Anatomy of an enterovirus / Coxsackie B virus outbreak — overt illnesses and subclinical symptoms

[Wonkmonk]

Would it make sense to start an own thread for this topic so it's more visible and more people may want to comment?

 

[Wonkmonk]

It's available as a generic medication in Germany. 2000mg costs €193.

https://www.docmorris.de/gemcitabin-hexal-40-mgml-2000-mg-konz/07395668

It's also available as 200mg for €29 for lower dosing.

https://www.docmorris.de/gemcitabin-hexal-40-mgml-200-mg-konzh/07395467?sc=PKV

 

[Wonkmonk]

However, the authors suggest that these tentacle-like protrusions may be co-opted by non-cytolytic CVB infections in order to transmit the infection into adjacent cells. The authors suggest non-cytolytic viruses may induce cellular protrusions to create a bridge to adjacent cells, which they then cross, so as to be able to infect nearby cells.

This seems to be a rather slow process compared to lytic infection and might explain why ME/CFS progresses slowly in some patients.

 

[Hip]

Would it make sense to start an own thread for this topic so it's more visible and more people may want to comment?

I am still looking into gemcitabine at the moment, trying to figure out whether this drug would be a viable treatment for ME/CFS.

For antiviral purposes in ME/CFS, it's likely that you would need to take this drug indefinitely, otherwise the enterovirus infection may return. This is often what is observed in antiviral treatment of ME/CFS. Although sometimes ME/CFS patients do make permanent improvements after a long course of antiviral treatment, ie, improvements that are maintained after stopping the antiviral.

I am not sure what the implications of taking such a chemotherapy drug indefinitely would be, even at say 10th of the normal dose. But if a short course of gemcitabine could lead to permanent improvements in enterovirus-associated ME/CFS, then it makes the treatment more viable.

It's also something that would best be done under research study conditions, as you need a qualified medical professional perform the infusion once weekly, and you need to have your white and red blood cells and platelets monitored (if they decrease, it puts you at risk of anemia and life-threatening infections — apparently during chemotherapy minor infections can become life-threatening in a matter of hours if left untreated).


Note that it is conceivably that the reduction in white blood cells (immune cells) may actually negate the antiviral effect, because the weakened immunity may allow the enterovirus infection to proliferate. Gemcitabine has potent antiviral effects in vitro in an isolated cell line infected with CVB3 replicons; but in vivo, gemcitabine can reduce white blood cell counts, weakening immunity, which may in part counter the antiviral effect.

This paper says that the incidence of severe neutropenia (= low neutrophils, the most common white blood cell) during gemcitabine treatment was 17%.

It's possible that using a 10th of the normal dose may minimize these effects on white blood cells; but you would want this sort of thing to be monitored under research study conditions. It would be interesting to see a study examining whether gemcitabine has efficacy for enterovirus-associated ME/CFS.

This seems to be a rather slow process compared to lytic infection and might explain why ME/CFS progresses slowly in some patients.

Non-cytolytic enterovirus infection has been described as a "smoldering" infection. It is a slow and gradual intracellular infection, but nevertheless very hard to get rid of.

 

[Wonkmonk]

For antiviral purposes in ME/CFS, it's likely that you would need to take this drug indefinitely

One could hope that an effective antiviral would allow patients to get off the drug after some time, like it seems to b the case with Valcyte etc.

But in the link you posted above, it says it is only gien for 3 consecutive weeks. It doesn't say if the side effects limit treatment duration or if it is not needed for more than that amount of time.

Regarding the side effects, it is also important to note that these were studied in cancer patients whose health is already severely compromised and some of whom might receive additional toxic drugs.

 

[Wonkmonk]

Gemcitabine, a broad-spectrum antiviral drug, suppresses enterovirus infections through innate immunity induced by the inhibition of pyrimidine biosynthesis and nucleotide depletion.

https://www.ncbi.nlm.nih.gov/pubmed/29383162

 

[Wonkmonk]

It seems to have a pretty broad antiviral spectrum, also active against HIV, rhinovirus and influenza:

https://www.ncbi.nlm.nih.gov/pubmed/28705625

http://aac.asm.org/content/56/4/1942.full

http://www.jbc.org/content/287/42/35324.full

"Gemcitabine efficacy was observed at doses as low as 1 mg/kg/day in the absence of toxicity." (in mice)

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015840

 

[Kenshin]

Great post Hip, I now realize I have suffered with anhedonia and with memory/word recall. During the earlier stage of my illness, I had trouble with basic words and sentences. "Boiling the kettle" would be something like: "doing the water heater thing." Sometimes I would even slur like I'm drunk.

