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

[Hip]

I disagree with the statement that the work shows promise and I certainly don’t agree with you in that it has a good evidence base.

You are providing an opinion that enterovirus research does not show promise, and say that "there are many more interesting avenues that show promise", but you don't explain why; you don't provide a factual or theoretical explanation for why you believe that. That's not really conducive to any discussion, because you have not provided any points to discuss. I'd like to see a discussion based on facts that we can get to grips with.

I find often when people criticize the pathogen theories of ME/CFS, the don't seem to explain in factual terms why they take a negative view.

It would help to read a bit about enterovirus, because if you have only scratched the surface of this subject, what is the basis of the opinions offered? For example, you say "there is little or no evidence of infection", so clearly you did not read my above post which showed ample evidence of enterovirus infection in ME/CFS, with numerous positive replication studies. There is no other pathogen that has been so thoroughly linked to ME/CFS as enterovirus.


I am not in any way against other angles of research examining ME/CFS from other perspectives not directly involving pathogens; the more the merrier, as far as lines of research are concerned. In particular I'd like to see a lot more research on the mitochondrial and energy metabolism dysfunctions of ME/CFS, and on the nature of any immune abnormalities of dysfunctions in ME/CFS. I think that's very important. We need to increase the momentum of all areas of ME/CFS research.

 

[arewenearlythereyet]

You are providing an opinion that enterovirus research does not show promise, and say that "there are many more interesting avenues that show promise", but you don't explain why; you don't provide a factual or theoretical explanation for why you believe that. That's not really conducive to any discussion, because you have not provided any points to discuss. I'd like to see a discussion based on facts that we can get to grips with.

I find often when people criticize the pathogen theories of ME/CFS, the don't seem to explain in factual terms why they take a negative view.

It would help to read a bit about enterovirus, because if you have only scratched the surface of this subject, what is the basis of the opinions offered? For example, you say "there is little or no evidence of infection", so clearly you did not read my above post which showed ample evidence of enterovirus infection in ME/CFS, with numerous positive replication studies. There is no other pathogen that has been so thoroughly linked to ME/CFS as enterovirus.


I am not in any way against other angles of research examining ME/CFS from other perspectives not directly involving pathogens; the more the merrier, as far as lines of research are concerned. In particular I'd like to see a lot more research on the mitochondrial and energy metabolism dysfunctions of ME/CFS, and on the nature of any immune abnormalities of dysfunctions in ME/CFS. I think that's very important. We need to increase the momentum of all areas of ME/CFS research.

Tbh @Hip I’ve had this conversation with you a couple of times before at the other place...I recall you didn’t accept what I said then either.

I have read many of the papers you have suggested and I found them lacking in many respects, from memory extremely small,sample sizes, no convincing signs of infection, the conclusions drawn did not match the data, there was confusion on the term infection, there was no robust control or healthy references given in a lot of them, and the conclusions you drew trying to glue all the papers together didn’t seem to add up in my mind.

 

[Snow Leopard]

People with ME have sensory symptoms and problems using muscles, and even sometimes involuntary movements, that do not resemble what you get in viral illness much at all. That suggests that ME is not just ticking the hypothalamus. It is something we do not yet have a grip of - because it is different - there is no close analogy with other illnesses.

The underlying cause(s) may be different, but there are common elements with other illnesses, though I agree most cases appear to be different from chronic viral illness.
People with other neurological or autoimmune diseases who I have talked to personally often describe similar severe fatigue and post-exertional "flares". I think this is why there is a lack of specificity when looking at biomarkers simply for "chronic fatigue syndrome".

Before the current fad of exercise as a cure-all, exercise was found to be a problem in GBS, example:
Bensman A. Strenuous exercise may impair muscle function in Guillain-Barré patients. JAMA. 1970;214(3):468–9

post-GBS patients talking about Fibro/CFS diagnoses:
https://forum.gbs-cidp.org/forums/topic/fibromyalgia-and-chronic-fatigue/
https://www.steadyhealth.com/topics/guillain-barre-and-chronic-fatigue

They have the same debates about what constitutes recovery too:
https://pdfs.semanticscholar.org/d201/fd6258336d8bf918738b4acd9197adfcad37.pdf
(European Journal of Neurology 2010, 17: 677–683)

 

[Hip]

I have no desire to be critical, I just want to prompt a good discussion on the subject, that addresses specific points and details. Skeptical views are very useful, but only if they provide supporting facts and references, otherwise no dialogue can be had.

