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

[Sasha]

@JenB is tweeting about a review she's doing of the 'atypical poliomyelitis' approach to ME/CFS she's doing for MEpedia and asked:

https://twitter.com/jenbrea/status/1016917192426655745

IIRC it was to do with people's concerns about the validity of the testing but I'm not sure and don't know the details. In the other place, people often raised the idea that the idea had been unfairly overlooked.

Does anyone know the ins and outs of this?

 

[ScottTriGuy]

From what I recall in a chat with Dr Byron Hyde (who contends that "ME is analog to polio", and the difference is the location of the enteroviral infection on the spinal cord), said that funding for enteroviral research dried up once the polio vaccine was widely used. Problem solved, right?

Iirc, he also said that Canada stopped testing for enteroviruses in the '80s.

So no enteroviral research funding = no enteroviral research.

No enteroviral testing = no enteroviral diagnosis.

No diagnosis = no disease.

No disease = conversion disorder.

 

[Sasha]

I don't think Jen follows the forum here very closely - I wonder if someone could tweet her a link to the thread?

 

[Jonathan Edwards]

@JenB is tweeting about a review she's doing of the 'atypical poliomyelitis' approach to ME/CFS she's doing for MEpedia and asked:

Does anyone know the ins and outs of this?

I don't know all the details but I assume it has been dropped because several labs have looked and not found anything interesting. Most of the claims of a link come from Dr Chia and I have not yet found any formal study from him of the sort that an infectious disease physician would take seriously. He gave a very long talk at IiME one year and at the end I did not feel there was ay substantive evidence. The problem with small biopsy studies is that there are significant interpretation issues.

If Jen Brea wants accurate information she should contact people like Mady Hornig, Ron Davis and Eliana Lacerda. If I am not mistaken all three groups have looked for viruses of this sort and found nothing of note. The problem with negative studies is they often do not get published. However, my memory is that Hornig and Lipkin published their lack of finding of evidence for viruses in ME/CFS.

 

[ScottTriGuy]

Last I heard, Ron Davis had yet to do RNA testing for enterovirus. Hopefully his team will get that done soon.

Irrc, the other site to test for enterovirus is a gut sample. Or at post-mortem.

Here, Dr Hyde states:

"...vascular injury in the brain can be demonstrated in the live patient with HMPAO SPECT Segami Oasis brain scan software..."

and

"By definition employing SEGAMI Oasis software: all M.E. patients have a perfusion damaged anterior temporal lobe and damaged cingulate gyrus."

 

[adambeyoncelowe]

Last I heard, Ron Davis had yet to do RNA testing for enterovirus. Hopefully his team will get that done soon.

Irrc, the other site to test for enterovirus is a gut sample. Or at post-mortem.

Here, Dr Hyde states:

"...vascular injury in the brain can be demonstrated in the live patient with HMPAO SPECT Segami Oasis brain scan software..."

and

"By definition employing SEGAMI Oasis software: all M.E. patients have a perfusion damaged anterior temporal lobe and damaged cingulate gyrus."

The problem with Hyde is that he doesn't do peer-reviewed studies. He needs to do the damn studies, and then his so-called 'One True Way' to diagnose the 'Proper ME' can be put to the test. The cynic in me thinks that if he's the only person who can do these tests properly, then he's going to stay in business forever.

Likewise, he did one tiny, non-peer-reviewed study of inosine pranobex which is useless because nobody will pay attention to it. He needs to play ball or his work will continue to be ignored.

 

[Cinders66]

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.

 

[Mithriel]

The VP1 test which detects actual viral particles found evidence in the brain of enteroviruses. Patients were getting tested and being found positive. 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

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. Instead the emphasis was on herpes infections (They also dropped the connection with exercise for fatigue as the main symptom) It was very bewildering - and frustrating - at the time.

I don't think Ron Davis looked at enteroviruses, seem to remember reading that they are harder to find as they are RNA viruses.

Another problem was that microbiology was downgraded by the 80s. HIV gave it a boost, but the older idea that most things that go wrong in the body are due to infections became lost (to the extent that a lot of people feel it is someone's fault if an infection happens whereas it is a continual war to stop infections) The experts in enteroviral infections died off and took their knowledge with them. Medical students no longer had a proper grounding in viruses.

