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

https://www.bbc.co.uk/iplayer/episode/b0445c5d/the-battle-to-beat-polio

“Stephanie discovers that it is the story of decades of battling between good and bad science, celebrity scientists with giant egos, prepared to take enormous risks to be first with a vaccine, and countless innocent victims.”

The Battle to Beat Polio, BBC4 tv documentary. Very interesting. I’ll have to leave it for others to comment in more detail, severe brain fog here... but I’ll try and put down a few key points:

- First reported polio epidemics only occurred in early 1900s with the arrival of improved sanitation, in one example 9/10ths of cases were from prosperous neighbourhoods, it became regarded as a disease of the clean.

- Britain showed little to no interest in trying to understand the cause of polio, only coping with symptoms.

- It was left to America and research funded by rich philanthropists, and efforts later lead by a President, Franklin D Roosevelt, who himself had the disease.

- Early research on vaccine development set back 30 years by the power and ego of one man.

- Medical fraud in early efforts to produce effective vaccine.

- Fewer ethical restrictions placed on scientists in those days, meant potentially faster breakthroughs (and greater risk for research subjects).
 
Dear @JenB
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.

That is interesting - I did not know that Coxsackie B was the ‘flavour’ of the 80s, being held responsible for all sorts! All I know is it made me horrendously ill in autumn 1982 and at some point in the months that followed it evolved into ME.

Yes, I have never heard Coxsackie mentioned specifically in relation to the Incline outbreak either. I have only heard of that outbreak specifically associated with mould - and that is a whole other thread (controversy)!

FWIW, I still feel - whatever its shortcomings - that Ramsay’s description of ME fits my own experience of the illness very well. It captures how absolutely desperately ill you feel esp in acute stages of onset, it is not just about fatiguability.
 
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

Enterovirus is also a good candidate for explaining the ME/CFS outbreaks, because only certain viruses are capable of causing epidemics, and enterovirus is one of those.

By contrast HHV-6 and CMV never create outbreaks. They are not the sort of viruses that appear in epidemics. I don't think EBV outbreaks generally occur either, though I did see one paper detailing a local EBV mononucleosis outbreak, but that appears rare.

So when we examine these ME/CFS outbreaks, we can rule out these herpesviruses as the causal pathogen (although once you catch that pathogen, if it causes immune weakness, I guess it is possible herpesviruses existing in your body may reactivate).

Of course herpesviruses like EBV, HHV-6 and CMV are likely responsible for many sporadic cases of ME/CFS.



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

My understanding is that decades ago, there used to be some controversy about whether enterovirus could persist in the body after the acute infection is over. Enterovirus is an RNA virus, and RNA viruses are not normally able to form a latency state like DNA viruses are, and latency was thought necessary in order to have a chronic infection.

But we now know that some species of enterovirus, including coxsackievirus B, can transform in the body into an entity called a non-cytolytic infection (aka: non-cytopathic infection), which can create a chronic intracellular infection. The non-cytolytic infection is just the naked RNA genome of enterovirus, which lives inside cells.

We have good evidence that non-cytolytic coxsackievirus B causes chronic CVB myocarditis. And Dr Chia thinks these non-cytolytic enteroviruses may be the major cause of enterovirus-associated ME/CFS. A post on non-cytolytic enterovirus here.



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.

The positive enterovirus studies significantly outnumber the negative ones.

I've just updated my post that lists all the enterovirus ME/CFS studies I know of, and I added ▶︎ to indicate a positive study, and ▶︎ a negative one. So you can now see at a glance that the greens outnumber the reds (19 greens, and only 3 reds).

In spite of that, I know from some very brief email conversation with Ian Lipkin that he does not think the evidence supports a role for enterovirus in ME/CFS, though he did not explain why.



3) Polio virus causes a massive decrease in cellular respiration in vitro: http://me-pedia.org/wiki/Poliovirus

That paper on decreased mitochondrial functioning in poliovirus infected cells looks very interesting, though my first thought is that it probably would not account for ME/CFS, as from glancing at the paper, I think the effect only occurs within virally infected cells, and in ME/CFS patients we can assume the majority of their body's cells will not be infected with enterovirus, just a tiny subset.

So I would think you need to find a factor that may be created or induced by an enterovirus or herpesvirus infection, but a factor that globally affects cells, even those that are not virally infected.

Fluge & Mella found "something in the serum" of ME/CFS patients that appears to alter the energy metabolism of healthy muscle cells from healthy controls exposed to it. That suggests ME/CFS could involve a factor in the blood which globally inhibits cellular energy metabolism.
 