Let's focus down on the specifics:

no convincing signs of infection

Why do you say there is no convincing signs of infection when no less than 7 separate studies listed in this post found direct evidence of enterovirus in the muscles using PCR. What exactly is unconvincing about that? There were 2 studies which did not find enterovirus in the muscles (but these had smaller cohorts), but 7 which did.

Using PCR is direct evidence of the virus. One you get a positive PCR result, you know the virus is there.

the conclusions drawn did not match the data

Which specific conclusions are you referring to?

from memory extremely small,sample sizes

The two negative muscle biopsy studies had small sample sizes (only around 30 patients), which might explain the negative results. But the 7 positive studies had reasonably large sample sizes: a couple of the positive studies had 60 patients, and others which had 140 patients, 158 patients, 121 patients and 48 patients.

I would not call that an extremely small patient sample.

there was no robust control

All of the studies mentioned just above had control groups.

 

[arewenearlythereyet]

Why do you say there is no convincing signs of infection when no less than 7 separate studies listed in this post found direct evidence of enterovirus in the muscles using PCR. What exactly is unconvincing about that? There were 2 studies which did not find enterovirus in the muscles (but these had smaller cohorts), but 7 which did.

Using PCR is direct evidence of the virus. One you get a positive PCR result, you know the virus is there.

Just because it’s there doesn’t mean it’s necessarily a problem. Equally if its there, we may have already dealt with it?

Definition of infectious:

“Infection: The invasion and multiplication of microorganisms such as bacteria, viruses, and parasites that are not normally present within the body. An infection may cause no symptoms and be subclinical, or it may cause symptoms and be clinically apparent. An infection may remain localized, or it may spread through the blood or lymphatic vessels to become systemic (bodywide). Microorganisms that live naturally in the body are not considered infections. For example, bacteria that normally live within the mouth and intestine are not infections.”


So the debate is whether their presence is a problem and if it is a problem, what is the exact mechanism by which it is a problem. How does that compare to people who have it and don’t have ME. How does this result in symptoms ...what is the mechanism for this etc etc

And I’m saying ....I’m not convinced by this argument because you could equally find some gut bacteria and say exactly the same thing ...or some other virus ....it doesn’t equate to causation or perpetuating symptoms

 

[Hip]

Just because it’s there doesn’t mean it’s necessarily a problem

Agreed, in other words, association does not automatically imply causation.

But earlier you were saying that there were no convincing signs of infection, which is a different thing to saying there is an infection, but it's uncertain whether this infection is the cause of ME/CFS.


But if we agree that there is an enterovirus infection present in a subset of ME/CFS patients, and much less common in healthy controls, then that's where we are at this stage with enterovirus research. At this stage we know that enterovirus is found associated with ME/CFS, but we don't know for sure at present whether it causes ME/CFS. The next step in the research is to determine whether or not it causes ME/CFS.

As I mentioned earlier, one piece of suggestive evidence that it does cause ME/CFS is the fact that ME/CFS symptoms improve when antivirals or immunomodulators are given which demonstrably reduce enteroviral load in the body; in these cases, as enteroviral load goes down, then ME/CFS symptoms substantially improve. And when this antiviral treatment is discontinued and enteroviral load goes up again, then ME/CFS symptoms get worse again.

If we can convince the pharmaceutical companies to produce better enterovirus antivirals, we may use these to get further evidence of a causal role. In fact, the Rega Institute in Belgium already has two new antiviral compounds which are a potent inhibitors of coxsackievirus B, but they are taking time to come to market. When these drugs become available, then we can give it to ME/CFS patients with active CVB infection, and observe whether it improves symptoms.



