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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. Hip

    Hip Senior Member (Voting Rights)

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    Here is something that those skeptical of the enterovirus theory might like: I just came across this 1991 paper, which found that there was no difference in IgM and IgG antibody titers for coxsackievirus B in ME/CFS patients and controls.

    This is in contradiction with Chia's results, which found that when using the micro-neutralization antibody tests provided by ARUP lab, there was a major difference in the titers of patients and controls, as the graphic given in this earlier post illustrates.


    I am not sure how to explain this at the moment, but it could be due to the antibody titer testing methods used. The 1991 paper used ELISA for the IgM tests, which we know from Chia is not very sensitive. But for the IgG, they used the micro-metabolic inhibition test, which appears to be a form of plaque reduction neutralization test (aka: neutralization test), according to this paper. And neutralization tests are the gold standard of sensitivity.
     
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  2. Hip

    Hip Senior Member (Voting Rights)

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    A possible explanation for the above contradiction: the answer may relate to the fact that the ARUP lab tests John Chia uses are capable of detecting and measuring individual titer levels for each of the 6 Coxsackie B virus serotypes, whereas in the 1991 paper, their IgG test just measured the overall coxsackievirus B titers in general; it was not able to distinguish individual serotypes.

    I don't know about the intricacies of antibody testing, but possibly this might mean you get an averaging effect in the 1991 study IgG test, which might blur any individual high titers found for any particular coxsackievirus B serotype.
     
    Last edited: Jul 20, 2018
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  3. Guest 102

    Guest 102 Guest

    This 1991 paper is v interesting to me, Hip, as I was actually diagnosed in *Dunbartonshire* in late 1983, post-Coxsackie by one of the authors - Behan - with new technology (would this have been PCR? - sorry I am basic in my knowledge, see photo attached). I also had abnormalties in both electromyelogram (EMG) and muscle biopsy, which resulted in a diagnosis of 'severe postviral fatigue syndrome/myalgic encephalomyelitis'. This diagnosis of ME was approx 15 months after onset of the viral illness. Of course, I had never heard of ME or Coxsackie before this.

    My Coxsackie diagnosis led to my being referred to Behan in first place. All was delayed as I was studying in France in autumn 1982, having unknowingly picked up Coxsackie before leaving Dunbartonshire (region of my hometown) - I'd had to return home from France to Scotland a couple of months later due to illness. My first GP missed that I had Coxsackie, all tests came back negative (the foolish man concluded I was a homesick 18-year-old), and it was only a locum GP months later, called out to visit me at home by mother, as I was so very ill, who recognised the symptoms, having had Coxsackie himself. He requested viral studies and the Behan referral followed on from evidence from blood tests that I'd had Coxsackie.

    I do recall when I saw Behan, who is brilliant, but could be a wee bit gruff, that when I told him I had Coxsackie he said 'half of Glasgow has Coxsackie!'. I guess by this he meant you could show antibodies but be asymptomatic? My initial symptoms were hideous and there was a very definite acute gastric infection which had evolved into ME by the time I saw Behan.

    behan.png

    Edit: sorry I meant to reply to the actual comment where @Hip mentions the 1991 paper, not sure why that didn't work.
     
  4. Alvin

    Alvin Senior Member (Voting Rights)

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    Mine was elevated (or is it positive?) when i was tested more then 10 years ago. I have the report kicking around somewhere i bet.
     
  5. Hip

    Hip Senior Member (Voting Rights)

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    I would not have thought it was PCR, as I think that only became available in the late 1980s or later, but it seems you had a CVB antibody test, and possibly they may have tested your muscle tissues for the presence of enterovirus VP1 protein.

    Did you actually have the muscle biopsy mentioned in your text upload? That involves making a small incision, and extracting a bit of muscle tissue, which I believe may leave a small scar.
     
  6. Guest 102

    Guest 102 Guest

    Yes, had the biopsy, that text was from my med records, still have the scar, was v painful at time too!
     
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  7. Hip

    Hip Senior Member (Voting Rights)

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    Amazing, at least in those days they did ME/CFS testing thoroughly in the UK. But the pain of the muscle biopsy is the reason why Dr Chia pioneered using stomach biopsy instead, as this is painless. You find enterovirus in the stomach as well as the muscles, so may as well use the stomach for biopsy purposes.
     
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  8. Guest 102

    Guest 102 Guest

    Yes, I am ‘lucky’ that I got ill before the Wessely and co hijacking, unlucky to have been for most of my adult life. My understanding is though the muscle biopsy was to test for abnormality in muscle function not presence of virus in muscle tissue.
     