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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?

Erik Johnson proposed a good explanation for why the Lake Tahoe ME/CFS epidemic remained fairly localized: he theorized that the toxic cyanobacteria bloom which was growing all along the beach of the lake at the time of the outbreak was a cofactor that, in combination with the virus, triggered ME/CFS. Biotoxins from the cyanobacteria may have inhibited the immune response, making people more susceptible to the virus.

That would explain why when the virus left the vicinity of Lake Tahoe, it lost most of its ability to cause ME/CFS (though I expect it may have caused a few sporadic cases away from Lake Tahoe).

In this post I generalized Erik's theory, toying with the concept of a dual-factor theory for ME/CFS, where a virus plus immune-suppressing factor in combination leads to ME/CFS.
 
To me, ME looks a lot like Guillain Barre syndrome or some similar post-viral peripheral nerve damage process. At times I wonder why it is so hard to be taken seriously when it is accepted that Guillain Barre type things can happen after infections.

From the NIH Fact Sheet on GBS:
In GBS, deep tendon reflexes in the legs, such as knee jerks, are usually lost.

And yeah, I was rarely examined.
I went maybe 9 months after what seems to have been the triggering gastro-flu illness before having my reflexes checked. Finally a very good infectious diseases doctor (a young associate professor) gave me a proper examination. She failed to find patellar reflexes. She tried very hard, I forget exactly what she did, but I think at one point I was lying on my side, doing stuff with my arms to distract me from influencing the reflex. She sent me off to see a neurologist to get it checked out. Of course by the time I saw the neurologist, months later, the patellar reflexes were back. He was disparaging of the infectious diseases doctor's ability to find reflexes and put me firmly in the 'middle aged woman who is turning usual aches and pains and tiredness into a big deal' box.

I think it would be the exception rather than the rule that we get given good examinations early in the illness.
 
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The feeling that I have about this is that there are quite a few of us here who started out with an illness very like the Ramsay defined ME, but whose illness has morphed, over the years, into something rather different. There are others, equally ill, whose illness followed a different course. The difficulty is that we have little idea of the outcomes for the original epidemic patients at twenty or thirty years and whether a proportion of them were similar at the same stage of the illness.

I think it will be difficult to persuade some of us who had an acute onset with an unidentified virus and who have ben unwell ever since that the virus is not responsible. The difficulty was created in the early 1990s by the BPS brigade saying that everyone was probably exposed to half a dozen viruses a year and that the virus was merely associated with onset rather than being causative. They really do have contempt for our intelligence..

It is frustrating that we have made so little progress in understanding the role of different viruses in ME, though they seem to be wholly implicated. While I know Coxsackie b4 was responsible for my illness I tend to think I had an abnormal immune response rather than it being the virus per se. Of course I cannot know.
 
Erik Johnson proposed a good explanation for why the Lake Tahoe ME/CFS epidemic remained fairly localized: he theorized that the toxic cyanobacteria bloom which was growing all along the beach of the lake at the time of the outbreak was a cofactor that, in combination with the virus, triggered ME/CFS. Biotoxins from the cyanobacteria may have inhibited the immune response, making people more susceptible to the virus.

That would explain why when the virus left the vicinity of Lake Tahoe, it lost most of its ability to cause ME/CFS (though I expect it may have caused a few sporadic cases away from Lake Tahoe).

In this post I generalized Erik's theory, toying with the concept of a dual-factor theory for ME/CFS, where a virus plus immune-suppressing factor in combination leads to ME/CFS.

I can understand hypothesis that these biotoxins can weaken immune system and make more susceptible to virus but what I don’t understand is that why eradicating mould then leads to miraculous recovery from ME since ME is an aftermath of whatever triggers it. It is a post-trigger state if you like. But I don’t want to derail the thread with mould debate!
 
Could a virus be creating some sort of proteins that act as a signal and cause particular responses (say with the metabolic processes) without the virus really doing much in terms of damage to the tissue? Even if this was at quite a low level of infection?

All sorts of things are possible but I cannot think of a plausible story that would link gastric mucosal cells apparently being stuffed full of a protein and yet looking very happy and the symptoms of ME.
 
Enterovirus is also a good candidate for explaining the ME/CFS outbreaks, because only certain viruses are capable of causing epidemics, and enterovirus is one of those.

