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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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    There was a reported case of an American who caught polio in Iceland in about 1955. His return home was followed by an outbreak of ME in his local community.

    It might have been a coincidence.

    EDIT Steigman AJ HartRH AdamsonJR Epidemic Neuromyasthenia
    N Engl J Med 1969:281: 797-798
     
    Last edited: Jul 13, 2018
  2. Alvin

    Alvin Senior Member (Voting Rights)

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    That is a good point
     
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  3. JenB

    JenB Senior Member (Voting Rights)

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    Yes, but I do think the outbreaks themselves are of interest as they are a unique opportunity to study the disease and have *very* high rates of long-term disability as compared to, say, the flu. It's possible that that strain(s) came and went and we just don't see enteroviral outbreaks like that anymore. Regardless of which infections cause them, we should be aware of and on the hunt for clusters (which do still happen). We may start to "see" clusters again as an organic outgrowth of greater medical education and scientific awareness of the condition.

    The epidemics were also noticeable in the acute stage. Many did not follow patients for more than a few months. Some did do longer-term follow-ups. Regardless, the condition was recognizable in its earliest stages due to the onset, symptoms, course, spread.

    And it was definitely what we now call ME. Our definition/idea of ME came from these epidemics.

    Right

    Again, in these outbreaks the "chronic" symptoms were observable very quickly. I think it was 4-7 days incubation, 1 week prodromal symptoms, and then as soon as 1-2 weeks after that, the CNS, ANS and muscle involvement. Some noted that second phase came later, but in many cases it was super quick.

    I don't know if it has been. 99% of people with MS have EBV (v. maybe 85% of gen pop), so it's considered a necessary but not sufficient condition. We may come to find that herpesviruses are not the causes but rather the mediators/mechanisms of a wide range of diseases: http://me-pedia.org/wiki/Epstein-Barr_virus#In_human_disease

    My ME symptoms used to flare *horribly* (go to the ER horrible) every time I had an HSV1 outbreak. Antivirals prevent this and have raised my baseline. Don't know why. Really lucky I don't need a clinical trial to have access to them.

    We have no idea what the trigger is for most people so we have no idea whether most people had an enterovirus or not. I imagine it's a significant subset, just like mono is a significant subset but giardia is probably less common. Some of this will have to do with how common the exposures/infections are. It will also related to which infectious agents can cause these changes (I imagine some will be more likely to than others).

    Also, it may be that trigger relates to symptoms. For example, I know people with ME who have cognitive dysfunction and PEM but little or no muscle involvement. I have comparatively little cognitive dysfunction but major muscle PEM. If my trigger was Coxsackie B4, and Coxsackie has a tropism for muscle cells, maybe the trigger does relate to the symptom. It could also relate to site(s) of initial infection (even if no persistence), genetics, a host of other things. But an interesting question to ask. I would be surprised if the nature of the trigger matters nothing and we all arrive at some generic end state. It's a complex interaction of environment, host genes, infectious agent's genes.

    Absolutely. See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528287/ Understanding what viruses are doing on the epigenetic level is important.

    I don't think this makes sense until we understand why would we be using antivirals. I think there is a good chance we'd be applying treatments to a heterogenous population and getting murky or null results for interventions that might work for a more clearly-defined subset. For example, if we had a better way to measure a smoldering herpesvirus, we would do a trial of herpesvirus drugs *only* on those patients. I was having recurrent HSV1 outbreaks. I know people who get shingles monthly. Maybe that would be a good place to start. But we'd need to be clear on what subsets we are talking about.

    Similarly, I think it would be worth trialling an antienteroviral if we had one, but only, say, on a population with high titers to Coxsackie and confirmed viral RNA via biopsy.

    I think we can get specific then yes, absolutely we should trial these drugs.


    I disagree re: limited resources. The world is vast and sits on a sea of trillions of dollars. It's always a mistake to think of what we have as a fixed pie. We can and will attract more interest. And certainly the NIH keeps asking for more applications. As for private donors, some give because they believe in a certain organization. Others because they want to see a certain theory tested. Having more high-quality work being done in new areas will just increase the opportunities for new funders. Some donors are generalists and will support the whole field, but I know of people who could give but sit on the sidelines because they don't see the work that would motivate them to give.