If we want to get drug companies to invest the money to develop better enterovirus antivirals — perhaps even an antiviral that is able to totally eradicate enterovirus from the body (just like these newer antiviral drugs do for hepatitis C virus) — we need to all be singing from the same hymn sheet.

We need to send the message the drug companies that enterovirus is a very likely possible cause of ME/CFS, and that there are 17 million ME/CFS patients worldwide, with perhaps one third of them (we might estimate) with enterovirus-associated ME/CFS, so that's a big market.

Throwing cold water on the enterovirus theory for no good reason is not doing anyone any favors, certainly not the ME/CFS community. We need the pharmaceutical companies to develop these anti-enteroviral drugs.

 

[arewenearlythereyet]

Agreed, in other words, association does not automatically imply causation.

But earlier you were saying that there were no convincing signs of infection, which is a different thing to saying there is an infection, but it's uncertain whether this infection is the cause of ME/CFS.


But if we agree that there is an enterovirus infection present in a subset of ME/CFS patients, and much less common in healthy controls, then that's where we are at this stage with enterovirus research. At this stage we know that enterovirus is found associated with ME/CFS, but we don't know for sure at present whether it causes ME/CFS. The next step in the research is to determine whether or not it causes ME/CFS.

As I mentioned earlier, one piece of suggestive evidence that it does cause ME/CFS is the fact that ME/CFS symptoms improve when antivirals or immunomodulators are given which demonstrably reduce enteroviral load in the body; in these cases, as enteroviral load goes down, then ME/CFS symptoms substantially improve. And when this antiviral treatment is discontinued and enteroviral load goes up again, then ME/CFS symptoms get worse again.

If we can convince the pharmaceutical companies to produce better enterovirus antivirals, we may use these to get further evidence of a causal role. In fact, the Rega Institute in Belgium already has two new antiviral compounds which are a potent inhibitors of coxsackievirus B, but they are taking time to come to market. When these drugs become available, then we can give it to ME/CFS patients with active CVB infection, and observe whether it improves symptoms.



If we want to get drug companies to invest the money to develop better enterovirus antivirals — perhaps even an antiviral that is able to totally eradicate enterovirus from the body (just like these newer antiviral drugs do for hepatitis C virus) — we need to all be singing from the same hymn sheet.

We need to send the message the drug companies that enterovirus is a very likely possible cause of ME/CFS, and that there are 17 million ME/CFS patients worldwide, with perhaps one third of them (we might estimate) with enterovirus-associated ME/CFS, so that's a big market.

Throwing cold water on the enterovirus theory for no good reason is not doing anyone any favors, certainly not the ME/CFS community. We need the pharmaceutical companies to develop these anti-enteroviral drugs.

I think this is exactly where we ended up last time @Hip ... next time just remind me to cut and paste my comments from before.

I’m not pouring cold water on anything, though just trying to point out the flaws in this rather oversimplistic “nuke the bastards” thinking.

 

[Hip]

I think this is exactly where we ended up last time @Hip

No, this time we seem to have made progress: I've shown in the post above that several of the things you believed about enterovirus research were not correct.

And you now seem to have shifted your position from "no convincing signs of infection" to accepting enterovirus infection exists in ME/CFS, but may not necessarily be the cause, ie your statement: "just because it’s there doesn’t mean it’s necessarily a problem".

That's a great advance!

 

[arewenearlythereyet]

No, this time we seem to have made progress: I've shown in the post above that several of the things you believed about enterovirus research were not correct.

And you now seem to have shifted your position from "no convincing signs of infection" to accepting enterovirus infection exists in ME/CFS, but may not necessarily be the cause, ie your statement: "just because it’s there doesn’t mean it’s necessarily a problem".

That's a great advance!

I haven’t shifted my position

 

[JES]

Throwing cold water on the enterovirus theory for no good reason is not doing anyone any favors, certainly not the ME/CFS community. We need the pharmaceutical companies to develop these anti-enteroviral drugs.

IMO this cannot be stated often enough, not only because of the connection to ME/CFS, but due to other potential diseases it may treat as well. Just like for thread starter, it boggles my mind why the research hasn't progressed more in this area.

