Are Infections Just a Trigger of ME/CFS, or an Ongoing Cause of ME/CFS?

[halcyon]

Something i read recently stated that EV was the most likely cause of viral meningitis. The figures were something like 90% were probably caused by EV, the remaining were mostly hsv1/2 and the small remaining were the rest of the herpes family.

Yes, enteroviruses, and especially echoviruses, are one of the most common causes of aseptic meningitis.

 

[Hip]

So yes, they don't generally cause persistent infection in healthy people as far as we know, but there is a mountain of evidence showing it can persist for long periods of time in a subset of the population and does cause disease.

I think it an interesting question, though, whether enteroviruses like coxsackievirus B and echovirus, which are known to cause chronic infections in ME/CFS, are also capable of causing chronic infections in healthy people. I had not considered this question before.

Because if chronic enterovirus infections do not occur in healthy populations, it perhaps suggests we should be looking for reasons (such as immune problems) why these infections arise in ME/CFS patients. However, by contrast, if chronic enterovirus infections do occur in healthy populations, then this suggest that there is nothing particularly unusual about chronic enterovirus in ME/CFS; the only unusual thing is the fact that the infections are somehow able to precipitate ME/CFS symptoms.

@Eeyore said that in his virology classes, it was stated that enteroviruses never form chronic, lifetime infections in the way herpes family viruses do. With herpes family viruses, one you have caught them, they stay with you for life.

But according to Eeyore, the received wisdom is that in healthy people, enterovirus infections will be fully eliminated, although it can take up to 3 years for the body to eliminate them. The received wisdom is that enterovirus infections are never lifelong in the healthy.

So it would be interesting to try to find evidence that either confirms or refutes this idea that enteroviruses never form lifelong infections in the healthy population.


It's interesting to look at Dr John Chia's stomach biopsy study on ME/CFS patients: although Chia's study found 82% of ME/CFS patients biopsies contained enterovirus VP1 protein, he also found that 20% of the healthy controls contained enterovirus VP1 protein as well. However, whether this 20% is evidence for chronic enterovirus infections in the healthy is unclear, since Chia states in that study that:

Finding enteroviral protein in some of the control subjects could be explained by the high prevalence of enterovirus infections throughout the year, affecting as many as 50 million Americans per year, or 17–25% of the population. Viral shedding in stool can persist for weeks after acute infections. It is probable that the control subjects had an asymptomatic or self-limited enterovirus infection within the preceding months.

 

[halcyon]

I think it an interesting question, though, whether enteroviruses like coxsackievirus B and echovirus, which are known to cause chronic infections in ME/CFS, are also capable of causing chronic infections in healthy people. I had not considered this question before.

I guess it depends on what your definition of healthy is. Would someone with a chronic infection be considered healthy? If you look at Chia's most recent paper, he has found that people with chronic GI problems also seem to have persistent enterovirus infection in their stomach. I wouldn't be surprised if some healthy people end up with longer term asymptomatic enterovirus infections of just the gut. Chia could longitudinally follow his positive controls to see if any of them continue to show infection.

Because if chronic enterovirus infections do not occur in healthy populations, it perhaps suggests we should be looking for reasons (such as immune problems) why these infections arise in ME/CFS patients. However, by contrast, if chronic enterovirus infections do occur in healthy populations, then this suggest that there is nothing particularly unusual about chronic enterovirus in ME/CFS; the only thing unusual is the fact that the infections are somehow able to precipitate ME/CFS symptoms.

I think that specific host factors lead to persistent, disseminated infections in those that develop ME from a sudden infectious onset. In enteroviral myocarditis, for example, it was found that those that produced larger amounts of IFN-β during the initial infection had a much better outcome. Also as I mentioned above, people with antibody production problems tend to develop severe enterovirus infections. It has been noted that antibody production is a critical factor in fighting an enterovirus, perhaps even more so than innate immune factors. There seems to be a number of ME patients with IgG1 and IgG3 subclass deficiencies. Perhaps these were preexisting before the onset of ME and something prevented them from mounting a robust humoral immune response.