I met some of the researchers who said that enteroviruses were not involved in ME and I was not impressed. They did not seem to know that polio infected lots of people but it was a complication of the disease that caused what we think of as polio so the fact that most people had had coxsackie B infections did not mean anything.

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

 

[adambeyoncelowe]

The VP1 test which detects actual viral particles found evidence in the brain of enteroviruses. Patients were getting tested and being found positive. 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

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. Instead the emphasis was on herpes infections (They also dropped the connection with exercise for fatigue as the main symptom) It was very bewildering - and frustrating - at the time.

I don't think Ron Davis looked at enteroviruses, seem to remember reading that they are harder to find as they are RNA viruses.

Another problem was that microbiology was downgraded by the 80s. HIV gave it a boost, but the older idea that most things that go wrong in the body are due to infections became lost (to the extent that a lot of people feel it is someone's fault if an infection happens whereas it is a continual war to stop infections) The experts in enteroviral infections died off and took their knowledge with them. Medical students no longer had a proper grounding in viruses.

I met some of the researchers who said that enteroviruses were not involved in ME and I was not impressed. They did not seem to know that polio infected lots of people but it was a complication of the disease that caused what we think of as polio so the fact that most people had had coxsackie B infections did not mean anything.

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

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.

ETA: Though there are flaws in the 'positive' studies too, so it may be as much an issue with a lack of reproducibility as anything else.

 

[duncan]

Not sure Lipkin looked at tissue. As I recall he looked at plasma and CSF, and he drew a blank for enteroviruses and EBV and HV6 and Borrelia - which is somewhat counterintuitive.

One needs to look at tissue for some of these infections, if you go by experts in those respective pathogens.

 

[Jonathan Edwards]

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.

There are certainly some negative studies on pubmed. I think the problem may be that nobody really knows what would be a meaningful test for a persistent enterovirus infection. If it finding virus in tissue then the tissue ought to show some sign of being diseased. My memory of the staining of gastric biopsies is that the tissue looked entirely normal. Why would viral RNA in healthy looking stomach tissue have anything to do with PEM or light sensitivity?

 

[Perrier]

There are certainly some negative studies on pubmed. I think the problem may be that nobody really knows what would be a meaningful test for a persistent enterovirus infection. If it finding virus in tissue then the tissue ought to show some sign of being diseased. My memory of the staining of gastric biopsies is that the tissue looked entirely normal. Why would viral RNA in healthy looking stomach tissue have anything to do with PEM or light sensitivity?

Dear Dr Edwards,
So what would it mean if in a stomach biopsy test for enterovirus came out positive. And the patient had constant GI and digestive distress, in addition to the regular ME symptoms, but the tissue did not look abnormal. We had sent a stomach biopsy slide to Dr Chia and he said it was high positive.

 

[duncan]

If it finding virus in tissue then the tissue ought to show some sign of being diseased.

Why? This would be an infection that is built to survive long-term, not kill. Why then would the infected organ necessarily appear diseased by typical or conventional standards? Such standards don't seem to apply to most other normal overt metrics, e.g. fever, for pwME.

 

[Jonathan Edwards]

Dear Dr Edwards,
So what would it mean if in a stomach biopsy test for enterovirus came out positive. And the patient had constant GI and digestive distress, in addition to the regular ME symptoms, but the tissue did not look abnormal. We had sent a stomach biopsy slide to Dr Chia and he said it was high positive.

I don't know what that means. I would want to know what a virologist with no commitment to a research theory in ME, and expertise in immunochemistry thought. My suspicion is that it does not mean anything relevant to the symptoms.

 

[Jonathan Edwards]

Why? This would be an infection that is built to survive long-term, not kill. Why then would the infected organ necessarily appear diseased by typical or conventional standards? Such standards don't seem to apply to most other normal overt metrics, e.g. fever, for pwME.

If a virus is not interfering with cell function then it is hard to see why it should cause any symptoms.

