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

[Hip]

It was very exciting but unfortunately it was just at the time when ME suddenly became CFS when our favourite BPSers met together, with no input from anyone previously working on ME and formulated the Oxford definition. Before it had been properly researched it was all just dropped in favour of psychological treatments

Exactly, the ME/CFS enterovirus research pioneered in Britain was not really proven wrong, but simply psychobabbled out of existence.

The researchers in the US at the time acted as if the expertise and knowledge accumulated in the UK did not exist so research into enteroviruses and the polio connection were never taken up there.

Yes, they ignored the British research in the US. But the reason the significant body of British enterovirus research was discounted over the pond is because US researchers tried to replicate the positive British findings, but got a negative result.

But, whereas the British researchers were testing ME/CFS patient muscle tissues and finding chronic enterovirus infections there, the US researchers tested the blood of ME/CFS patients, and did not find the infection.

But as Dr John Chia is at pains to point out, in ME/CFS the infections are in the tissues, not the blood. Quite a simple thing to understand really, but you'd be surprised how many ME/CFS researchers don't seem to.

Even virus hunter extraordinaire, Prof Lipkin, tested the only blood and CSF, but not the tissues. Which explains why his study could not find enterovirus in ME/CFS patients. He's looking in the wrong place if he wants to find enterovirus.

Unless you chop out a bit of the patient's tissues out and check the tissues, it's hard to get direct evidence of enterovirus infection. So until researchers start testing the tissues for infection, we are never going to make much progress in ME/CFS viral research.

As Jo said, there's an assumption that there was a negative finding somewhere which wasn't published. I think if it exists, that study should be dug up, because otherwise we're left always wondering.

Yes, my explanation above refers to the unpublished negative (but flawed) study in the US. The study was by one Dr Hardy Robart in Denver, USA.

At timecode 6:53 in this video of Dr Chia's enterovirus presentation at the NIH's State of Knowledge Workshop on ME/CFS 2011, he explains the failure of the American researchers to replicate the British studies:

The problem was our [American] studies did not replicate this.

But this problem was addressed and mentioned in this editorial Dr Stephen Strauss, who wrote for this report of the Joint Working Group of the Royal College of Physicians, psychiatrists and General Practitioners on CFS.

I quote: "In Britain pre-eminence of a neuromuscular hypothesis of CFS sustained a pre-occupation with enteroviruses as etiologic factors for two decades, the weight of the evidence stands largely against this now. The report does note one blinded study, in which enterovirus sequence were detected more often in the sera from patients than from healthy controls, still awaits repetition. Our own blinded studies using PCR found no enterovirus RNA in the sera or other specimens from patients or control subjects."

This was unpublished, the work was done by Dr Hardy Robart in Denver. Exactly how blood samples were handled and details of the experimentation are unclear.

So they were unable to find enterovirus in ME/CFS patients in the US because they looked in the wrong place. They looked in the blood rather than the muscles. And thereafter, the British enterovirus research was ignored in the US. Until Dr John Chia came along.

That I believe is why in the US, interest switched to researching herpesviruses as the possible cause of ME/CFS. Which I guess is a good thing, because it seems that both enteroviruses and herpesviruses are linked to ME/CFS, and in the UK, the focus was solely on enterovirus; so in that respect it's fortunate that the US went down the herpesvirus route.

But I'd like to see the US pick up the pieces of the enterovirus research that got blown out decades ago because of Dr Hardy Robart's negative result in 1996.

I thought Chias findings were through biopsy and no one else has done it to confirm or disprove. I thought doing biopsy in CFS wasn't typical which is why dr shepherd struggled to get his muscle biopsy results from years ago replicated. I still don't know if they've been.

There have been 8 different studies that found enterovirus infection in the muscles of ME/CFS patients. So these muscle biopsy studies are well replicated.

But muscle biopsies are painful and leave a scar, and so are not ideal for routine clinical use. Dr John Chia's great innovation is that he realized that in ME/CFS, enterovirus also infects stomach tissues, and that it is much easier to take a stomach tissue biopsy than a muscle biopsy. So this stomach tissue biopsy is what Dr Chia uses in routine clinical use for enterovirus testing.

But nota bene that Dr Chia is not saying that enterovirus infection of the stomach is necessarily the cause of ME/CFS; don't forget that other studies have found chronic enterovirus in the muscles and brain tissues too, so the infection is widespread in the body. Dr Chia just found that the stomach is an accessible tissue, which makes routine biopsies of the stomach for enterovirus testing straightforward.

But to answer Jen's question, I think biopsing nervous tissue, where presumably is must be near or around, seems to be a difficult task.