I used to follow these enterovirus discussions closely on Phoenix Rising, so here's my two cents. Enteroviruses are all but harmless and have been linked with type 1 diabetes (paper), chronic myocarditis, the 2014 EV68 and other outbreaks where children have died, etc. The enterovirus foundation website gives a good overview on how big this problem is. I would agree that it seems unlikely that enterovirus infection itself would directly cause all the diverse symptoms seen in ME/CFS, but what if all the changes are downstream effects as in the hypothesized type 1 diabetes causation or chronic myocarditis? IMO with current evidence we are nowhere close to make a statement that enterovirus is of no significance in ME/CFS.

Due to all these enterovirus caused health issues, especially the recent EV68 outbreak, I'm hopeful that enterovirus drug development will be accelerated and that an effective drug against enteroviruses will reach the market in the next few years. In Finland there is now a vaccine in development against enterovirus in order to prevent or at least reduce likelihood of developing type 1 diabetes. This vaccine has been successfully tested on mice and they are looking to start a human trial by the end of this year. And then as was mentioned there are the two Belgian drugs being developed. Response to these drugs could finally shed some light on whether enterovirus on its own can cause and/or maintain ME/CFS.

As it happens, there is also an anti-enterovirus drug already available that can achieve high enough antiviral concentrations in vivo, namely Fluoxetine. I personally trialed Fluoxetine, which is antiviral against CVB4 in particular, but without any success. Hip then explained to me that the way in which Fluoxetine works (by targeting viral proteins) would likely have little or no effect against non-cytolytic forms of enteroviruses. But it could of course also be that I don't have any enterovirus infection and that my ME/CFS was triggered by something else. Either way, Fluoxetine is one of the drugs that Montoya's Stanford clinic are using on patients, so it's not inconceivable that it may help some patients.

 

[Melanie]

I'll jump in. No, I didn't read every post so sorry if I am reapeating what was already posted.

I could have sworn Solve ME/CFS Initiative had said they analyzed the Chia samples and found no enteroviruses. I just googled now and can't find the information but I really thought they did check the samples over the past year and came up with nothing.

 

[Hip]

I could have sworn Solve ME/CFS Initiative had said they analyzed the Chia samples and found no enteroviruses.

I believe it was the CDC which analyzed some of Dr Chia's stomach tissue biopsy samples, and could not find enterovirus.

I know that when the CDC received Chia's samples, instead of getting on with the job of testing them, they left them on the shelf for a year before they got around to analyzing the samples (that's CDC enthusiasm for you). Chia thinks the reason the CDC failed to find enterovirus was because the samples were too old.

Chia then suggested to the CDC that they try a more sensitive technique, but the CDC declined. Ref: here.

I wonder why the CDC did not get their own fresh samples from ME/CFS patients. It's a fairly routine procedure for a gastroenterologist to take a stomach biopsy using an endoscope. You'd think that the CDC would show more initiative.

 

[Melanie]

Chia thinks the reason the CDC failed to find enterovirus was because the samples were too old.

I'm no expert, but I don't think they go anywhere once you have the sample. I think Chia is wrong, but that's just me.

 

[duncan]

You'd think that the CDC would show more initiative

No, I wouldn't, and I've experience with government medical sleuths. The concept of persistent infection doesn't seem popular in Bethesda or Atlanta. I have seen the CDC deny a pathogen as it slowly killed a patient, even though they were in receipt of her plasma and tissue and CSF, and those were riddled with the pathogen in question. Legacy and dogma can be powerful forces for inertia.

Thank God some clinicians show the courage to launch an initiative on their own, virtually unilaterally. Of course, this limits the utility of the findings.

I think each report of a class of pathogens being responsible for various flavors of ME/CFS should be exhausted as a possible source. I think where you find one, you can find another, and maybe another.

In an age of suspect diagnostics and the embarrassing baggage lugged in by the Bayh-Dole act, which choice seems more straightforward: Chronic infection vs. corrupted immune systems? Which leaves insurance companies more in the lurch?

 

[Dr Carrot]

No, this time we seem to have made progress: I've shown in the post above that several of the things you believed about enterovirus research were not correct.