But according to Eeyore, the received wisdom is that in healthy people, enterovirus infections will be fully eliminated, although it can take up to 3 years for the body to eliminate them.

I'm not sure exactly where he gets the 3 year number but it seems to be his interpretation of something that Dr. Hyde said. I don't agree with his interpretation. If the virus can persist for 3 years, why not 5, why not 10, 20? As you showed, indefinite infections can be produced in vitro.

If we could ever get a damn antiviral specific for enterovirus then we could really get down and dirty with a blinded placebo controlled drug trial that could show some serious results. Personally, I think his interferon/ribavirin paper and oxymatrine trials are really compelling, but if we could produce lasting remission with a real targeted drug that would cinch it.

 

[halcyon]

If the root cause of the problem is the enterovirus, then why can't Dr. Chia achieve permanent cure?

How is he supposed to do this without a targeted antiviral?

Also, Dr. Chia would find the same virus or group of viruses in all patients, and he hasn't.

He has found enterovirus in 82% of patients. There are a number of other pathogens listed above by Hip which probably represent the remaining percentage of patients.

How does it exist over the long term without triggering normal cellular responses?

Like most viruses, enteroviruses have evolved countermeasures to these responses. The enteroviral proteases 2A and 3C interfere with the RIG-I and MDA5 PRRs. They also interfere with IRF7 and STAT-1, the latter of which would block the interferon stimulated genes and prevent PKR and RNase deployment. Also, the viral replication process shuts off host translation (by breaking the cap dependent mechanism) and this causes, among other things, a downregulation of MHC expression as Hip mentioned above. So yes, enterovirus doesn't form a proviral or episomal latency like other persistent viruses, but when the virus becomes non-lytic (for whatever reason this is), there is probably a standoff where the virus doesn't lyse the cell and the immune system can't get rid of the virus.

Keep an eye out for Chia's presentation at IiME later this month. It's going to be interesting.

 

[Eeyore]

How do you know they are chronic? Finding the viruses in ME patients doesn't show causation, or even duration of infection - it could simply reflect a vulnerable state.

Has Chia done longitudinal studies over many years that show the persistence of the same enteroviruses in all patients who continue to experience symptoms, but not in any healthy controls?

 

[Hip]

Finding the viruses in ME patients doesn't show causation

Not on its own, sure, but when you use interferon or oxymatrine on these chronic enterovirus infections, and the level of infection is thereby significantly reduced, along with a concomitant reduction or complete remission of ME/CFS symptoms, that does suggest a causal role.

 

[Eeyore]

I want at least the first 2 of Koch's postulates fulfilled - these are the basis of infectious disease. The 3rd is important too but impractical (if you look it up you'll see why...) =P

He is proposing one possible mechanism for why certain drugs seem to help people - whether it is correct we don't know, and much more proof would be needed.

Also we'd need very much larger trials, and they'd need to be double blinded, randomized controlled trials.

I don't find what I've read so far very convincing. Maybe worth some more study - but not convincing.

 

[halcyon]

How do you know they are chronic? Finding the viruses in ME patients doesn't show causation, or even duration of infection - it could simply reflect a vulnerable state.

Of course. That's why I think Chia's treatment studies are compelling.

Has Chia done longitudinal studies over many years that show the persistence of the same enteroviruses in all patients who continue to experience symptoms, but not in any healthy controls?

See my list of links above. Chia has done a longitudinal from acute infection onwards. Others have sequenced the virus and found it's the same.

 

[Eeyore]

@heapsreal - If VZV is causing problems, even moderate dose valtrex would control it. Unlike the gamma and beta herpesviruses, the alpha are very sensitive to acyclovir, which is not very toxic unless you get to very high doses. (The drugs used to treat beta and gamma herpesviruses, like ganciclovir, are much more toxic because they aren't as selective as acylovir, which relies on the viral thymidine kinase in the alpha herpesviruses - HSV1/2 and VZV.)