    Who knows? Maybe we can get Gates obsessed/intrigued by enteroviruses given his interest in polio.


    Absolutely! I've learned so much from this discussion, including the homework I still need to go do.
     
    Last edited: Jul 13, 2018
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  4. JenB

    JenB Senior Member (Voting Rights)

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    This puzzles me. We have ample reason to think these outbreaks could have been caused by enteroviruses, namely the first-hand accounts of the physicians who observed them and who almost universally said "I think this is an enterovirus." We also know that the incubation period was 4-8 days, which eliminates a lot of culprits (http://www.virology.ws/wp-content/uploads/2014/10/Screenshot-2014-10-07-13.18.17.png), and that it was spread from person-to-person, so was definitely viral and not, say, vector-born, (solely) water-born or bacterial. The indirect evidence is tantalizing (http://me-pedia.org/wiki/Epidemic_myalgic_encephalomyelitis#Relationship_to_polio) but not enough. Agreed that we can never prove this directly and will never know.

    There's a very big difference in statistics between knowing nothing and knowing something (and no such thing as certainty). I disagree with "there is no reason to think" but agree that there is no way to know.

    We can certainly restrict the range of virus families. @Hip @Jonathan Edwards do you know what other families of viruses can cause the symptoms we saw in the pre-1984 outbreaks, highly contagious, with that length of incubation period? Also, is there any evidence that can help us distinguish between DNA v. RNA viruses. I know for example, RNA viruses have a higher mutation rate which could perhaps explain sudden appearance and disappearance. (Yes, just conjecture.)
     
    Last edited: Jul 13, 2018
  5. Hutan

    Hutan Moderator Staff Member

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    Yes, a nice summary @Trish.

    I'd add that another takeaway from the thread, not necessarily related to the enterovirus hypothesis, is the need for better data from both epidemics that look like ME and the sporadic cases. Given that I am a member of a mini-outbreak (three of us in my family getting ME at the same time after a 'gastrointestinal flu' with symptoms that sound a lot like Ramsay's description), I do think past outbreaks could be relevant. I would like to see efforts to get the people involved in outbreaks to donate their bodies for analysis upon their deaths.

    There needs to be much better investigation and data recording early on in the illness. I know some members have reported brain lesions that showed up on MRIs early on but disappeared on later imaging. I gave the example of my patellar reflexes that seemed to disappear in the first year of illness and then came back.

    If we had specialised centres where people with ME symptoms could be seen early in their illness and properly examined rather than after a year or years of banging their head against the medical system, perhaps interesting things would be found. Maybe we need more prospective studies, following people from the point they first report to the doctor with an infection known to be a trigger for ME, like the Dubbo study but throwing a lot more modern diagnostic tools at the problem to narrow down what hypotheses are worth pursuing.
     
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  6. Nasim Marie Jafry

    Nasim Marie Jafry Senior Member (Voting Rights)

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    Behan and Behan (his late wife) studied some of the original Royal Free patients three decades later and found muscle/mitochondrial abnormalities, they detected ‘early’ switching from aerobic to anaerobic pathway.


    Agree that while the atypical polio reference certainly has historical significance it is irrelevant now. I could not in any context in 2018 refer to my illness as atypical polio. As an aside, I took part in clinical trial for Imunovir in 1984, it made no difference though turned out I was on placebo.
     
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  7. Alvin

    Alvin Senior Member (Voting Rights)

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    I agree, we just need to get more redirected to us
     
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  8. chrisb

    chrisb Senior Member (Voting Rights)

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    I am not sure that anyone is saying that ME is atypical polio. There may however be a case for arguing that a subset of patients have their illness triggered by a virus related to the polio viruses and which has evaded discovery.

    In any event it could be argued that "polio" is atypical polio in that it has been said that for each symptomatic case there were 140 or more asymptomatic cases of people infected by the virus-or, perhaps more correctly, a particular form of a virus within the group of polio viruses. Nature is complex.
     
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  9. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    Re @Trish's nice summary, I'd like to add one thing. While herpesviruses may not, alone, cause or perpetuate ME, I suspect that it's a hole-in-my-bucket scenario. One hole in your metabolic/immune bucket is somewhat easier for your body to plug by itself (or at least the leak of water, or in this case energy, may be relatively slow).

