@Eeyore
You make some very interesting points, which I have had to think about, and do some Google research on.
Were your virology classes part of a medical degree or similar, by the way?
I don't believe any cases of ME are known to be caused by any pathogen. Triggered, yes, caused, no.
Just to make sure we are using the same terminology:
I presume by the term
trigger you mean something like viral "hit and run" damage to the body, or viral instigation of autoimmunity; and you also mean that once such triggering events occur, they cannot be easily undone; that is, there is a certain irreversibility about a condition or disease that a pathogen
triggers.
Whereas by contrast, if a pathogen is
causing and maintaining a disease such as ME/CFS, I presume what you mean is that the disease only exists because the pathogen is still in the body, and still causing the disease on a day by day basis.
In other words, if you could remove a viral
cause from the body, the disease would disappear; but if you could remove a viral
trigger from the body, the disease would continue.
Would you say that is an accurate definition of what you mean by
trigger and
cause? That's generally how I use the terms
trigger and ongoing
cause.
OK, well given this terminology, how would you then interpret the appearance of ME/CFS in some people on contracting parvovirus B19 or Coxiella burnetii, and the sudden disappearance of all ME/CFS symptoms on eradicating these infections with antivirals/antibiotics?
If these infections
triggered the condition of ME/CFS, then clearing the infection would not cause ME/CFS to disappear, because a trigger has this irreversibility.
Whereas if these infections are
causing and maintaining ME/CFS, then clearing them would result in ME/CFS being cured.
So the fact that the ME/CFS disappears on clearing infections like parvovirus B19 or Coxiella burnetii suggests these pathogens are ongoing
causes, rather than
triggers of ME/CFS.
Or can you suggest an alternative interpretation of this?
I know few researchers seem to want to call parvovirus B19, Coxiella burnetii or Chlamydia pneumoniae
known causes of ME/CFS (except Dr Chia, who entitled one of his papers as:
Chronic Chlamydia Pneumoniae Infection: A Treatable Cause of Chronic Fatigue Syndrome); however, the evidence for a causal role seems reasonable to me.
Similarly with enterovirus. Although you unfortunately cannot at present eradicate chronic enterovirus infections in ME/CFS, you can greatly reduce viral loads using interferon. Once the enteroviral loads are so reduced, you often find ME/CFS disappears, at least for a few months to a year, after which the virus returns, and so do the ME/CFS symptoms. One of Chia's papers on interferon treatment of ME/CFS is
here, and he also talks about interferon in his major studies on enterovirus and ME/CFS
here and
here.
John Chia got similar results with the immunomodulator oxymatrine: in some patients, this herbal extract dramatically reduced viral loads, and led to huge improvements in ME/CFS (you can see Chia's before and after pictures of stomach tissue enteroviral load reduction due to oxymatrine treatment in my post
here). In patients who got much better but then discontinued oxymatrine, their ME/CFS returned.
So to me these observations suggest that enteroviral and other infections are not a
trigger of ME/CFS, but an
ongoing cause, which once eradicated, leads to cure / remission of ME/CFS.
Again, if you have an alternative explanation or hypothesis for this data, please do elaborate. To me it seems like reasonable evidence of a
causal rather than
triggering role of enterovirus (and the other above infections) in ME/CFS.
I think we may be defining chronic/persistent infections differently. I think of chronic infections as being more like HIV or herpesviruses - i.e. for life. This is not the general understanding of how enteroviruses work. It may be that in a few cases, in people with severe immune dysfunction, what would normally be cleared could become chronic, but I've never seen anything very convincing. If you have a link to published research I'd be happy to look at it, but it's definitely against conventional medical understanding of enteroviral infections - they are viewed as infections that either you clear or that kill you.
Coxsackievirus B3 is, as you mention, a cause of cardiac infection and ultimately, in some cases, DCM. B4 is associated with diabetes. Usually, however, most of the damage occurs early on, and there may then be a low level persistence of a virus in a non-lytic cycle, but eventually the infection is cleared. Even then, it can stimulate an autoimmune response which probably plays some role in long term disease progression. Sometimes it can take years to clear enteroviral infection (probably up to 3 or so).
I too am defining chronic/persistent infections as ones that stay in the body for life.
I don't actual know how long CVB myocarditis and dilated cardiomyopathy can last, and whether they can last a lifetime, so I am not sure if these can be examples of a lifetime CVB infection.
In adult type 1 diabetes, though, there are many studies that have found enterovirus / CVB / echovirus antibodies or RNA. I have just been looking through these, ignoring studies that examined recent-onset or juvenile diabetes (because the presence of enterovirus in these cases might just be a short-term presence), and instead I just fished out a few studies which found enteroviral RNA in longer-term diabetes patients. Some of these studies, listed as follows, are at least suggestive of a lifetime presence of this virus in the body:
Type 1 diabetes is associated with enterovirus infection in gut mucosa
Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies
Detection of enteroviruses in the intestine of type 1 diabetic patients
I'm not sure I believe in the existence of persistent, non-lytic enteroviral infection. I can't rule out the possibility, but it doesn't really seem to fit with our understanding of how the viruses work. For one, they cannot incorporate into cellular DNA, as they have no DNA at all. Herpesviruses can (they are DNA viruses) and so can HIV or other retroviruses - they can convert their genomes to DNA with reverse transcriptase. At no point in the enteroviral life cycle is it DNA.
Therefore, where is it stored? How does it exist over the long term without triggering normal cellular responses? RNA should be triggering various PRR's / TLR's. Protein Kinase R would be triggered, MHC expression would be upregulated, etc. It doesn't seem to make basic virological sense. That doesn't mean it can't happen, but rather that I'd have to see a lot of evidence before I was convinced, and a lot of questions would have to be answered.