 

[Eeyore]

@halcyon - Sorry, still not that impressed - studies are small, not long enough, and not double blinded randomized controlled trials. It's not enough to convince me.

Furthermore, the mechanism by which the drugs might be working is not clear.

I don't want to read a hundred scientific papers - but if you link one with a reason why you are linking it, I'll look. A thorough, critical read of a paper can take some time.

 

[Eeyore]

Also - we find high rates of certain infections in many autoimmune diseases, and sometimes treatment of the infections improves the symptoms - but it doesn't cure the disease, and it doesn't mean the infection is the cause.

Any alteration in the immune system can cause increased rates of certain infections.

 

[Hip]

I guess it depends on what your definition of healthy is. Would someone with a chronic infection be considered healthy? If you look at Chia's most recent paper, he has found that people with chronic GI problems also seem to have persistent enterovirus infection in their stomach. I wouldn't be surprised if some healthy people end up with longer term asymptomatic enterovirus infections of just the gut. Chia could longitudinally follow his positive controls to see if any of them continue to show infection.

Well that's something that did occur to me: perhaps it is not possible to have a chronic enterovirus infection without some form of disease appearing. Perhaps there are no asymptomatic long-term carriers of enterovirus.

Also we'd need very much larger trials, and they'd need to be double blinded, randomized controlled trials.

I agree, but good luck with that one on the meagre ME/CFS research budgets, and the general lack of interest in this disease by medical researchers. Dr Chia himself is quite upset that his results, which were published 10 years ago now, have not been replicated anywhere so far. Considering how many XMRV replication studies there were, it is ridiculous that Chia's very promising work has not bee taken up by a research team somewhere.

I want at least the first 2 of Koch's postulates fulfilled - these are the basis of infectious disease. The 3rd is important too but impractical (if you look it up you'll see why...) =P

HIV and AIDS does not really fulfill Koch's first postulate, as there are people with genetic immunity to developing AIDS from HIV.



But what of the clearcut case of parvovirus B19, which is known to cause symptoms identical to ME/CFS, and treatment of this virus is known to cure those symptoms. Is that not acceptable evidence demonstrating that ME/CFS can have a viral cause? And parvovirus B19 is not the only pathogenic cause of ME/CFS: the CDC say that:

Infection with Epstein-Barr virus, Ross River virus, and Coxiella burnetti will lead to a post-infective condition that meets the criteria for CFS in approximately 10-12% of cases.

You have to see the enterovirus studies not in isolation, but in the light of the fact that many other pathogens are known to cause ME/CFS.

 

[halcyon]

I don't want to read a hundred scientific papers - but if you link one with a reason why you are linking it, I'll look. A thorough, critical read of a paper can take some time.

You have impossibly high standards for research, especially on this disease. No one study by one group is going to be a slam dunk. You have to look at the preponderance of the evidence pointing towards chronic infection in this disease. The work on this goes back well into the 1970s. If you're not willing to read all of the research, I don't think you're going to be able to accurately answer the question you posed in the title of the thread.

 

[Eeyore]

@halcyon - Right, but if you make a given point, provide a source for it, and I'll look at it. e.g. "Chia has done longitudinal studies showing enterviral persistance for X years" - link a paper that shows *that* - not just all of Chia's papers.

I do not see a preponderance of evidence pointing to chronic infection. I see a biphasic illness (as described by Ramsay) with an infection that clears but leaves residual damage, and that does not affect all people equally - suggesting genetic or other predisposition.

i see thousands of papers trying to find an infectious cause and all failing to show proof. Some show correlation - most don't even do that. Most have not been replicated (e.g. defreitas was never replicated, although many tried). People were all sure XMRV was the mystery infection, and it seemed to have some of the best evidence out there, and it turned out to be nothing - even though a few labs seemed to "replicate" it.