Yes, biopsies on the brain can only really be performed on deceased patients, but 3 different ME/CFS brain autopsy studies all found good evidence of chronic enterovirus infection in the brain, whereas none of the control brains were infected.

 

[Alvin]

I'm not convinced eneterovirus has anything to do with ME but who knows, it could be the key to the disease mechanism. With the recent funding and hopefully equal future funding we can hope real research will lead us to a mechanism and if it includes enterovirus then it will be found.

 

[Hip]

With the recent funding and hopefully equal future funding we can hope real research will lead us to a mechanism and if it includes enterovirus then it will be found.

Not unless ME/CFS researchers get to grips with the idea that the infection is in the tissues, not really in the blood. If they keep pumping out studies examining the blood, we are never going to advance.

The only reliable blood tests in ME/CFS are antibody tests (by the neutralization method, not ELISA or IFA), which of course do not detect the virus directly, but measure the immune response to it — and an immune response will appear even if the infection is hidden in the tissues.



But if you perform PCR tests on the blood for enterovirus, more often than not you will not detect anything.

At timecode 7:55 of this video, Dr Chia explains that he collaborated with doctors at UCLA who used nested RT-PCR on samples from the sickest ME/CFS patients with high antibody titers to coxsackievirus B, and found enterovirus RNA in 30% of the PBMC and in 10% the plasma samples (with all the 6 control patients negative).

So clearly when you PCR test the blood of ME/CFS patients with enterovirus infections, you only find enterovirus around 30% of the time. The rest of the time the test comes back negative. That's because there is not much virus in the blood. The virus is to be found in the tissues, as a chronic intracellular infection of the non-cytolytic form of enterovirus.

Dr Chia has also repeat-tested ME/CFS patients using blood PCR every 3 to 6 months, and a patient who is positive on a blood PCR test may be negative in the next PCR test 3 to 6 months later; and then positive again in another 3 to 6 months. This demonstrates that with so little of the virus in the blood, PCR testing on blood samples is hit and miss. See timecode 9:47 of the video.

 

[Mij]

There have never been proper studies of enteroviruses in ME not the way that herpes viruses have been looked at.

Which is interesting because enteroviruses can trigger Herpes viruses to re-activate.

 

[Alvin]

Not unless ME/CFS researchers get to grips with the idea that the infection is in the tissues, not really in the blood. If they keep pumping out studies examining the blood, we are never going to advance.

IIRC Dr Davis has said he is happy to hear ideas from patients so i would run it by him.
Its also worth contacting other researchers and suggesting it and the NIH claims it will fund good submissions (not that they are being very generous or forthcoming) so its also worth researchers submitting applications for research funding covering the avenues you suggest.

 

[Hip]

IIRC Dr Davis has said he is happy to hear ideas from patients so i would run it by him.

Coincidently, 3 weeks ago I did actually email Ron Davis at his address MECFSResearchQuestions@gmail.com on this very issue (of needing to test the tissues not the blood for viruses). I did not get a reply, but then I expect he is very busy and gets a lot of emails.

If anyone knows of a new ME/CFS viral study that's about to be conducted, please let me know, as I am happy to write to the researchers and give some pointers about the blood versus tissues issue.

But I think part of the difficulty is that drawing blood is a lot easier and cheaper than performing tissue biopsies.

 

[Webdog]

There are a few of us with childhood onset resembling acute flaccid myelitis, which is thought often to be caused by Enterovirus D68.

 

[JenB]

I'm still very much at the beginning of this. Below, a few random thoughts. I am not going to draw the implicit lines between them because I don't know enough at this point to support or defend...and there is important research that hasn't been done, but given the below, I think really should be:

1) I've now read about 15-20 articles on outbreaks and am probably only 25% of the way through the literature. Pre-Incline Village, everyone was convinced this was an enterovirus. The incubation period, pattern of contagion, symptoms, and various dynamics with polio suggestive of cross-immunity all pointed strongly to that: http://me-pedia.org/wiki/Epidemic_myalgic_encephalomyelitis This was the near-universal view of clinicians at the time, some of whom were mutually ignorant of each other's outbreaks.

I am not saying everyone who meets our present-day description of the disease has a persistent enterovirus infection, simply that that was the most likely causative agent of these outbreaks and that this could play a role in a significant subset of us. If it does, and the infection persists, then we should try to eradicate it and see if people feel better. As compared to everything else we are trying to do, it strikes me finding a way to eradicate a Coxsackie infection is entirely within the realm of our technology and understanding.