As far as I am aware the same standards apply to trying to understand ME as any other condition. The absence of fever presumably means that whatever produces ME symptoms does not stimulate fever pathways. There is no particular reason why it should. Lots of chronic diseases occur without fever.

 

[duncan]

If a virus is not interfering with cell function then it is hard to see why it should cause any symptoms.

Yes, no easy answers with ME/CFS, so the "why" component is pretty much uncharted territory. But a short answer might be that the immune system senses the antigen, regardless of whether it is an exogenous pathogen or not. I am not sure if enteroviruses fit the bill.

As far as I am aware the same standards apply to trying to understand ME as any other condition.

How's that been working for us so far?

The absence of fever presumably means that whatever produces ME symptoms does not stimulate fever pathways. There is no particular reason why it should. Lots of chronic diseases occur without fever.

Nods. I brought up fever by way of an example only. There are many ways we are nonconformists to the core. Remember that whole Exercise-is-good-for-you thing?

I think we need to be actively looking at tissue. Not sure if Davis is. Pretty sure Lipkin/Hornig did not.

 

[Sisyphus]

“ There are many ways we are nonconformists to the core. Remember that whole Exercise is good for you thing?”

What’s your point here?

Exercise is required for normal health, until the most recent five seconds in history what we call exercise was a constant of human existence.

We are not anywhere near normal. We have broken systems and are confined to bed most of the time or at best too much of the time. What’s broken with us involves basic provision of energy, and Attempting to ouput normal amounts of energy breaks us further. Yeah, big sooper seekrit there.

 

[duncan]

What’s your point here?

What's my point?

We are not anywhere near normal

This.

So why confine the parameters of exploring for answers to convention?

I think we need to be looking for enteroviruses and other pathogens where we don't normally and by using means that are not restricted to standard interpretation. I think we will find few answers via the text-book route.

I think the answer may well prove to be autoimmune, but I think we better rule other stuff out as well. I don't believe we have yet.

 

[Pechius]

There are certainly some negative studies on pubmed. I think the problem may be that nobody really knows what would be a meaningful test for a persistent enterovirus infection. If it finding virus in tissue then the tissue ought to show some sign of being diseased. My memory of the staining of gastric biopsies is that the tissue looked entirely normal. Why would viral RNA in healthy looking stomach tissue have anything to do with PEM or light sensitivity?

I don't think the tissue has to necessarily show sings of being diseased according to conventional standards. I think what should be looked at is how the particular virus could alter intestinal permeability, potentially exposing the intestinal bacteria to host immune system, or letting endotoxins into the blood, etc. maybe even triggering autoimmunity or activating the bloody T-cells or god knows what.

I don't know what that means. I would want to know what a virologist with no commitment to a research theory in ME, and expertise in immunochemistry thought. My suspicion is that it does not mean anything relevant to the symptoms.

And I believe these things wouldn't be checked or considered by most people outside the field. E.g. H. Pylori eradication in otherwise asymptomatic patients seems to produce some iprovement in patients with ITP, and reduce thyroid antibodies in Hashimoto's. Evidence is, of course, weak, but we're just beginning to explore it, so I wouldn't expect anything more at this point.

As far as I am aware the same standards apply to trying to understand ME as any other condition.

For someone not involved in the ME/CFS, the things that I just described may sound like a wild speculation, but I think most people involved would disagree. The differences that most doctors would call insignificant may be very significant in the context of ME. You have to know what to look for.

Personal example, I have some gut symptoms, had both ends scoped, biopsies taken. Results: ileocolitis with active inflammation(mild edema on macro level), some lymphocyte infiltration in small intestine, few eosinophils, etc. So it's not normal, but such findings are never taken seriously, because there's no overt tissue damage, but the damage is irrelevant, imo. What's important is how does it affect the immune system and it certainly does.

 

[dreampop]

I don't personally see the logic in the enterovirus causing M.E., but I am always in support of more testing. But to answer Jen's question, I think biopsing nerve tissue, where presumably the infection must be near or around, seems to be a difficult task. And it must have been near impossible to do proper studies without any money or interest 30 years ago. I'd be very interested in that line of inquiry, because I believe M.E. is neurological, and your gonna have to dig in to find something we haven't found already and you could look at enterovirus along the way.