In medical science, something considered statistically significant with a p value of around .05 has only about a 50/50 chance of replication. That assumes the first trial was double blinded, randomized, placebo controlled.

Lipkin/Hornig's studies had VERY small p-values. No one else has gotten p-values like that. They also show a bi-phasic illness, the first of which appears to be immune activation and the second of which appears to be immune deficiency or at least dysregulation. The decoupling of cytokine messenger networks is very odd in acute ME - and suggests that there is an immune problem in the first phase. Even a failed immune response leading to death doesn't generally result in that type of a cytokine network decoupling. Klimas has showed some similar concepts in her work.

 

[Eeyore]

@Hip - Chia has definitely found enterovirus infection (active) in healthy controls (using the standard definition - the person claims to feel well and there are no tests to indicate otherwise prior to the study - it doesn't require ruling out other illnesses in advance).

I can think of many worse uses of funds than follow up studies to Chia's work. I think he has likely found something - and understanding it would give us a clue as to the pathophysiology of ME. Even if it's just due to increased vulnerability or immune compromise, that would still be useful, and if he's right and it's causative, a larger study would show it. We waste 100x that much on male pattern baldness each year, or botox for wrinkles research.

HIV is considered to fulfill Koch's postulates. Even the third in a way- although we don't do it on purpose - people exposed to it have developed the disease. Exceptions due to uncommon genetic mutations don't really disqualify it.

I don't really trust a CDC statement that Parvo B19 can cause symptoms consistent with CFS - the problem there is probably one of definition. They probably just said that people were tired knowing the CDC... I'm not an absolute stickler on ME vs CFS, and most specialists can tell the difference between ME and "I'm tired" - but it's not clear in this case that that is true. They make similar claims about depression.

I think many pathogens DO trigger ME. Everyone pretty much thinks so who knows anything about ME. I don't think they cause it by means of a chronic, unresolved infection, and I do not believe it is possible to cure ME with antivirals - *maybe* if you got it REALLY early, like the first or 2nd day of fever with a really good antiviral (which we don't even have yet).

There is a reason Hyde doesn't treat. It doesn't work. He opposes all treatment with antivirals and is of the opinion that there is no effective treatment for ME. I don't particularly agree that there is no treatment - but I think he has a good point. I think there is damage to the CNS - and that young people tend to bounce back and repair it better after viral clearance, but older people have less plastic brains.

 

[heapsreal]

@heapsreal - If VZV is causing problems, even moderate dose valtrex would control it. Unlike the gamma and beta herpesviruses, the alpha are very sensitive to acyclovir, which is not very toxic unless you get to very high doses. (The drugs used to treat beta and gamma herpesviruses, like ganciclovir, are much more toxic because they aren't as selective as acylovir, which relies on the viral thymidine kinase in the alpha herpesviruses - HSV1/2 and VZV.)

I still had a shingles episode on my legs while on famvir a week or 2 after head shingles so probably not 100% effective and maybe the infection could have been worse. I guess alot of shingles studies and antivirals wouldnt take into account of low nk function and other immune abnormalities etc which would make it harder to control viruses even with avs.

im not sure whats going on at moment but could be PHN so more to do with nerves damaged the active virus. The other thing i keep find is low grade chronic meningitis . Avs seem to help but not 100% in info im reading. Avs may get virus down but need immune system to keep it down???

im not sure whats going on at moment , will have to wait on more testing i guess.

 

[Eeyore]

@heapsreal - Actually, shingles takes a few weeks to clear up at least, even with antivirals - but if you take it longer term it's almost 100% effective in suppressing it (the main variable being resistant strains, not our particular immune systems, and resistant strains remain extremely rare despite decades of acyclovir/pencyclovir use because herpesviruses are genetically complex and very stable).