2) It is a VERY different thing trying to define endemic, chronic ME, X months or years after the trigger v. seeing a large number of people presenting with the same pattern of acute symptoms. Compared to what we have now, ME in epidemic form was incredibly well-defined. We should be monitoring and studying future outbreaks.

3) Enteroviruses can persist in tissue. This should be completely uncontroversial.

Do they persist in ME patients? Several studies have shown that they do in a subset. Others have not. I don't know enough / have not dug in to find out differences between +/- studies.

These pages are very incomplete but have many citations (see "Discussion" page for more):
http://me-pedia.org/wiki/Enterovirus
http://me-pedia.org/wiki/Coxsackie_B_virus

3) Polio virus causes a massive decrease in cellular respiration in vitro: http://me-pedia.org/wiki/Poliovirus I am sure many infectious agents do. Chronic infection of muscle tissue with an enterovirus could conceivably be connected to low oxygen consumption in muscle tissue/decreased cellular respiration/PEM (specifically, "muscle fatiguability") that we see in ME patients.

4) We need brain donations.

5) Please, please bring as much as possible of this discussion onto MEpedia. These are evergreen but living pages that have the potential to be such an important resource. I have already had a handful of epidemiologists/scientists get in touch with me, intrigued, from this one page alone: http://me-pedia.org/wiki/Epidemic_myalgic_encephalomyelitis I'm reading every article available on every outbreak (including translating some for German and Hebrew) and am going to do same for Enterovirus, Coxsackie B and muscle pages. High-quality literature reviews would make it much easier to articulate what is known (and sometimes forgotten) to a wider audience, lower the barrier to entry/understanding, help get more students and researchers get interested, etc. There is so much out there, but it needs to be packaged, assembled, synthesized, cited.

Someone said we've forgotten about infectious disease. Absolutely. This exploration I am on was started in part by some reading I was doing about polio eradication. We're far enough away from the pre-vaccine era that we've forgotten so much. I routinely hear people say of virus X "well, but everyone has that and they are fine, that's a really common virus." Polio was extremely common and the vast majority of people infected by polio were also fine. Only 0.5% developed permanent paralysis, but that terrified people, and entire countries mobilized to eradicate it from the globe.

There are so many really horrible outcomes caused or possibly caused by non-polio enteroviruses (myocarditis, aseptic meningitis, possibly ME + T1D), but we are nonplused, as though infectious disease is well behind us and everything can now be cured by wellness...or magic (whether tech as magic or psych as magic). Anyway...

 

[Alvin]

Polio was extremely common and the vast majority of people infected by polio were also fine. Only 0.5% developed permanent paralysis, but that terrified people, and entire countries mobilized to eradicate it from the globe.

I had read this but completely didn't relate it to this thread till this line (brain dysfunction extraordinaire)
https://www.vox.com/science-and-health/2018/7/4/17530642/polio-vaccine-outbreak-drc-who

 

[JenB]

IIRC Dr Davis has said he is happy to hear ideas from patients so i would run it by him.
Its also worth contacting other researchers and suggesting it and the NIH claims it will fund good submissions (not that they are being very generous or forthcoming) so its also worth researchers submitting applications for research funding covering the avenues you suggest.

Let's do the work of summarizing the literature well, then we can reach out to anyone (including new researchers).

The # of folks who have responded to my tweets with: "Didn't they disprove that?" makes me realize that even within our community, we don't really know what's in our own literature, let alone what sits just adjacent to it. And there is no way every researcher has read everything, especially articles that are essentially outside their field.

Scientists are not generalists. That is, they tend to use the tools and training they have to study a thing, which is great, but it's frequently a case of looking under the lamp post for your keys because that's where the light is. So if we want people to explore enterovirus infections, we need at least to engage people interested in infectious disease, if not the top people in enteroviral virology. Then they can collaborate with clinicians & researchers already in the field for patients, samples, etc.

Full disclosure: I am 1:640 for Coxackie B4. At onset had stiff neck & back, low grade fevers, stabbing pain in chest, pain in legs, numbness, etc. It sounds exactly like the early phase described in the epidemic literature, so I'm very interested in this line of inquiry.

 

[Alvin]

Let's do the work of summarizing the literature well, then we can reach out to anyone (including new researchers).

I very much agree, i would love to put together everything we know about ME/CFS, in a way like a textbook (i had tried to get a purple book from the UK to see what it had to offer but had no success). Unfortunately my cognitive dysfunction is very bad these days, and i've had to prioritize my own personal stuff (which i am years behind on, just my budget and bills to be paid is too much right now) so i am useless in helping so even though i have some ideas i have not even been able to converse with the right people with them yet

Full disclosure: I am 1:640 for Coxackie B4. At onset had stiff neck & back, low grade fevers, stabbing pain in chest, pain in legs, numbness, etc. It sounds exactly like the early phase described in the epidemic literature, so I'm very interested in this line of inquiry.

