Which doctor is right about chronic EBV?

Patrick*

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I'm at a complete loss whether to treat chronic EBV, and I have two doctors recommending different things. I don't know which one to believe, so I'm hoping PR will have some opinions. If you make it through this long explanation, thank you!

Background: Since getting ME in 2011, I've always had positive IgG tests for EBV, with titers that are perhaps considered equivocal for possible reactivation. I've been on an off antivirals such as Famvir, Acyclovir and Valacyclovir since 2011 and never noticed much of a difference in how I felt. The drugs never made a difference in the antibody levels either.

Over the past 12 months, however, I have also had 5 tests that were positive IgM for EBV. This got my attention more than the IgG because it's more suggestive of an active re-infection as opposed to relying on interpretation of IgG results. Now I have two doctors giving me opposite interpretations and both seem logical. I don't know who to believe and whether to focus on treating EBV.

Doctor 1: She is an integrative medicine doctor who doesn't necessarily focus on ME, but treats many patients with Lyme, mold sensitives, MCS, etc. While she has been useful for treating hypothyroid and a few other treatments, her judgment and medical knowledge can seem questionable. A couple of times she has suggested treatments that have no basis in science and seem to be almost quackery.

She is the one who's been ordering the repeated EBV IgM tests and she, at my suggestion, put me on the doctor Lerner antiviral protocol a couple/few months ago. This protocol involves high doses of Valacylovir: 1 gram, 3x/day. [Edit: the official protocol is actually 4x/day but I was only taking 3.]

Doctor 2: Doctor 2 is known as one of the better infectious disease specialists in my area, but she is very much from the traditional school of medicine. Although she is a former partner of the famous Dr. Chia, she doesn't know the first thing about ME. She took one look at the repeated IgM+ results and said they are false positive. (This was consistent with my original understanding of how IgM antibodies work--that they are only present during the first 3-14 of an infection.) She said she didn't need further convincing, but if it would help convince me, she would order a PCR test for EBV. I accepted. The PCR test came back negative.

At first I thought the negative PCR test settled the issue once and for all: I don't have active EBV. But then Doctor 1 said those results don't mean anything -- or rather that they just mean the virus isn't in that one sample of blood, but the virus could be in other parts of the body.

Dr. Chia, by the way, also thinks the IgM test results are false positive. It's two doctors with good reputations against one who is, in my opinion, questionable. But then again, why me (why us)? I would bet a normal healthy person wouldn't keep triggering positive IgM results.

I can't decide who's right. Any thoughts would be appreciated.
 
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Ema

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Lerner antiviral protocol a couple/few months ago. This protocol involves high doses of Valacylovir: 1 gram, 3x/day.
Dr Lerner actually used 4g/day for the majority of his patients, either Valtrex or Famvir.

Do you have symptoms that are indicative of a viral reactivation? Swollen lymph nodes, fever, etc?
 

Galixie

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I don't have an answer, but maybe my experience will be of some benefit.

I consistently tested positive on all four EBV antibody tests (VCA IgG, VCA IgM, EA IgG, & NA IgG). Last June, when I spoke to a hematologist and happened to mention this fact, it peaked his curiosity and he reran the tests - which all came back positive again - and he also ran the PCR and EBV DNA tests. The new tests, which check for the virus in the blood, came back negative.

The hematologist consulted a virologist, who found it puzzling that I perpetually have positives on all of the antibody tests. According to the virologist, there is nothing to be done because the virus is not detected in the blood.

This makes sense to me because the antiviral drugs circulate in the blood and, if that's not where the virus is, they can't do much to kill it off.

Also, just thinking about it, if the virus were 'lurking' somewhere in the body, there is no place in the body that is not serviced by the bloodstream. So if the virus were really there, it would have to show up in the blood eventually. The fact that it doesn't would point more to an immune system dysfunction than an active virus. That's just my two cents.
 

BadBadBear

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This makes sense to me because the antiviral drugs circulate in the blood and, if that's not where the virus is, they can't do much to kill it off.
AV gets transported to cells which take it up, and when viruses in the cell try to replicate, they use the AV in replication and it causes replication failure. It is not supposed to be only killing viruses in blood. It doesn't kill viruses directly at all. Just prevents replication and your immune system does the virus killing when viruses emerge from latency.
 

Gingergrrl

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@Patrick* I will be doing a phone consult with my doctor later today and one of the main topics we will be discussing is EBV b/c at present, I am testing positive on PCR meaning (if the test is correct), I have virema and he will want me to go back onto an anti-viral to reduce it and stop it from replicating in the blood.

I know he plans to re-run the test first b/c the PCR is such a slight positive. The lab cut-off for positive is 100 and mine is only 110 (and it can go into the millions). Because it is so low, he wants to make sure it was not contamination or a false positive. But I assume if the second test is still 110 or has gone up, that he will put me back on Famvir. Vs. if it has gone down or is now negative, we will continue to monitor but I would not go onto Famvir.

In my case, I was IgM+ and EA+ for EBV for 3-4 yrs post mono (which I had in early 2012) but at this point, I'm almost certain that we cannot rely on antibody testing b/c I have done 1.5 yrs of IVIG (and still doing it now) so there can be false or passive immunity and therefore my antibody testing would not be considered accurate (vs. I believe the PCR testing would have no relation to IVIG and would be accurate).