We have good evidence that non-cytolytic coxsackievirus B causes chronic CVB myocarditis. And Dr Chia thinks these non-cytolytic enteroviruses may be the major cause of enterovirus-associated ME/CFS. A post on non-cytolytic enterovirus here.

I recall ages ago reading in one paper, sorry don’t have reference, that Behan was getting increased referrals from cardiologists for patients with chest pain/symptoms - and I think those patients had had Coxsackie.
 
I am still trying to catch up with responding to various bits.

I mean the epidemiology, symptoms, and course, not findings. I also mean that it is much easier to see that people have been hit by the same thing when you are there within the first few days and weeks of the acute illness, a phase of the illness which today, no clinician or researcher has access to.

Why do you think these outbreaks didn't have an illness classifiable as ME/CFS? The concept (well, of ME) was invented to define these outbreaks.

As you have noted yourself, @JenB, the epidemiology was not actually well defined. To define epidemiology you need to cover a population completely and in most cases nothing like that was done. Moreover, because the clinical features are actually also poorly defined it is impossible to get a real idea of how many people were really ill. It may sound as if the symptoms were defined but looking at the descriptions my view as a doctor would be that they are far too subjectively described to be much use for diagnostic or epidemiological purposes. It is highly likely that some sort of virus was spread around at the time but the clinical description is not specific enough to be able to conclude that the same virus is involved in any of these outbreaks.

The reason why I do not think these outbreaks are classifiable as ME/CFS is that they are accounts of acute illnesses. By definition ME/CFS is a syndrome of long term disability, not an acute illness. I am now beginning to realise after reading Acheson that the name ME was invented to cover two quite different concepts in the minds of different people. Ramsey was clearly interested in what we now call ME - in the long term sequelae. Acheson, on the other hand, was obviously interested in defining a potential unidentfied 'polio-like illness' based on an acute paralytic presentation. The two concepts have got confused.

Me as we now understand it has no real similarity to polio at all. Polio is a one off acute illness during which cell damage occurs in the spinal cord. ME is not a one off illness and there is no evidence of damage to the spinal cord. ME may consist of repeated episodes that feel like viral infections but so does familial Mediterranean fever, which has nothing to do with viruses. We know that ME/CFS can be triggered by a wide range of infections so we are not wanting to make ME/CFS the name of an infection. It is the name of a syndrome that follows various infections or occurs without infection. Acheson may well have thought he was thinking up a name for a new specific viral infection but that has not panned out at all. And it looks to have been based on bad clinical assessment in that it seems that few if any of these people actually had the sort of nerve damage he thought they must have had.
 
It's very hard to get tissue from healthy controls. In the studies that we have been done, in controls you either find the virus at much lower rates or not at all. Again, I'm very early in my reading on this and think it's important to read much more widely than the ME literature.

It is not difficult to get controls for things like gastric biopsy. They are done every day. They may not be entirely healthy but controls from people with other problems are often better than so-called healthy controls. From what I have heard and read there are very few studies and the rates of finding evidence of virus in controls is high enough to indicate that whatever is found is pretty unlikely to be causing a severe illness like ME. Remember, the consensus of the ME research community is that these findings are not worth following up because they really don't look very convincing.
 
But I don't think the standard should be "can be pinned down." Surely nothing has been pinned down, but I think we should look at what is interesting and unanswered.

In that context I was talking of pinning down a neurological lesion through a combination of clinical signs. Neurology can absolutely pin down lesions like that and in fact it does so pretty much all the time. In the days when I was a neurology resident we used to walk the hospital doing referrals examining everyone supposedly having a neurological lesion needing diagnosing. Good neurological assessment is extraordinarily reliable. It is a bit like doing a sudoku. There is only one right answer and if you are thorough you reach it. In all the accounts I have seen from the outbreaks I have not seen any presentation of clinical signs that would allow me to be sure what neurological lesion was present. Ramsey's accounts are much too vague.

So to put it simply we need some reports of these so called outbreaks with some competent neurological documentation.
 
And may you think it's a red herring and that scant evidence should be left to history. I'd want to gather more data so we could either confirm or reject these implicit hypotheses: a) a subset of ME patients had as their trigger an enterovirus b) that enterovirus persists in muscle and brain tissue c) the persistence of the virus causes or contributes to symptoms d) the eradication of that virus improves outcomes.

We definitely don't know enough to reject these hypotheses, but I guess the answer to my initial question of why is no one looking into this further is probably that either a) no one finds this interesting or b) few people care about enteroviruses anymore (in general) and those that do aren't working in this field.