Sure, the NK function deficiency isn't going to help you, and would likely make viral infections more persistent. Actually - it's not the NK function that's the problem. It's just easy to measure it, and it corresponds to CD8 suppressor T-lymphocyte function (both kill target cells via a perforin/granzyme or Fas/FasL mechanism). When one is defective the other is too, almost always. You can take NK cells out of a random person and put them in culture with some cancer cells and they go to town killing - CD8 are very specific and need priming by CD4 and certain cytokines, etc., so they are not practical to test cytotoxic function. In viral infection, NK cells do play a role, but increased severity of viral infection in people with low NK cell function is more tied to its correlation with low CD8 cytotoxic activity in those patients.

Sometimes there is damage which persists after resolution of an infection, and the body has to heal, and if your NK function is impaired, your body is slow to transition from fighting infection and feeling sick to calming the immune system down and healing damage.

Do you have visible signs of VZV?

 

[heapsreal]

@Eeyore reliable signs of vzv, yes rash similar to chicken pox but only a strip across side of my head with pustules that scabbed up. 1 to 2 weeks later a similar strip of rash pn right lower leg with pustules that dried up. Several days after onset on my left lower leg.

The location of this rash correspond with past symptoms as i use to feel a brain fog sensation on that left side of my head. Neuropathy pain down both shins. Was this some type pf subclinical infection.

your probably right about cd8 cells as the study i was in found these abnormalities in the group i was in although we only got told our individual nk function.

antibody test to vzv was done as considering shingles vaccine. It came back saying i have very good immunity to vzv. After shingles my dr said it was either my crappy innate immune system or i have a chronic low level vzv that has caused this.

as for current chronic headaches, i have researched that one can get low grade meningitis from vzv. Also PHN nerve damage??

cheers

 

[Eeyore]

@heapsreal - Yep - I'm not a doctor but that sure sounds like it. VZV, unlike HSV1/2, is often not symmetrical and affects only one side. It usually follows a dermatome (the area of skin innervated by one nerve).

They don't test CD8 function - too hard to do - but NK function is a near-perfect proxy for the ability of the cells to lyse targets (but not to recognize them - that mechanism is different - but the former seems to be more relevant).

You would have good humoral immunity - not surprising. When cell-mediated immunity is impaired, viruses replicate more, antigen presentation increases, and titers go up. So that all makes sense. The vax may help but it will mostly just stimulate more antibodies. You might do well with a th1 shifter like imunovir if your doc agrees to prescribe it (in addition to the antivirals you are already getting).

Also take a look at Jay Goldstein's work on cimetidine in treating mono - the mechanism would likely apply to shingles as well, although not sure if he has tried it. Cimetidine is very cheap and OTC (it's an H2 blocker / acid reducer). Some of the newer ones have fewer side effects (like zantac / ranitidine) and I believe studies showed they worked just as well - so I'd try that if doc thinks it's reasonable / harmless (even maybe if he doesn't think it would help - few are aware of Goldstein's very interesting work on this).

I don't think it's your innate immune system that is the issue - I think it's the adaptive cellular response that is impaired. If you don't mind my asking, what is your age? Shingles is uncommon in younger people but gets more common by the 50's. Not unheard of in 40's, pretty rare before then.

I'm not sure how often headaches accompany shingles. While possible that it's a low grade meningitis, there are some reasons to doubt this. First, VZV travels along a given nerve. It doesn't generally travel through the blood stream - although oddly you have it in 2 very different locations. I believe that is not the norm - it's usually on 1 dermatome or 2 closely related ones, suggesting the VZV worked its way back to the intersection of the 2. There's also the BBB which offers some protection to the brain and CNS, but that's obviously not perfect since VZV meningitis can occur.

I'm not sure what the penetration of various drugs through the BBB is - that might be worth looking at (e.g. valaciclovir, famciclovir, ranitidine, cimetidine, etc.)

 

[Sidereal]

Cimetidine helps my VZV problems, definitely worth looking into, @heapsreal. I still take Valtrex but a much lower dose. Ranitidine doesn't cross the BBB so if you suspect low-grade meningitis it would be useless, I'd go with cimetidine which does cross the BBB.