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

[JenB]

Looks like I might have to eat my words about lack of evidence that herpes could have anything to do with ME. I love it when science proves me wrong!

I'm not sure this is proof re: role of herpesviruses in ME specifically. Several intracellular pathogens induce mitochondrial change. e.g., HSV1 http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.81949-0 It's part of how they are able to persist long-term in tissues without causing apoptosis.

Hepatitis C: http://jvi.asm.org/content/84/1/647.short "viral-protein expression leads to severe impairment of mitochondrial oxidative phosphorylation and to major reliance on nonoxidative glucose metabolism."

The question of course, which @Hip raised earlier, is whether a chronic infection could be disseminated enough to cause PEM, not to mention whether a latent infection in humans even induces the types of changes you see in an active infection of cells in vitro.

(Trish, might you add what you found to this page? http://me-pedia.org/wiki/Human_herpesvirus_6)

 

[Dechi]

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.

This reasoning could be true if it wasn’t Dr Hyde we’re talking about. Dr Hyde runs a charitable foundation in order to help patients who can’t afford to defend themselves and find care. He has put a lot of his own money in it. A lot.

He is a very generous and caring man and only charges patients what is necessary. He does pro bono around the world.

Just to put the facts straight.

 

[Inara]

The other pathogens linked to ME/CFS have longer incubation periods:

EBV: 4 - 7 weeks

Didn't know EBV has such a long incubation time. Do you know how it is with reactivation? Is there something like an incubation time?

Does someone know if EBV can affect the liver, also during incubation time?

 

[JenB]

Quick question @Jonathan Edwards, would you not consider titers of 1:640 (the test's maximum) to Coxsackie B4 a strong sign of an active infection, especially with repeated testing? The lab interpretation instructions say that this should be considered "strong evidence" of recent or active infection, but I am not sure if there can be another explanation?

There is of course very little I can do about it as there are no anti-enterovirals.

 

[Trish]

(Trish, might you add what you found to this page? http://me-pedia.org/wiki/Human_herpesvirus_6)

Sorry, @JenB, I think MEPedia is great, but I use up all my limited energy helping run this forum. I can't do any more.

 

[adambeyoncelowe]

This reasoning could be true if it wasn’t Dr Hyde we’re talking about. Dr Hyde runs a charitable foundation in order to help patients who can’t afford to defend themselves and find care. He has put a lot of his own money in it. A lot.

He is a very generous and caring man and only charges patients what is necessary. He does pro bono around the world.

Just to put the facts straight.

And yet, I've heard stories of people being sent on endless tests out-of-pocket, costing thousands of dollars. So it's apparently a mixed bag, which I think is fair to say, as we're talking about a very vulnerable population here.

I don't dispute his intentions, but the road to hell and all that. If he really cares about ME patients, he could publish his findings properly, and give everyone around the world the benefit of his expertise. As it is, he claims to be the only person who can properly diagnose the illness, and yet won't back it up with peer-reviewed evidence. If he really does have the answer, how much in research funds would be saved?

 

[adambeyoncelowe]

Certainly out of the list of pathogens that we know through studies are associated with ME/CFS, it's only enterovirus that fits in the incubation period of 4 to 8 days observed in the outbreaks.

The incubation period of coxsackievirus B is usually stated to be 3 to 5 days, and the for echovirus its 2 to 14 days. So both would fit.

The other pathogens linked to ME/CFS have longer incubation periods:

EBV: 4 - 7 weeks
CMV: 3 - 12 weeks
HHV-6: 9 days (but virtually all adults are already infected with HHV-6, it's usually acquired in infancy)
Parvovirus B19: 4 - 14 days
Chlamydia pneumoniae: 3 - 4 weeks
Coxiella burnetii: 2 - 3 weeks typically

Parvovirus B19 might approximately fit the observed 4 to 8 day incubation period of the outbreaks, but acute parvovirus in adults often causes joint soreness that lasts weeks, and causes a distinctive "slapped cheek" rash in children, so I think any parvovirus outbreak would be recognized as such.

But of course there is the possibility that some of these ME/CFS outbreaks may have involved some unknown virus, rather than a known virus like CVB and echovirus. Even in the world of enteroviruses, new enteroviruses are often discovered, and Dr John Chia suspects that some cases of ME/CFS might be caused by enteroviruses other than the CVB and echovirus serotypes that we can currently test for using antibody tests.



I've also wondered whether the high mutation rate of enteroviruses might explain the sudden appearance and disappearance of outbreaks. When you get infected with coxsackievirus B, the mutation rate in your body is high, and the virus starts genetically diverging into multiple sub-species of itself, which are called quasispecies of CVB. So you catch one Coxsackie B virus, but end up being infected with multiple sub-species of that virus.


I don't know offhand if there is any way to distinguish between RNA and DNA virus infections.

Re: these incubation periods, do you have references for them? I've seen these claims made before, and yet I've also seen it argued that the incubation periods are outdated or otherwise disproven.