For me it is more likely that the answer is that any reasonably intelligent scientist who has looked at the background to this will have concluded that 1) the story never really stood up in the first place and 2) the positive data available are unconvincing. It is perfectly plausible that some ME is triggered by enteroviruses, although I am not sure there is much evidence. Enterovirus certainly seems to persist in tissues but too often in controls to suggest that matters much. From what I have read evidence linking enterovirus signal in brain or muscle in ME is unconvincing.

I agree that further research is always justified when one has no answer. Trials of anti-vitals might be justified but the evidence at present looks thin and that is presumably why none are being done. What worries me is when physicians prescribe anti-virals based on speculations from the 1950s without doing any trials. My concern in particular is about parents searching for physicians who will prescribe anti-vitals for their children, who are not themselves in a position to make informed decisions. I see as much potential harm coming from treating children as having a 'specific disease called ME due to persistent virus' as from sending them for CBT or exercise. Anti-viral's can cause serious side effects like Stevens Johnson syndrome and their overuse may produce resistance in viruses that really do need dealing with.

The bottom line for me is that ME is not like polio at all and the way to sort it out needs to be thought through from scratch.
 
While I know Coxsackie b4 was responsible for my illness I tend to think I had an abnormal immune response rather than it being the virus per se. Of course I cannot know.

If think an ongoing abnormal immune response is also a good hypothesis to explain ME/CFS. There may be low level viral infection in ME/CFS, but it may be that infection combined with an abnormal immune response that creates ME/CFS.

So that's another possibility.



The reason why I do not think these outbreaks are classifiable as ME/CFS is that they are accounts of acute illnesses. By definition ME/CFS is a syndrome of long term disability, not an acute illness.

ME/CFS is a long term condition, but also usually has an acute illness onset. Melvin Ramsay said:
Although the onset of the disease may be sudden and without apparent cause, as in those whose first intimation of illness is an alarming attack of acute vertigo, there is practically always a history of recent virus infection associated with upper respiratory tract symptoms though occasionally there is gastro-intestinal upset with nausea and vomiting.

So provided that the accounts of the outbreaks describe both the acute and long-term symptoms, and the long-term symptoms look like ME/CFS, surely that counts as an ME/CFS outbreak?



Me as we now understand it has no real similarity to polio at all.

The acute phase of poliomyelitis does not bear much resemblance to ME/CFS, but post-polio syndrome (PPS) does. And as with ME/CFS, in PPS there is also the question about whether it might be caused by a chronic low-level viral infection:

Is the post-polio syndrome due to chronic poliovirus infection?

The above article explains that "poliovirus remnants" are found in most post-polio syndrome patients. Poliovirus remnants means finding poliovirus genomes and low-level virus activity in the PPS patient, but without this virus being able to infect other people (so it's not like regular poliovirus).

Poliovirus remnants sound to me like they might just be a non-cytolytic form of poliovirus, analogous to the non-cytolytic form of coxsackievirus B found in chronic CVB myocarditis, and of course ME/CFS.


But I agree that PPS aside, there is not a great deal of connection between poliomyelitis and ME/CFS.
 
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I have just read through this entire thread. Fascinating. I have Ramsay's book and read with interest the section on epidemic outbreaks.

I am trying to put together for myself some sort of conclusion about what I have learned from this afternoon's reading.

Here's my very simplistic overview:

There have been outbreaks of infections scattered around the world which were probably caused by enteroviruses and were noticed particularly because there were large numbers affected in communities living in close proximity such as nurses or soldiers, but they were also prevalent as sporadic cases in the local community at the same time. (eg Royal Free 1955).

Enteroviruses are more likely to cause such noticeable outbreaks than viruses such as herpes or mononucleosis because of the route of infection (fecal/oral for enteroviruses), and because some enteroviruses occur in epidemics that come and go and don't seem to recur, like the ones in Iceland, Adelaide etc. This may be the result of the fact that enteroviruses have a high mutation rate, so particular strains may arise and then die out particularly in geographically isolated communities - I guess that's a bit like strains of flu that change and mutate rapidly.

Some of those outbreaks which occurred before the days of polio vaccinations may have been similar enough to polio virus to lead to some level of immunity from polio in people affected. This may be of historical interest, but is irrelevant now since polio has been practically eliminated world wide through vaccination.

Some of these outbreaks seem to have triggered enough cases to be noticeable of a long term disabling chronic illness which was probably what we now call ME, defined by PEM and muscle fatiguability among many other symptoms.