    However, if there are lots of holes--even small perforations--then more water/energy will eventually get out, which is harder for your body to cope with.

    Alternatively, it might be a straw and your immune system or metabolism is the camel's back. One straw too many (whether herpes or something else) and the back breaks.

    What strikes me is that ME is a 'clusterfuck' illness. It's not usually just one thing that goes wrong, but a series of sometimes very little things and sometimes fewer but bigger things. OI or IBS or new sensitivities add veneer upon veneer. Treating one of these layers may mitigate the illness somewhat, but you rarely get lasting benefits unless you address all of them.

    So plugging holes, or removing straws, might help. Maybe. Unless, of course, it's a single underlying problem that causes or exacerbates all these other issues that might not be a problem otherwise. But that still might mean it's important to treat, it just might not be a cure, exactly.
     
  10. Nasim Marie Jafry

    Nasim Marie Jafry Senior Member (Voting Rights)

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    Hey, Chris, I was referring to Jen Brea’s MEDIUM narrative, sorry, I should have made that clear. It was late when I commented last night.



    Jen starts off saying she has ‘atypical poliomyelitis’. While I think it is very useful and educational to be doing a ‘deep dive’ into the history of ME pre-80s, I could not personally say I had atypical polio in 2018. (I understand Jen also had a Coxsackie B trigger.)

    I guess that because young children in areas of Pakistan are still being diagnosed with polio - which is hideous - I’m also hesitant to use polio (atypical) to describe ME currently, as polio has been eradicated in west since all of our respective experiences of ME.

    As far as I know, no one on the forum has an ME diagnosis pre-polio vaccine/eradication. As I have said already, my own ME was triggered by a severe enteroviral infection - after an outbreak of Coxsackie - so I fully get/accept the historical perspective of enterovirus/atypical polio, but since polio was eradicated when I got ill, I could not have atypical polio. I hope that makes sense.

    Speaking of deep dive, I am very interested in Nath Avindra’s ‘deep-diving’ and his hypothesis that ME is ‘virally-triggered, leading to immune-mediated brain dysfunction’. That is not a million miles from Peter Behan’s hypothesis in 1985 of viral infection and abnormal muscle metabolism. I have linked to an older blog of mine, to save me writing it all out again.

    https://velo-gubbed-legs.blogspot.com/2017/05/dr-avindra-naths-research-and-lovely.html
     
    Last edited: Jul 14, 2018
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  11. Trish

    Trish Moderator Staff Member

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    I can't get medium to give me access to that article.
     
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  12. chrisb

    chrisb Senior Member (Voting Rights)

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    Hi @Nasim Marie Jafry Thanks for putting me right on that. For anyone interested in the complexities of the polio epidemics at a personal level this discussion with Shelokov is interesting.
    https://history.nih.gov/archives/downloads/ashelokov.pdf

    From about p48 he discusses the possibility of patients having more than one form of polio and the discovery of ECHO virus and @p84 he describes his contracting the first recorded case of Coxsackie B2. Hope this is not off topic.
     
  13. Nasim Marie Jafry

    Nasim Marie Jafry Senior Member (Voting Rights)

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    Thanks, Chris, I will check out the link.
     
  14. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    One thing to note is that enteroviruses are fairly small and simple viruses, contrasted with herpes viruses like CMV and EBV that are large complex viruses with many genes, some of which are there to confuse the immune system.

    The fact that both can lead to the same illness is strange.
     
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  15. JenB

    JenB Senior Member (Voting Rights)

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    Last edited: Jul 14, 2018
  16. JenB

    JenB Senior Member (Voting Rights)

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    Atypical polio was a misnomer as epidemic ME was not ultimately an atypical presentation of polio. It's the title of a piece of writing, not the name of my disease. I could as easily have called it "I have Iceland Disease." I just think it will be interesting to go back into that time and understand what people thought when they initially observed this and why.

    I don't really have the energy or brain to research and structure a massive piece, so am trying to write tidbits when I can and not worry too much about the order/structure. I do wish the "series" feature on Medium was a little more accessible (it's basically for smart phones) but I hope to repackage it later.
     
  17. Hip

    Hip Senior Member (Voting Rights)

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    Certainly out of the list of pathogens that we know through studies are associated with ME/CFS, it's only enterovirus that fits in the incubation period of 4 to 8 days observed in the outbreaks.