And you now seem to have shifted your position from "no convincing signs of infection" to accepting enterovirus infection exists in ME/CFS, but may not necessarily be the cause, ie your statement: "just because it’s there doesn’t mean it’s necessarily a problem".

That's a great advance!

Do you have to be so patronising in your approach? I don’t have a horse in this race but some of your arguments come across as a little preachy.

I’m sorry if that sounds blunt, but it’s ok if people disagree with your theory of ME. There are plenty of them around.

 

[Inara]

I think this is exactly where we ended up last time @Hip ... next time just remind me to cut and paste my comments from before.

For some people this is a repetition, but for me and I suppose many other (future) members it's new, so all the arguments are interesting.

 

[chrisb]

Before the current fad of exercise as a cure-all, exercise was found to be a problem in GBS, example:
Bensman A. Strenuous exercise may impair muscle function in Guillain-Barré patients. JAMA. 1970;214(3):468–9

There is also this intriguing reference;

The strongest evidence, however implicates Coxsackie viruses. These are known to be myotropic, as in Bornholm disease. They show an increased ability to replicate in muscle which has been denervated 16, or severely exercised 17.In the latter case they resemble polioviruses which, in the days of the polio epidemics, were known to have a predilection to attack the motor neurones of recently active muscles.18

16 Sato T Chou SM Effect of denervation on Coxsackie A virus infection on mice: an electron microscopic study.
Neurology1978 28 1232-1240

17 Lerner AM Wilson FM Virus myocardiopathy. Prog Med Virol 1973 15 63-9

18 Debre R Duncan D Enders JF et al Epidemiology. In: poliomyelitis Geneeva WHO Monograph 1955 pp 21-22

Amplification and identification of enteroviral sequences in the postviral fatigue syndrome JW Gow WMH Behan
British Medical Bulletin (1991) vol 47 No 4 pp 872-885 @p874

I know this is now all long ago and far away, but it was not in1989, when exercise was recommended -and these were the views of the more established researchers of the time.

 

[Guest 102]

It may well be relevant to whatever your disease process is. Uveitis does not occur in RA, or in any B cell drive diseases I can think of off hand. It is a characteristic feature of the MHC Class I (HLA B) associated T cell disorder ankylosing spondylitis. You are pretty likely to carry HLA-B27.

Thanks for this, Jonathan, interesting to learn about HLA -B27. I wonder if I was tested for this when I got uveitis, it does seem familiar, though maybe I just googled at time and have forgotten, was 9 years ago. I have done a cursory search of HLA-B27 and ME, it does seem to be something that is being explored.

I knew of links with AS and uveitis but reason I associated uveitis with RA is a neighbour of my mother’s had juvenile arthritis as child and also uveitis, and she still gets flares of uveitis as adult.

 

[Inara]

Do you have to be so patronising in your approach? I don’t have a horse in this race but some of your arguments come across as a little preachy.

I’m sorry if that sounds blunt, but it’s ok if people disagree with your theory of ME. There are plenty of them around.

I understand many of you have a "history", and although I understand you here, I am a bit sad. Several people whose posts I valued were chased away, last one is @Lucibee even though this was not the intent. Please, can we not do that?

 

[Hip]

Do you have to be so patronising in your approach? I don’t have a horse in this race but some of your arguments come across as a little preachy.

I’m sorry if that sounds blunt, but it’s ok if people disagree with your theory of ME. There are plenty of them around.

Preachy is not really my style, so sorry if my comments read like that. It's not the disagreement that concerns me, it's the fact that those disagreeing are not really explaining why they disagree. I like discussions based on facts, evidence and theoretical considerations, rather than based on evangelizing a point of view, either for or against.

With generic negative comments, or generic positive comments for that matter, without a reasoned argument or specific details, it comes across as evangelizing, which becomes a little frustrating, as dialog can descend into a "yes it is", "no it isn't", "yes it is".

A lot can be learnt from a sharp and incisive skeptical argument; but there's not much to learn from some generic, nonspecific negative comments.

I think if you are going to be skeptical about something, or positive about it, presenting a factual and detailed argument is more conducive to discussion.