe. I have not had PEM for at least 2 years from pacing.
     
  17. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    Good to know.

    And I've seen studies showing that diabetes and metabolic syndrome can cause cognitive problems in children. So could this be tied to the metabolomics stuff in some cases, and perhaps to nerve issues in others? Those dorsal root ganglion problems some patients have could perhaps cause something?

    That new study showing brainstem problems is interesting. Not that it's done on very many patients, but that it yet again implicates the brainstem. Could a problem there have repercussions? It would certainly impact the ANS, wouldn't it?

    I also read something about heat in MS reducing nerve conductivity, and therefore causing increased neurological symptoms. The brainstem study mentioned conduction specifically in that area. Is that's what happening?
     
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  18. Hip

    Hip Senior Member (Voting Rights)

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    There were lots of studies in the 1990s that found chronic enterovirus infection in the muscle tissues of ME/CFS patients, using PCR on the muscle biopsies to detect the enterovirus RNA. Those studies are listed in this post. For example, this 1993 study of 158 ME/CFS patients found enteroviral RNA in 26% of the patients' muscle biopsy samples, compared to only 1% in healthy controls.

    At the time of those ME/CFS studies the 1990s, non-cytolytic enterovirus had not been discovered, so although they found the chronic presence of enterovirus RNA in the muscle, they did not quite understand what they were dealing with.

    Historically the first evidence that these enterovirus infections found in ME/CFS patients' muscles were somewhat unusual came from a 1990 study by Cunningham et al, who found something rather odd about these ME/CFS patient muscle infections: whereas in regular enterovirus infections, you find 100 times more positive strand viral RNA than negative strand viral RNA in the cells, by contrast in ME/CFS patients' muscle cells that were infected with enterovirus, they found equal amounts of positive and negative, which was very strange.

    Later it would be understood that equal amounts of positive and negative RNA is characteristic signature of non-cytolytic enterovirus, but at the time Cunningham et al did not know what to make of their findings. But we now know realize that Cunningham et al were the first to detect the characteristic signature of non-cytolytic enterovirus in ME/CFS.

    So Cunningham et al showed that these enterovirus infections that numerous studies found in ME/CFS patients' muscles were in fact non-cytolytic enterovirus, although they did not know it at the time.



    That was the 1990s. Then in 2008 John Chia published a paper showing that these same non-cytolytic enterovirus infections could be found in the stomach tissues of ME/CFS patients as well. By the time of Chia's paper, non-cytolytic enterovirus had been discovered and understood, so Chia knew what he was dealing with when he found enterovirus infection in the stomach of ME/CFS patients.

    Note that these non-cytolytic enterovirus infections are now known to be the cause of chronic coxsackievirus B myocarditis, so they are not unique to ME/CFS.


    Oh and by the way, in chronic coxsackievirus B myocarditis it has been shown that this enterovirus infection triggers the production of an autoantibody that targets and disables the mitochondria in the heart muscle...
     
    Last edited: Jul 17, 2018
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  19. arewenearlythereyet

    arewenearlythereyet Senior Member (Voting Rights)

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    I can think of plenty of areas I would like to see more work develop ...the specifics around mitochondrial dysfunction for one and a lot of the metabolomics work. However I’ve also already said many times where I think the priorities should lie? There are many more interesting avenues that show promise, but as I said earlier this isn’t about comparing evidence bases ...we don’t have very much anywhere. So it falls down to likelihood and hard solid scientific graft to get the basics sorted out to act as a springboard for further research.

    But this thread is about discussing the enterovirus theory and as I have said I disagree with the statement that the work shows promise and I certainly don’t agree with you in that it has a good evidence base. it’s a cluster of mismatched low level studies that speculate a lot and have very little tangible proof of anything really that relates to ME symptoms or a pattern of illness that makes sense. Then when you add in that there is little or no evidence of infection it just looks very shaky as a theory.

    As far as the physics analogy.... aren't protons and neutrons a bit old hat? Isn’t it all about the quark? Could be wrong ....I’m no Sheldon Cooper.

    More importantly I would like to just draw a more apt comparison and that is conflating presence of a microorganism to infection, especially when a reliable frame of reference for healthy controls is not used or absent.

    I have read many papers that equate presence of a microorganism without signs of infection as proof of an effect ...this isn’t so and I often wonder whether these authors just really should have a closer look at their microbiology for basics text books.
     
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  20. duncan

    duncan Senior Member (Voting Rights)

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    Sure, but what if these are downstream effects? Yes, they are still important, perhaps critically so, but shouldn't the goal be to resolve what is causing the downstream effect?

    What kinds of signs? Many clinicians and researchers conflate acute signs with chronic; that may be dangerously close to one assumption too many. Our health system is not built for chronicity, and our health professionals not really trained to identify it.
     

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