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).

 

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.

 

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.

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.

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.

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.

 

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.

 

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.

 

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!

 

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.

 

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.

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 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.

 

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.

 

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.

 

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.

ME/CFS is a long term condition, but also usually has an acute illness onset. Melvin Ramsay said:

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?

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.

 

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.

 

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

 

A nice summary @Trish. My only caveat is that I don't think we have reason to think any of the outbreaks that have been linked in the historical narrative to ME or CFS were enterovirus. In most cases nobody knows what they were.

 

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.