But the anhedonia is worse, I think it's more deppressing than the fact that I'm bedridden.
Luckily, I've found pregabalin to help in this regard, it's no cure but gives some energy so
you connect with things and people more.
I want to try some of the things you've mentioned help, the hydrogen water sounds like a benign place to start.

 

[Hip]

But the anhedonia is worse, I think it's more deppressing than the fact that I'm bedridden.

I also find the anhedonia that my viral infection caused to be just as bad if not worse than my ME/CFS.

 

[Wonkmonk]

I was thinking about what speaks for and against my having the same or a similar kind of chronic enterovirus infection as described in this thread.

Speaks for enterovirus:

* As I remember the infection that triggered my CFS, it was exactly as described here. I also think I know the person I got it from and I became ill right on the next morning and I thought "wow, that was fast". It was a brief, cold-like illness, and I think I remember a sore throat, which resolved quickly. It was not too severe. I continued to work while sick (which may have contributed to the virus getting out of control).
* There is amazing congruity of almost all long-term symptoms mentioned here except anxiety/depression
* Very high dose anti-herpetic drugs had no substantial effect on symptoms (suggests it might not be a herpesvirus after all)

Speaks against enterovirus:

* I am very confident I know from which person I got the trigger infection in 2007 - she did not have CFS or, as far as I know, any of the symptoms mentioned here
* I have super high Herpesvirus IgG titers for HSV-1 (>1:20,000) and VZV (1:1000 - 1:3000), which suggests that there is in fact herpesvirus involvement
* No one in my family showed the symptoms mentioned here (so far) and no one else I know has them or has CFS * CVB4 is hypothesized here to be contagious if social interaction extends over a longer time, but it has not happened in my family and among my social contacts.

Unclear:
* Slow progression: Symptoms developed very slowly over 10 years, whereas onset of severe symoptoms after CVB4 is described here as happening much faster in a few months. However, with noncytolytic infection, there is a theoretical rationale for the possible existence of slowly progressing variants.

It is also very interesting that among the 30 CVB4 cases mentioned here, only one developed CFS (= Hip himself). And in that case (like in mine), there are abnormal herpesvirus titers present.

So maybe CVB4 causes a lot of nasty symptoms, but co-infection with out-of-control herpesvirus is needed for people to also get CFS.

 

[Hip]

I was thinking about what speaks for and against my having the same or a similar kind of chronic enterovirus infection as described in this thread.

Speaks for enterovirus:

As I remember the infection that triggered my CFS, it was exactly as described here.

I would not use the similarity of your circumstances to mine as a test for having chronic active enterovirus, because you could have chronic enterovirus even without experiencing the same circumstances.

First of all, the illnesses triggered by the virus I caught (illnesses described in the first post) as my virus spread to over 30 friends and family are likely caused by coxsackievirus B4, but I cannot be 100% sure of this.

Secondly, even if this outbreak of illnesses was due to CVB4, which I think is very likely, it is possible that the virus causing all this ill health may have been a particularly virulent strain of CVB4, in which case, you would not generally expect coxsackievirus B to produce so much illness.

I have talked to other ME/CFS patients with high antibody titers to coxsackievirus B, and most do not remember any outbreak of illnesses that occurred in their friends and family around the time that they first contracted their ME/CFS-triggering virus (although that may also be down to lack of observation and awareness). But at least one other ME/CFS patient I know with coxsackievirus B observed a very similar mini-epidemic of illness in the people around him, as his virus spread to others.

Another possibly is that CVB4 is one of the more virulent and illness-triggering viruses out of the 6 viruses in the Coxsackie B group; it is interesting that when Dr John Chia performed enterovirus antibody titer testing on healthy controls (in order to validate the ARUP Lab antibody tests), he found CVB4 titers would run higher in the controls than the other CVBs, suggesting that CVB4 is a more aggressive and more chronically active virus compared to other 5 CVBs.



But if you want to test for high titers to coxsackievirus B, the Hellenic Pasteur Institute in Greece provide a coxsackievirus B antibody neutralization test for €68.

Alternatively can get a coxsackievirus B and echovirus antibody neutralization test from ARUP Lab in the US: the coxsackievirus B and echovirus tests cost around $440 each.