As you undoubtedly know, very few viruses can incorporate themselves into human DNA, and as far as I am aware, most lifelong viruses use genetic episomes as their latency mechanism.
Though enteroviral non-cytolytic infections are not quite the same as a latency state; these non-cytolytic infections are active, albeit low-level "smoldering" infections.
I have not come across any articles or studies indicating scientific doubt about the existence of non-cytolytic viral infections.
I believe non-cytolytic infections are similar to (or possibly the same as — but I am unclear on this)
defective interfering viruses. Dengue virus is an example of an infection that comprises both a defective interfering virus as well as a regular virus in tandem. See this article:
'Defective' virus surprisingly plays major role in spread of disease, UCLA life scientists report | UCLA
Non-cytolytic enteroviruses comprise both viral ssRNA and dsRNA, and live in the cell's cytoplasm. These RNA strands are able to resist eradication by the cell's immune system because:
(1) dsRNA is very hardy, and the immune system has trouble destroying this.
(2) ssRNA is easier to destroy; however, as is well known, the RNAse L enzyme responsible for destroying ssRNA is dysfunctional in ME/CFS patients (this enzyme is unfortunately cut up into smaller ineffective pieces in ME/CFS patients), so that make it harder to fight non-cytolytic infections. If you Google
RNAse L chronic fatigue syndrome you'll find lots of info on this.
Also, CVB3 down-regulates MHC expression in order to make infected cells invisible to CD8 T cell surveillance (ref:
here).
More info on non-cytolytic enteroviruses:
This was a groundbreaking study of its time:
Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA
The above study found that whereas in normal enterovirus infections in human cells, the positive strand RNA out numbers the negative strand RNA by around 100 to 1 (the -strand is the template, and the +strand the copies of the viral genome), in the muscles of ME/CFS patients, there was approximately equal the amounts of positive and negative strands. This is in fact characteristic of non-cytolytic infections, and what is thought to happen is that many of the positive and negative strands then join to form this very hardy dsRNA.
If you want to search the Internet, using various synonyms for non-cytolytic enteroviruses, see
here.
Non-cytolytic / non-cytopathic / defective / terminally-deleted enterovirus — MEpedia
As an aside: in EBV latency, partial reactivation
can occur in some ME/CFS subsets, where some viral proteins are produced. So in ME/CFS, EBV may also be in active state, but without necessarily producing viral particles.
Also, in interpreting Coxsackievirus antibodies, the body actually stops making them pretty early after infection, suggesting there is no persistence of antigen.
I think the antibodies drop to a very low level soon after the acute infection, but I know that when Dr Chia uses ARUP Lab, he reliably finds antibody titers in ME/CFS patients. And several studies have found CVB / echovirus antibodies in a large percentage of the general population:
This study found coxsackie B virus IgG antibodies in 55% of the population in Scotland.
This study found coxsackievirus B pretty prevalent in the general population in Greece. And
this study found various coxsackievirus B and echovirus species pretty prevalent in infants in Norway.
Everything I've seen though is that despite many attempts to show long term persistence of enterovirus infection, we have failed to do so. Yes, they can cause permanent disease states, but that is not the same as permanent infection.
Are you saying that in chronic disease states, you can find chronic CVB, whereas you don't think there is evidence for chronic CVB in healthy people?
Certainly there is no question that you can detect enterovirus RNA in chronic CVB myocarditis, ME/CFS, and in type 1 diabetes.
But if I understand you correctly, you are saying that there is no evidence for lifetime enterovirus infections in healthy people without diseases. By evidence, I presume you mean finding enteroviral RNA in the body (as opposed to enteroviral antibodies, which perhaps might persist even if the enterovirus infection was eradicated).
OK, well I have been Googling on this, and all I have found so far in terms of evidence of chronic lifetime enterovirus in healthy populations is the following:
• Many decades after being infected with poliovirus, around 30% of polio victims experience post polio syndrome later in life, and some studies have found poliovirus RNA in the CNS in these people (ref:
here).
• Long term persistence of coxsackievirus B infection in the brains of mice: mice infected with CVB as neonates still have the virus present as adults:
Viral persistence and chronic immunopathology in the adult central nervous system following Coxsackievirus infection during the neonatal period
The pathogens you list would cause dramatically different syndromes. The fact that people with ME share symptoms implies shared pathology - some sort of immune dysregulation makes the most sense to me, and the research supports it reasonably well (or at least is consistent with it) - although the precise nature remains unclear. EBV doesn't look clinically like c. pneumoniae infection, yet ME triggered by each looks pretty much the same.
Absolutely. If these diverse pathogens can cause/trigger ME/CFS, there must be a good explanation as to why they all produce very similar or identical ME/CFS symptoms and pathophysiology.
The best theory I have come across with the power to explain this is
Michael VanElzakker's vagus nerve infection hypothesis of ME/CFS.
In case you are not familiar with this theory: VanElzakker points out that
sickness behavior has very similar symptoms to those of ME/CFS, and that sickness behavior can be switched on by nerve signals sent to the brain via the vagus or trigeminal nerves, when either of these nerves sense infection and inflammatory cytokines in the body.
VanElzakker hypothesizes that a chronic infection of the
vagus nerve itself, from one of these ME/CFS-associated pathogens, would result in the vagus nerve constantly sending inflammatory signals to the brain, thereby permanently switching on sickness behavior, and thus constantly causing the symptoms of ME/CFS.
In VanElzakker's theory, it's not so much the type of pathogen that is important; it's simply whether that pathogen infects the vagus nerve or not.
Whether this intriguing theory is true or not remains to be seen. However, the remarkable thing about this theory is that it does offer an explanation of how ME/CFS may be caused/triggered by disparate pathogens, yet looks pretty much like the same disease in every case.