 

[Inara]

I was just reading that article on Dr Bhupesh Prusty's HHV-6 research the other day. This preliminary finding of HHV-6 being able to remotely affect the mitochondria in healthy uninfected cells sounds a promising line of investigation.

I remember I once contacted him. He was very nice. Maybe it's worth reaching out to him and his team?

 

[Dechi]

And yet, I've heard stories of people being sent on endless tests out-of-pocket, costing thousands of dollars. So it's apparently a mixed bag, which I think is fair to say, as we're talking about a very vulnerable population here.

I don't dispute his intentions, but the road to hell and all that. If he really cares about ME patients, he could publish his findings properly, and give everyone around the world the benefit of his expertise. As it is, he claims to be the only person who can properly diagnose the illness, and yet won't back it up with peer-reviewed evidence. If he really does have the answer, how much in research funds would be saved?

He does really care and I don’t think he claims anything. He is not in the research field, he is a family doctor. He has published many comprehensive books about ME, and sells them at a fair price, even giving the electronic versions for free when he can. If he didn’t care, I doubt that he would still be seeing patients at 82 years old, when he doesn’t need the money...

He is quite the character and probably not everyone’s cup of tea, but he definitely cares very much about ill people, and particularly people with ME.

I’ve said my peace. Have a great day !

 

[Guest 102]

Atypical polio was a misnomer as epidemic ME was not ultimately an atypical presentation of polio. It's the title of a piece of writing, not the name of my disease. I could as easily have called it "I have Iceland Disease." I just think it will be interesting to go back into that time and understand what people thought when they initially observed this and why.

I don't really have the energy or brain to research and structure a massive piece, so am trying to write tidbits when I can and not worry too much about the order/structure. I do wish the "series" feature on Medium was a little more accessible (it's basically for smart phones) but I hope to repackage it later.

Ah, I see, thanks for clarifying, I guess I was a little confused as you had also changed your Twitter name to Jen atypical poliomyelitis Brea. As I said, I think it is important to be informed of the historical perspectives on ME, but of course since I was diagnosed in early-mid 80s, I already know that perspective. But I do appreciate others wanting to deep-dive and to be honest you have probably read much more than I have if you are looking in detail at all these old papers. I do agree it would be brilliant if we’d had the tools back then that we have now.

 

[Hip]

Re: these incubation periods, do you have references for them? I've seen these claims made before, and yet I've also seen it argued that the incubation periods are outdated or otherwise disproven.

Can you link to the article you read which said they were outdated or disproven, I'd like to read it. I've never come across any suggestions that the concept of incubation period is disproven or outdated.

You'll find the incubation periods listed in standard medical literature, if you Google for example: "Epstein-Barr virus incubation period" Or you might like to read this article by Vincent Racaniello on the incubation periods of pathogens.

 

[Hip]

Didn't know EBV has such a long incubation time. Do you know how it is with reactivation? Is there something like an incubation time?

I am not really sure. I guess your question is: if there were an immune weakness appearing in the body, how long would it take for a latent EBV infection to become active again? But I think it would be hard to measure that.

In principle incubation periods are straightforward to measure: if you know the time that someone was exposed to the pathogen, then the incubation period is simply the time between that exposure and the time of the first symptoms of the infection (like fever, malaise, etc).

 

[Hip]

Quick question @Jonathan Edwards, would you not consider titers of 1:640 (the test's maximum) to Coxsackie B4 a strong sign of an active infection, especially with repeated testing? The lab interpretation instructions say that this should be considered "strong evidence" of recent or active infection, but I am not sure if there can be another explanation?

ME/CFS researchers who are not much enamored with the viral theory of ME/CFS, like Dr Robert Naviaux for example, suggest that these high antibody titers found in ME/CFS (and in autism, where high titers to measles virus are found) are not due to an ongoing infection, but are posited to be caused by a dysfunction of the immune system, such that it pumps out high levels of antibodies in the absence of an infection.

Antibody testing is not direct evidence of infection, as it only measures the immune response to infection (an infection which could be hidden anywhere in the body); so antibody testing does not directly detect the infection itself. Whereas PCR testing directly detects the pathogen, by detecting its RNA or DNA.

In the case of herpesvirus infections in ME/CFS, you get these high titers in patients, and some patients seem to respond to antivirals, but the high titers are not direct evidence of infection. And when you perform PCR tests for herpesviruses in the blood, these are often negative in ME/CFS (but that could be because the herpesvirus infection is located hidden in the body tissues rather than in the blood). So we don't currently have much direct evidence for herpesvirus infection in ME/CFS.

By contrast, in enterovirus-associated ME/CFS, we not only get the high antibody titers (indirect evidence of infection), but also when you perform muscle, stomach or brain biopsies and test those with PCR, it comes also out positive (direct evidence of infection). And when you give enterovirus ME/CFS patients treatments that fight enterovirus, like interferon alpha, they often get a lot better along with a measurable decrease in enteroviral load (but unfortunately patients relapse some months later, as the enterovirus returns).

So as far as I can see, the evidence base for enterovirus in ME/CFS is stronger than the evidence base for herpesvirus in ME/CFS at this point.