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  9. Hip

    Hip Senior Member (Voting Rights)

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    That makes sense, because all the British studies that searched for enterovirus in the muscle tissue of ME/CFS patients used PCR to detect this virus, and PCR technology only became available in the late 1980s, and these British muscle biopsy studies using PCR were published in the 1990s.



    In the UK Professor James Mowbray (St Mary's Hospital London) developed a test for enterovirus based on detecting the VP1 protein made by this virus. Mowbray used a monoclonal antibody which targets VP1. I just found this 1988 New Scientist article about Mowbray's VP1 test for enterovirus in ME/CFS.

    Dr John Chia uses a VP1 stain to detect enterovirus in his patients' stomach tissue samples. The VP1 stain appears as a brown patch in the areas of a tissue sample that are infected with enterovirus.

    When Dr Chia stains stomach tissue from a biopsy with a VP1 stain, the slide below is what it looks like. The brown stained patches in the images on the left show the location of enterovirus; images on the right show a reduction in stomach tissue infection after oxymatrine (Equilibrant) antiviral treatment.

    Enterovirus Infection of the Stomach, Indicated by Brown VP1 Stain
    Oxymatrine Slide 8.png
    Source: Dr John Chia's 2010 Invest in ME conference presentation



    Interestingly enough, I just found this 2016 paper which details the development of a better VP1 monoclonal antibody, that overcomes the issue of false positive VP1 staining.
     
    Last edited: Sep 5, 2018
  10. JenB

    JenB Senior Member (Voting Rights)

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    Sorry if I'm missing some things – had to take a break due to health.

    This is a good possible explanation. Some labs are total crap. See for example Labcorp. I have apparently been exposed to every Coxsackie B virus any many types of A (this is 2014):

    Screen Shot 2018-07-19 at 1.40.51 PM.png
    Screen Shot 2018-07-19 at 1.40.36 PM.png

    Quest labs (2013) is similarly confused:

    Screen Shot 2018-07-19 at 1.42.31 PM.png

    ARUP, however, thinks that I ONLY have only been previously exposed to Coxsackie B4, as opposed to nearly every type of Coxsackie virus:

    2016:

    Screen Shot 2018-07-19 at 1.43.34 PM.png

    Screen Shot 2018-07-19 at 1.48.33 PM.png

    2016:

    Screen Shot 2018-07-19 at 1.49.44 PM.png Screen Shot 2018-07-19 at 1.49.37 PM.png

    Now obviously, researchers have access to even better tests, but the testing used varies widely from paper to paper and it MATTERS. A lot.

    I think @Hip already answered this but with current methods, you aren't going to find latent virus in tissues when you are looking in the blood. This may change. When we look in places other than the blood, we DO find direct evidence of viral RNA in a subset of patients.

    It has nothing to do with being the best researcher in the world. They're just not looking at tissue samples.

    None of this addresses the direct evidence. We should also be careful re: ad hominem arguments. Chia is so not in this for himself. He is one of the only doctors who actually, truly takes insurance. And frequently, he doesn't treat the people he diagnoses. He may try Equilibrant as it does seem to help some people (and did help me earlier in my illness), but there are loads of treatments I ask him about and he says "yeah, that didn't work so I don't try it anymore" or "1/3 or 50% got better but everyone relapsed after treatment." He is also down on experimental treatments that may be expensive but not covered by insurance as he doesn't think the evidence it there to justify either the risk or the cost. I find him to stick very closely to his observations. I expect he thinks we need anti-enteroviral drugs to truly deliver benefit to most patients.

    That's great. This is very important.

    Here is another citation Trish: http://me-pedia.org/wiki/Coxsackie_B_virus#Chronic_infection Mechanism seems to be change in ratio of positive to negative sense RNA. I believe there are other studies that find this general phenomenon (say, in mouse models of Coxsackie myocarditis) but I haven't finished pulling in all the citations into the Coxsackie B page. Many are on the discussion page: http://me-pedia.org/wiki/Talk:Coxsackie_B_virus But chronic infection is well studied in animal models and is not normal in the way that we consider chronic herpesvirus infection to be normal.

    This is also interesting and I think a direct affirmation of what Jane Colby has said, which is that early in a Coxsackie infection, rest is extremely important: http://me-pedia.org/wiki/Coxsackie_B_virus#Exercise

    I'm not sure what you mean by all but harmless. They are the most common cause of aseptic meningitis for example (85-90% of cases). Polio was harmless to the vast majority of people who contracted it (usually asymptomatically). The harm was in the tails, but it was on a scale large enough that people felt it was important. Re: myocarditis, I don't think there's good evidence this is a downstream effect. All animal evidence points to a direct effect of inflammation of the heart due to acute (or chronic) infection.

    This is all wonderful and absolutely.
     