It is difficult to find an antibody test by the neutralization method (other antibody testing methods such as ELISA, IFA and CFT are not as sensitive and reliable as the neutralization method for detecting the chronic active enterovirus infections found in ME/CFS. This is what Dr John Chia observed).

I also think I know the person I got it from and I became ill right on the next morning and I thought "wow, that was fast".

This very fast incubation period of less than 24 hours which your experienced I also observed on numerous occasions as my virus spread from person to person in my social group.

However, coxsackievirus B incubation periods are normally stated as the range of 3 to 5 days. So this does not quite match; although my guess is that if we are dealing with a more virulent CVB4 strain, the increased virulence may hasten the incubation time.

 

[Wonkmonk]

I would not use the similarity of your circumstances to mine as a test for having chronic active enterovirus, because you could have chronic enterovirus even without experiencing the same circumstances.

Yes, this is of course not a method to diagnose it. Given my serology and the prevailing theory of CFS etiology, I am still operating on the primary assumption that my CFS is herpesvirus-induced.

But I want to have an eye on enterovirus going forward. I'll probably do a blood analysis next week. Athe moment, I can't send my blood abroad for the more sophisticated tests. What tests would you recommend to perform in a normal lab?

 

[Hip]

Given my serology and the prevailing theory of CFS etiology, I am still operating on the primary assumption that my CFS is herpesvirus-induced.

In terms of published studies, there is probably more evidence of enterovirus in ME/CFS than herpesvirus. In the case of enterovirus, we know that chronic enterovirus infections are found in the muscle, intestine and brain tissues of ME/CFS patients, as tissue biopsies have proven this. We don't have this same level of evidence for herpesvirus infections in ME/CFS patient tissues.

In the US, I think more doctors are interested in herpesvirus infection etiologies just because they can offer a treatment for this (there are several good herpesvirus antivirals, but no good enterovirus antivirals; although the immunomodulator oxymatrine can be used to treat enterovirus).

What tests would you recommend to perform in a normal lab?

If you cannot get a coxsackievirus B and echovirus antibody test by the neutralization method, then possibly an antibody test by the ELISA method (enzyme-linked immunosorbent assay), also called EIA (enzyme immunoassay; ELISA is a specific type of EIA) might work, or an antibody test by the IFA method (immunofluorescence assay).

These may or may not pick up an active enterovirus infection, as their sensitivity and reliability is not as good as the gold standard neutralization method. I am not sure if ELISA and IFA distinguish between individual coxsackievirus B and echovirus serotypes: ie, they may tell you that you have an active CVB infection, but will not tell you which out of the 6 CVB serotypes is active.

An antibody test by the CFT method (complement fixation test) is useless for chronic enterovirus infections, so avoid this.

The coxsackievirus test at ArminLabs is pretty useless; it does not tell you on your test results or on the website, but this ArminLabs test only tests for CVB1 and CVA7. So avoid this one.

Athe moment, I can't send my blood abroad for the more sophisticated tests.

Is there any reason why you cannot send a blood serum sample abroad, to Greece for example?

 

[Wonkmonk]

Thank you for the information, very helpful as always.

Is there any reason why you cannot send a blood serum sample abroad, to Greece for example?

How would that work in Greece? At the Pasteur Institute, I didn't even find an English website. Also, given that blood samples would need to be sent to another country, I wouldn't be very confident of the result.

My lab does Coxsackie ELISA, but as I understand doesn't distinguish virus types. It says:

"The ELISA test system contains an antigen solution containing ECHO-Virus Type 6 and Coxsackie-Virus Type B5. These are sufficiently cross-reactive, so infections by other Enterovirus-Serotypes can also be detected." (own translation, only available in German)

Does it make sense to do this test?

 

[Hip]

How would that work in Greece? At the Pasteur Institute, I didn't even find an English website. Also, given that blood samples would need to be sent to another country, I wouldn't be very confident of the result.

For the ARUP Lab CVB antibody micro-neutralization tests, the stability of the serum at ambient temperature is specified as 48 hours. So if you use a 48 hour courier to send your serum to Greece, I would think that should be fine. Note that you need to send a serum sample (which is a yellow fluid), not a whole blood sample.

Their address is:

Public Health Laboratories
Hellenic Pasteur Institute
127 Vass. Sofias Ave
11521 Athens
GREECE

Does it make sense to do this test?