    The incubation period of coxsackievirus B is usually stated to be 3 to 5 days, and the for echovirus its 2 to 14 days. So both would fit.

    The other pathogens linked to ME/CFS have longer incubation periods:

    EBV: 4 - 7 weeks
    CMV: 3 - 12 weeks
    HHV-6: 9 days (but virtually all adults are already infected with HHV-6, it's usually acquired in infancy)
    Parvovirus B19: 4 - 14 days
    Chlamydia pneumoniae: 3 - 4 weeks
    Coxiella burnetii: 2 - 3 weeks typically

    Parvovirus B19 might approximately fit the observed 4 to 8 day incubation period of the outbreaks, but acute parvovirus in adults often causes joint soreness that lasts weeks, and causes a distinctive "slapped cheek" rash in children, so I think any parvovirus outbreak would be recognized as such.

    But of course there is the possibility that some of these ME/CFS outbreaks may have involved some unknown virus, rather than a known virus like CVB and echovirus. Even in the world of enteroviruses, new enteroviruses are often discovered, and Dr John Chia suspects that some cases of ME/CFS might be caused by enteroviruses other than the CVB and echovirus serotypes that we can currently test for using antibody tests.



    I've also wondered whether the high mutation rate of enteroviruses might explain the sudden appearance and disappearance of outbreaks. When you get infected with coxsackievirus B, the mutation rate in your body is high, and the virus starts genetically diverging into multiple sub-species of itself, which are called quasispecies of CVB. So you catch one Coxsackie B virus, but end up being infected with multiple sub-species of that virus.


    I don't know offhand if there is any way to distinguish between RNA and DNA virus infections.
     
    Last edited: Jul 14, 2018
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  18. Hip

    Hip Senior Member (Voting Rights)

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    I've just realized that the response of ME/CFS patients to corticosteroids might be more evidence for a chronic viral infection underlying ME/CFS:

    It's quite common for ME/CFS patients to feel rapidly and dramatically improved on corticosteroids; in fact one severe bedbound ME/CFS patient on the PR forum uses prednisolone once a week, and a few hours after taking this drug, he is fit and well enough to go for a major workout at the gym, without feeling any PEM repercussions! Which is quite remarkable for a normally bedbound patient.

    He's been using prednisolone once a week to facilitate a gym workout for over a year (see the corticosteroids section of this post for more info about this patient's gym exploits). And although his once weekly exercise regimen did not help his ME/CFS, it cured his POTS, he said (exercise is known to be good for POTS, but is normally bad for ME/CFS).

    And there are other stories of corticosteroids providing temporary relief from ME/CFS symptoms. (And incidentally, since corticosteroids suppress the Th1 immune response, suppress T-cell function, but boost the Th2 response, that suggests that ME/CFS symptoms may involve Th1 and/or T-cell responses.)

    But in the long term, when taking corticosteroids for weeks or months, patients usually report their ME/CFS becoming worse. So why would they initially feel a lot better on corticosteroids, but in the longer term become more ill? If ME/CFS was cause purely by an immunological dysfunction which the corticosteroids addressed, then you would expect corticosteroids to keep working even in the long term. But what actually happens is patients on steroids get worse in the long term.

    So one obvious explanation for this long-term worsening is that the Th1 and T-cell immunosuppression of corticosteroids is allowing underlying viral infections to proliferate, and thereby worsen ME/CFS.

    So the pattern of response to corticosteroids does suggest a viral infection playing a causal role.
     
    Last edited: Jul 14, 2018
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  19. Trish

    Trish Moderator Staff Member

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    Some fascinating information to add to the discussion on this thread. I've just been reading the latest SMCI research update and read this about one of the projects they funded:

    The article is here, and our thread about it is here.

    Looks like I might have to eat my words about lack of evidence that herpes could have anything to do with ME. I love it when science proves me wrong!
    Though it's not clear whether he's applied his research to ME yet???
     
  20. Hip

    Hip Senior Member (Voting Rights)

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    I was just reading that article on Dr Bhupesh Prusty's HHV-6 research the other day. This preliminary finding of HHV-6 being able to remotely affect the mitochondria in healthy uninfected cells sounds a promising line of investigation.
     
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