Personally I have no problem that there are researchers pursuing non-viral theories of ME/CFS, and I think it's advantageous to do this, as it is never good to have all your eggs in one basket. But I certainly don't want to see the viral research forgotten, or put on the back-burner.

 

[JenB]

LOL @Hip I'm realizing this exact conversation has been had many times before, on Phoenix Rising.

Let's try and go do something about this, to figure out what evidence would be required to either strongly confirm or disconfirm this line of inquiry, who should do it, how to fund it, and how to push drug development. If interested: jennifer@meaction.net.

 

[Webdog]

I'm increasingly thinking that all forms of acute flaccid paralysis/myelitis (and respiratory failure), including Poliomyelitis are in fact all forms of Guillain-Barré syndrome. The symptoms and long term outcomes are identical, the only difference is the underlying infectious trigger.

I hadn't considered that. Great insight!

 

[adambeyoncelowe]

Can you link to the article you read which said they were outdated or disproven, I'd like to read it. I've never come across any suggestions that the concept of incubation period is disproven or outdated.

You'll find the incubation periods listed in standard medical literature, if you Google for example: "Epstein-Barr virus incubation period" Or you might like to read this article by Vincent Racaniello on the incubation periods of pathogens.

I think it was Virology Blog? I could only find this article, though: http://www.virology.ws/2014/10/08/the-incubation-period-of-a-viral-infection/

The incubation period varies from the one you and Hyde give (6-12 days, not 3-8). I'll keep looking.

 

[Jonathan Edwards]

Quick question @Jonathan Edwards, would you not consider titers of 1:640 (the test's maximum) to Coxsackie B4 a strong sign of an active infection, especially with repeated testing? The lab interpretation instructions say that this should be considered "strong evidence" of recent or active infection, but I am not sure if there can be another explanation?

There is of course very little I can do about it as there are no anti-enterovirals.

Sorry, I have lost touch with this thread.

No, A high antibody titre is just a sign of good immunity. The myth that high titres indicate ongoing infection needs to wash out of the system. What indicates an active infection is a change in titre over a period of about two weeks. Repeated high titres do not mean active infection. I suspect that the lab interpretation instructions assume that the test is being done in the context of a new illness consistent with viral infection. In that context a high titre might provide circumstantial evidence but as soon as you have a history of two episodes you have no idea which if either gave rise to the high titre. And in the days when I did viral titres I never took notice of a single measure as an indication of recent infection - it was always done by comparing paired samples two weeks apart.

 

[Jonathan Edwards]

This puzzles me. We have ample reason to think these outbreaks could have been caused by enteroviruses, namely the first-hand accounts of the physicians who observed them and who almost universally said "I think this is an enterovirus."

The problem is that it is now clear that the reason why these physicians thought it was enterovirus was spurious. They appear to have thought it was enterovirus because they thought that there were signs of neurological involvement that mimicked polio. However, in retrospect it is clear that none of these patients had anything like polio.

I suspect that the physicians involved were infectious disease experts rather than neurologists. In one outbreak apparently they were orthopaedic surgeons. The reports we are left with do not suggest that anyone actually identified substantive nerve or muscle pathology. Apparent muscle weakness and real muscle fatiguability will occur during acute viral infection for reasons that have nothing to do with muscle damage - it is probably inhibition by transient release of cytokines. I well remember having a mock fight with a fellow undergraduate 50 years ago and suddenly finding myself 'paralysed'. I was initially shocked but over a period of minutes it dawned on me that I had other clues that I was developing a viral illness. By that evening I was vomiting and in bed with a temperature. Surely we are all familiar with that sort of thing. It seems that in these outbreaks similar phenomena are extended and exaggerated but there is nothing to indicate that they overlap with the lesions of polio.

I have forgotten most of my virology but my understanding is that there are a dozen or so families of viruses with short incubation periods. Maybe influenza, parainfluenza, adeno, rhino, entero, Norwalk, etc. etc. Back in the 1950s enteroviruses were uppermost in people's minds because polio was still around. In more recent outbreaks I am not sure that enterovirus was particularly singled out as the favourite.

 

[duncan]

No, A high antibody titre is just a sign of good immunity.

If I might be permitted a slight tweak of this observation, but an important one, perhaps. A high antibody titre MAY be just a sign of good immunity. I think, however, as a rule of thumb, antibody levels will peak as infection peaks; after that, they typically decline, at least to an extent. They may always be high, just not as. So level can matter.

On a purely theoretical level, an interesting test might be throwing antivirals at the level to see which way they incline. I cannot speak for enteroviruses, but for Borrelia, if you treat with antibiotics in late stage, it is not uncommon for titres to rise - in fact, you can pretty much expect them to. Kinda like poking the bear.

 

[Mij]

@Jonathan Edwards what is your opinion on immune modulators? I recall you mentioning on PR that there was no such a thing as "shifting" the immune system (TH1 and TH2). Do you feel it is just an immune response we are experiencing from immune modulators?