Many people with ME can pin the start of their ME to an acute viral infection of many different types including mononucleosis, Coxsackie (an enterovirus), influenza, and other viral infections of unknown specific viral origin, the acute symptoms of which resolved quickly but chronic symptoms started immediately following the acute infection.

The chronic symptoms of ME are usually different from the symptoms of the acute infection that triggered it. Viruses have not been found in blood of most ME sufferers. There is not sufficient evidence of sufficient quality or quantity to show whether any virus remains within some tissues of ME sufferers.

Many ME sufferers are likely to have herpes virus in nerve cells because there is a high prevalence of herpes in the population, and once in the system, herpes is there for life, lurking in nerve cells. Antivirals can reduce the symptoms of a flare of herpes symptoms, but don't get rid of the herpes stored in the nerve cells. Most people with herpes don't have ME. There is no evidence that herpes has a higher prevalence in ME than in the rest of the population. (has this been investigated?)

Flares of herpes simplex are nothing like ME, so reactiviation of herpes virus is not ME. A flare up of varicella zoster (chickenpox) produces shingles - again nothing like ME. So it seems reactivation of these viruses does not lead to ME symptoms. If some other virus, such as an enterovirus, is lurking within cells of some ME sufferers, there is no logical reason to believe it will cause ME symptoms either - it might, but its presence within cells is not evidence that it is causing ME symptoms.

Most people with ME didn't have an enterovirus as the trigger but had some other virus or a bacteria or something else as trigger. Is it plausible that the same symptom pattern resulting from all these different triggers, most of which are not still present in the cells, would result from lurking viruses in tissues in a subset of ME patients?

No large clinical trials have been done to demonstrate whether antivirals are effective in treating ME. Antivirals have serious potential dangers if taken long term, so should not be taken by pwME unless as part of a clinical trial - of if taken, should be done with full understanding of the risks and lack of evidence.

So we are left with the question of what direction research into viruses and ME should go, if any.

Should there be better research to look for viruses in tissues? Is there any point?

Should there be large clinical trials of different antivirals and antiretrovirals for ME? As I understand it, there is no antiviral treatment that eliminates viruses for chronic viral infections like HIV and herpes. That would suggest that it is not possible, with current drugs, to eliminate enterovirus chronically lodged in tissues, so would not be a cure, but a long term treatment, with all the risks that carries.
 
Most people with ME didn't have an enterovirus as the trigger but had some other virus or a bacteria or something else as trigger. Is it plausible that the same symptom pattern resulting from all these different triggers, most of which are not still present in the cells, would result from lurking viruses in tissues in a subset of ME patients?
If you find one pathogen that you discover conventional medical dogma is suspect and likely errant, you realize there can be others. This is where I would place my money, at least for a subset.

If you frame ME/CFS as a collection of symptoms only, then it is possible that different pathogens might cause similar clusters.
 
I'm skeptical of the persistent infection hypothesis, at least for myself and a majority of patients. But I also can't discount,the handful of people who I know personally who are currently experiencing true remission - all of them used either antiherpes or combination antibiotic/probiotic therapies. The latter person had their illness triggered after a bacterial infection and or the subsequent antibiotic therapy.
 
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I have just read through this entire thread. Fascinating.
I was just thinking that both sides have made good arguments but being convincing is not getting us anywhere. We do need to test all likely theories till we figure out the problem. That said we have very limited resources so we need to allocate very strategically but i really do think arguing back and forth won't get us the answer because the evidence is not giving us a clear direction.

What we need is more money, more researchers and more debunking lies. As for money and researchers in a way its a chicken or the egg problem, if the money was there researchers are more likely to move into this field because they can get funded and if there were more researchers then there would be more pressure to allocate more money. I suggest working on both fronts (not that we are not).
As for lies we need to decimate them pronto, and i think we need to pursue more avenues (as if we have that kind of energy).

Now that i've said that i'm going to get back to my regularly scheduled brain dysfunction :dead:
 
i really do think arguing back and forth won't get us the answer because the evidence is not giving us a clear direction.

I would not be so sure. Arguing back and forth was what got me to understanding enough about rheumatoid arthritis to develop an entirely novel treatment. We eventually realised all the evidence we needed was already available! I find arguing very helpful because at the end of it I tend to have a much clearer idea of the topic than when I started. And these illnesses are hugely complicated so getting ideas clear can make a big difference.
 
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