    Last edited: Jul 20, 2018
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  11. Hip

    Hip Senior Member (Voting Rights)

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    Also, enterovirus has been linked to fatal heart attacks: a 2007 study found that 40% of people who died suddenly of a heart attack had evidence of an enterovirus infection in their heart tissues (specifically their endocardial or myocardial tissues). So the question is, did enterovirus infection cause these heart attacks, or is it merely an innocent bystander?

    If enterovirus is the cause of 40% of fatal heart attacks, I worked out in this post that enterovirus would be killing 90,000 people each year in the US alone (as in total there are about 225,000 fatal heart attacks per year in the US). And coxsackievirus B in particular would be killing 36,000 people per year.

    That's an extraordinary death toll, yet I see little research interest in further investigating the role of enterovirus in these 90,000 yearly deaths.


    When the rather nasty virus which triggered my ME/CFS (which I think was a virulent strain of CVB4) spread to over 30+ friends and family, it caused some rather distinctive symptoms, so it was easy to observe who had caught the virus. In these infected people, it caused 4 heart attacks, one which was fatal, and two which also involved viral myocarditis, typically within months of catching the virus. So I have had first hand experience of how viruses can trigger myocardial infarction.

    I detail the various physical and mental symptoms my virus caused in these 30+ people in this post.
     
    Last edited: Jul 20, 2018
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  12. Hip

    Hip Senior Member (Voting Rights)

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    Very interesting to see the coxsackievirus B results from Labcorp, Quest and ARUP compared side by side.

    I believe the LabCorp and Quest coxsackievirus B antibody assays use the complement fixation test (CFT) method, which is the most insensitive method.

    I love the way John Chia describes CFT in his presentation at the 2009 Invest in ME London conference (available on DVD):
    So complement fixation is a useless type of antibody testing method for chronic enterovirus infections.

    ELISA and IFA are more sensitive antibody testing methods, but may not be reliable enough for testing chronic enterovirus.

    The gold standard antibody testing method is the plaque reduction neutralization test (PRNT), which is the method ARUP lab use for detecting coxsackievirus B and echovirus antibodies (ARUP use micro-neutralization, which I believe is a form of PRNT).

    There is also one lab in Europe which offers the plaque reduction neutralization test for coxsackievirus B: the Hellenic Pasteur Institute.
     
    Last edited: Jul 20, 2018
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  13. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Yes, that's right, uveitis of a particularly nasty sort goes with one of the form of juvenile arthritis. Now that I remember, this is an example of B cell driven unveitis (antibodies to 'DEK') but it is a pan-uveitis rather than an anterior uveitis.
     
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  14. Aroa

    Aroa Established Member (Voting Rights)

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    Sorry I couldn´t go through all the Reading. I am too sick.

    @JenB since you have access to top ME researchers I guess you may have discussed this issue with them.

    I am curious why they didn´t seem to follow this line of investigation. Do they think this may be related with a small patient subtype and the mainstream is autoimmune related.

    I think ME subtyping should be addressed openly by Researchers
     
    Last edited: Jul 20, 2018
  15. JES

    JES Senior Member (Voting Rights)

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    @JenB My bad, I meant to express that enteroviruses are "far from harmless" instead of "everything but harmless". Language / brain fog barrier.
     
  16. Roy S

    Roy S Senior Member (Voting Rights)

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    Dr. Byron Hyde
    "The cause of M.E. is not a myth.
    In the over 60 documented epidemics of Myalgic Encephalitis, the only causative viruses recovered, were enteroviruses. The majority of M.E. sporadic cases occur from June to December, the same period when enteroviruses do most of their harm in the north temperate zone. When known, in M.E. and paralytic polio epidemics the lowest incubation period tends to be from 3-6 days."

    https://www.healthrising.org/blog/2017/05/23/doctors-hyde-amy-browns-m-e-enterovirus-story

    Sorry if this has already been posted, but it is a fascinating read, IMO.
     
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  17. Perrier

    Perrier Senior Member (Voting Rights)

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    Thanks for the post. Not sure here, but I recall reading that there is at present no medication which addressed enteroviruses. I also heard that 'they' are working on one, but I have not seen any further news.
     
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  18. Roy S

    Roy S Senior Member (Voting Rights)

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  19. Sisyphus

    Sisyphus Senior Member (Voting Rights)

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    I apologize that I have not digested the contents of the thread, but brain fog prohibits this. Thus I have a question:

    Is this theory based on a chronic, continuing in Terrell virus infection, or is it a theory of a hit and run infection and susequent chronic condition?
     
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  20. Roy S

    Roy S Senior Member (Voting Rights)

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    As I understand it, it is based on a chronic infection.
     
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