The problem here is not just the lower sensitivity of the test, but also the interpretation of that test.

Diagnosis of chronic active infection in the context of ME/CFS is done differently to diagnosis of active infection performed by regular infectious disease doctors.

In ME/CFS you diagnose chronic active infection when IgG titers are much higher than the average IgG titers that the general healthy population would get on the same test.

In the case of the ARUP lab tests, Dr Chia validated this for ME/CFS usage by noting the average titers that the general healthy population get on the ARUP CVB and echovirus tests. Then once Chia knew these average titers in the healthy, he was able to set the threshold titer for diagnosis of an active infection (the threshold is typically taken to be 4 times the average titers in the healthy). Dr Chia's threshold for diagnosis of active infection is 1:320 or higher in the ARUP tests (but in the case of CVB4 the threshold is 1:640 and higher).

If you take the Greek antibody neutralization test, although this test has not been validated by Dr Chia, one can hope that it will have a similar range to the ARUP tests (but this is not guaranteed), so that you can also use 1:320 as the threshold for diagnosis. However, with the ELISA and IFA tests, I am not sure if their titer ranges are similar enough to the ARUP test.


The same diagnostic issues also apply to herpesviruses in ME/CFS. Dr Daniel Dantini only diagnoses a chronic active infection in ME/CFS patients when IgG antibody titers are at least 4 times higher than the average IgG titers that a group of healthy people would get on the same test. Ref: here.

 

[Hip]

@Wonkmonk, I should add that this issue with viral testing in ME/CFS is a major problem: if you go to one of the small number of ME/CFS specialist doctors in the US, they are familiar and experienced with the testing lab ranges for the various pathogens linked to ME/CFS, so when these doctors see your test results, they are able to interpret them, as they know from experience (or from their own test validations) what constitutes high IgG titers.

But for those of us in Europe and elsewhere who cannot easily see one of the US ME/CFS doctors, there is no easy way you can interpret your viral test results. The lab cannot tell you the threshold for a chronic active infection, and non-ME/CFS doctors cannot tell you this either.

So the problem is that there is no easy way that an ME/CFS patient can get some viral testing done themselves, or through their local doctor, and then know whether they have an active infection.

I want to start a thread on this subject, because this difficulty in testing is a problem for all ME/CFS patients who cannot get to see an ME/CFS specialist doctor who is familiar with viral testing in ME/CFS.

 

[Wonkmonk]

It sounds a bit complicated to me, so I probably won't send to Greece right now, also because my primary hypothesis is still that I have a herpes virus problem. As I wrote before, my HSV-1 IgG titer is ">1:20,000", so it is to be considered elevated by any standard. But when Valcyte fails to be effective, I might well seek the more sensitive test from Greece.

 

[Hip]

I read a bit about gemcitabine and as I understand it, it has very broad and strong antiviral properties.

The broad-spectrum antiviral properties of gemcitabine do look interesting. It's not a very potent antiviral for normal lytic enteroviruses, but is pretty potent for non-cytolytic enterovirus. It works for enterovirus by inhibiting pyrimidine synthesis, thereby inducing interferon-stimulated genes. Ref: 1

This paper describes another antiviral compound which works by inhibiting pyrimidine synthesis, but that compound is not available.

 

[Wonkmonk]

I am very far from understanding the biochemistry behind these papers, but all the papers talk about a connection between pyrimidine and stimulation of the innate immune system. If I'm not mistaken, the natural killer cells belong to the innate immune system and those are one of the most consistent markers found to be depressed in CFS patients.

Could that be a possible avenue for further research?

Btw. here is another paper (if I understood it correctly):

https://www.ncbi.nlm.nih.gov/pubmed/25658737

 

[frederic83]

https://www.ncbi.nlm.nih.gov/pubmed/26427042

Gemcitabin can be used as a lytic inducer for EBV stomach cancer. In this cancer, EBV latent infection causes cancer. The strategy used to treat it consists of inducing the lytic viral cycle then target the virus with an antiviral, Valcyte mostly.


Can Gemcitabin be used for EBV in the case of an abortive infection (Lerner theory) or a latent infection in non cancerous cells to induce a lytic state and then use Valcyte to remove the virus ?

I doubt Gemcitabin will induce a lytic replication in non cancerous cell and probably not in every type of cells - we don't know for sure which cells are infected and the state of the infection in CFS regarding the EBV infection theory - but that should be tested in different cell lines on different infection states.