I understand, i have not had any immune testing done at all because i came to this diagnosis from a different direction, from sleep and dementia neurologists because of how my symptoms and side effects presented in the early years plus what doctors at the time thought and sent me to (i have had brain spect, MRIs, dementia testing, cognitive testing, sleep studies and so on).
Its something i am planning on talking to my GP about at my next followup and one of the neurologists because university hospitals and big city hospitals around here are years ahead of small city specialists who are sometimes still on 1970s ish level medical advice...

 

[JenB]

I very much agree, i would love to put together everything we know about ME/CFS, in a way like a textbook (i had tried to get a purple book from the UK to see what it had to offer but had no success). Unfortunately my cognitive dysfunction is very bad these days, and i've had to prioritize my own personal stuff (which i am years behind on, just my budget and bills to be paid is too much right now) so i am useless in helping so even though i have some ideas i have not even been able to converse with the right people with them yet

Of course. I'm really sorry to hear that. It's really hard for most patients to write / edit. But for anyone who is able, good thing is it's always there, and benefits from tasks both large and very, very small. Even copying and pasting resources, links, studies you happen to come across to the "discussion" pages can be helpful. Someone else can come along later and incorporate them: http://me-pedia.org/wiki/How_to_contribute#Roles

 

[Alvin]

Of course. I'm really sorry to hear that.

Thanks

It's really hard for most patients to write / edit. But for anyone who is able, good thing is it's always there, and benefits from tasks both large and very, very small. Even copying and pasting resources, links, studies you happen to come across to the "discussion" pages can be helpful. Someone else can come along later and incorporate them: http://me-pedia.org/wiki/How_to_contribute#Roles

I've made a couple small edits before but i will try to add a bit more where i can. If everyone on the forum could spend a few mins a day adding to a page or two we could probably collectively accomplish a lot since between all of us we know a great deal about ME and the research.
I'll give it a whirl starting tomorrow, anyone else interested in just a couple mins a day?

 

[arewenearlythereyet]

I think we need to look at the most likely areas when you have a limited research budget and also conduct studies that have a robust design ...that means having a recognised test method that works on a large cohort and have a hypothesis that makes sense. We need to do the basics around the known science before tackling the time travel end of science.

The enterovirus idea is full of holes and seems to not show any merit when compared to other things that might give us a better return for the research money.

I’m glad eneterovirus stuff has been kicked into the long grass for the moment...it just seems quite ‘clutching st straws’ in terms of likelihood a bit like the microbiome stuff. I would like the basics done before we get to this

 

[Sasha]

Although enteroviruses may be in tissue, wouldn't tissue fragments end up in stool and any enterovirus get picked up in microbiome tests?

 

[chrisb]

This might represent one of the problems:

Tyrell: In my view, it is only fair that the test should be done in parallel in the laboratory that originally described the results. I have had the experience of sending infectious material to reputable laboratories (even to that pinnacle of American science the NIH!) and being told that there was no virus present, because they didn't do the test the way I said. So the correct way is to set the test up blind with other groups and see whether they can replicate the results.

Enteroviruses and postviral fatigue syndrome
Peter O Behan, Wilhelmina MH Behan, John W Gow, Heather Cavanagh and Sewart Gillespie
1993 Chronic Fatigue Syndrome. Wiley, Chichester (Ciba Foundation Symposium173) p146-159 discussion at p156

This sounds similar to the complaint which De Freitas made.

 

[Jonathan Edwards]

Dear @JenB,
Thanks for the thoughts.

I may not be a virologist but I may be something of that endangered species the generalist, being old enough to have had the chance to train in general medicine, immunology, rheumatology, neurology and pathology. Perhaps more relevant, I grew up with viruses like coxsackie B5, EBV and polio being frequent topics of conversation at dinner, since my mother worked at the central virus reference lab in the UK and was for many years the UK co-ordinator for EBV.

My perspective on this is that rather than forgetting promising work on these viruses I think we are in danger of re-inventing the wheel based on work that never got to the level of being significant findings in the first place. I have not yet seen anything that I would expect an academic virologist to feel the need to repeat. It is important to remember just how much of published biomedical science isn't really that good.

The reason why people thought ME/CFS was due to enterovirus in the 1980s is that in the 1980s everyone thought everything was due to coxsackie B. Jo Cambridge did her PhD on coxsackie B in childhood myositis and we talked of nothing else for about five years. Coxsackie seemed to cause every weird and wonderful symptom you could think of and it had the attraction of being elusive and mysterious. By 1990 we had concluded that it had nothing to do with anything much except rather rare post-infective reactions affecting cardiac and skeletal muscle. And as far as I am aware the study of Incline Village did not confirm specific enterovirus involvement. Enterovirus was the fashionable speculation, not the data.

There is also a problem with drawing conclusions from the 'outbreaks of ME', which I think you appreciate. If we model causation mathematically in terms of genetic, environmental and internal stochastic factors there is a paradox for these outbreaks. If they are due to common viruses that continue to be important in the causation of ME/CFS then why is there such a high local concentration of people affected at these times? With a common virus you may get an outbreak at the Royal Free this week and next week it will be Leeds Royal Infirmary and the week after Bart's Hospital and then Aldershot Barracks and so on. Isolated outbreaks are either due to rather restricted microbes where there are local propagation conditions (like hepatitis A in children's homes or Legionella in the Royal Free air conditioning some years later) or, presumably, they are due to microbes that have some unusual mutation and then die out. Otherwise, these outbreaks should occur repeatedly whenever a new group of people without immunity come together.

It was clearly quite wrong to conclude that the Royal Free outbreak was mass hysteria and therefore ME/CFS is mass hysteria. On the other hand post viral fatigue with odd neurological symptoms is commonplace and I strongly suspect that a lot of the cases in these outbreaks never actually have an illness usefully classifiable as ME/CFS. And my understanding is that we do not really have much useful information about these outbreaks. (I am not sure what yo mean by well-defined.) Did we learn anything helpful from Royal Free or Incline Village? We probably learned something useful from Dubbo, where there are well recorded data but my impression is that the classic outbreaks may if anything muddy the waters for understanding ME/CFS today.

If it is uncontroversial that enterovirus persists in tissue presumably it is uncontroversial that this is consistent with being healthy. We only have reason to blame a microbe for an illness if it is found more often in the illness than in healthy people and in most cases the distinction is pretty stark. I don't think we have any reliable evidence for enterovirus being present in ME/CFS more than normal. Subsets are of no interest until you have the basic observation on prevalence.

I don't think there is any real analogy with polio. As you say polio causes a trivial acute infection in many. It also kills motor neurons in some and the pathology and clinical signs are barn door obvious. ME/CFS does not remotely resemble either of these situations. I don't think changes in respiration in cells in culture tells us anything either. Virus infected cells are very sick - they often die. I don't think that tells us anything likely to be relevant to a metabolic shift in muscle in PWME following exertion.

I think there may well be value in examining brains from PWME post mortem, although there are significant practical problems with that. If narcolepsy is due to subtle cellular loss in a specific part of the brain then maybe something similar occurs in ME. I think it extremely unlikely that any virus would be found, however. I agree that current medical research has moved away from viruses but that is not so much because we have forgotten. At least those nearing 70 remember virus research only too well.

I agree that it would be good to have a comprehensive review of what we do know about viruses and ME, but I think it needs to be done by people who know all the pitfalls of virus research. Sadly, as of now I tend to go with the answer that the assembled scientists gave me at the 2014 IiME colloquium when I asked 'how much do we know so far'. The answer was an immediate chorus of 'nothing'. It is hard to motivate people to write a review that will end up saying that we have no information that really takes us anywhere. But maybe that is what we do need. The alternative is enthusiasts producing things like the Cochrane review of exercise therapy and most reviews these days - which are just ways of trying to persuade others to believe what the authors believe because it helps their CV.

 

[chrisb]

I don't think there is any real analogy with polio. As you say polio causes a trivial acute infection in many

Do you have any comment to make on the Iceland ME "epidemic" which appeared to confer upon those in the affected area immunity from polio in a later epidemic of that disease. That appears to have been an important driver for the supposed polio association.

 

[Jonathan Edwards]

Do you have any comment to make on the Iceland ME "epidemic" which appeared to confer upon those in the affected area immunity from polio in a later epidemic of that disease. That appears to have been an important driver for the supposed polio association.

I have not heard of that. Is it recorded somewhere?

 

[chrisb]

I have not heard of that. Is it recorded somewhere?

This is the ME- pedia link about it but I think Ramsay said more in his book, which I no longer have. I shall see what I can find. I think Acheson may also have mentioned it.

http://me-pedia.org/wiki/1948-49_Akureyri_outbreak