For me the anti-viral would purely be to stop the viral replication and would not be for symptom relief. I have no symptoms of viral re-activation (but maybe no one would at such a low positive of 110, I do not know). I am now strongly on the autoimmune side (and we believe the initial EBV virus finally shifted into autoimmunity) which my immunologist confirmed but that is a separate issue.

Edited for typos and clarity
 
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ljimbo423

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At first I thought the negative PCR test settled the issue once and for all: I don't have active EBV.
Hi Patrick- You have probably heard of Robert Naviaux the CFS reseacher, here are some of his qualifications-

He is a Salk-trained virologist, and molecular and cell biologist, the inventor of the popular pCL retroviral gene transfer vectors, and was trained at NIH in tumor immunology and natural killer cell biology.
http://naviauxlab.ucsd.edu/team/

This is his view on high viral antibody levels in CFS-

Some doctors and scientists have not done a good job at educating patients and other scientists about the difference between serological evidence of infection in the form of antibodies like IgM and IgG, and physical evidence of viral replication like PCR amplification of viral RNA or DNA, or bacterial DNA.

We have learned in our autism studies with Dr. Judy Van de Water that supertiters of antibodies do not mean new or reactivated viral replication. Supertiters of IgG antibodies mean that the balancing T-cell and NK cell mediated immune activity is decreased.

This is a functional kind of immune deficiency that causes an unbalanced increase in antibodies. Increased IgG antibodies to CMV, EBV, HHV6, Coxsackie, etc. are not good evidence of a reactivated viral infection. This can be proven in most cases by trying to measure viral DNA or RNA by PCR in the blood or swollen lymph nodes. In most cases, supertiters of IgG are PCR-negative.
https://www.omf.ngo/2016/09/09/upda...-fatigue-syndrome-q-a-with-robert-naviaux-md/


I hope this is helpful.:)

Jim
 

Gingergrrl

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That is really interesting @ljimbo423 and it was not until very recently that I actually understood the difference between the antibody testing and PCR testing for viruses like EBV. I will report back after my consult (which is in about 1.5 hours) and probably type it in my Rituximab thread but try to link it to this one, too, for anyone who is following. My preference is not to go back onto an anti-viral but if I really have a positive PCR and it is going up (which it might not be), then I will consider it.
 

Hip

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At first I thought the negative PCR test settled the issue once and for all: I don't have active EBV. But then Doctor 1 said those results don't mean anything -- or rather that they just mean the virus isn't in that one sample of blood, but the virus could be in other parts of the body.
Positive EBV antibodies but negative PCR blood tests are often found in ME/CFS, and these can be explained by Dr Lerner's abortive infection hypothesis of ME/CFS.

Abortive infections are ongoing viral infection in the tissues, but where no new viral particles are created. So this may explain why antibody tests suggest an ongoing infection in ME/CFS, yet there are no viral particles to be found in the blood by PCR— because abortive infections do not produce any new viruses.

Abortive herpesvirus infections are analogous to enterovirus non-cytolytic infections: in both cases there is a continual ongoing infection in certain cells, but no new viral particles are made.



Over the past 12 months, however, I have also had 5 tests that were positive IgM for EBV.
Dr Lerner says that ME/CFS patients are positive for Epstein-Barr virus abortive infections when there are elevated antibodies in the EBV IgM VCA test and/or the EBV EA diffuse test by ELISA. Ref: 1 More info in the roadmap of chronic fatigue syndrome treatment.

Dr Lerner's protocol uses Valtrex or Famvir 1,000 mg four times daily, with it taking up to 2 years for the full benefits to manifest (although the first signs of improvement manifest around 3 or 4 months). More info here.
 
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Galixie

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This question might need to be a separate thread, but reading this discussion is what is making me wonder:
How would a non-replicating virus that is lurking inside an otherwise normal cell trigger the production of antibodies? Doesn't the virus have to be circulating to trigger the immune response of increased antibody production?
 

Patrick*

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These are very helpful responses, thank you all.

@Galixie, what your virologist said makes a lot of sense to me.

@ljimbo423 That is really interesting. I wonder if the findings re IgG supertiters are applicable to IgM as well.

@Ema Thanks for asking about symptoms. I forgot to mention that. I have on-and-off swollen lymph nodes but never a fever. I have had mono before ME and this just doesn't feel like that.
 

ljimbo423

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That is really interesting. I wonder if the findings re IgG supertiters are applicable to IgM as well.

Hey @Patrick* - Dr. Naviaux seems to include both IgG and IgM in this comment. Saying that they are not good markers for an active infection and that PCR amplification is.

I think what he is saying is that only PCR testing will give you a true understanding weather you have a viral re-activation or not.

Some doctors and scientists have not done a good job at educating patients and other scientists about the difference between serological evidence of infection in the form of antibodies like IgM and IgG, and physical evidence of viral replication like PCR amplification of viral RNA or DNA, or bacterial DNA.
https://www.omf.ngo/2016/09/09/upda...-fatigue-syndrome-q-a-with-robert-naviaux-md/

Jim
 

Hip

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How would a non-replicating virus that is lurking inside an otherwise normal cell trigger the production of antibodies? Doesn't the virus have to be circulating to trigger the immune response of increased antibody production?
I am not sure if a viral particle circulating on its own will trigger the creation of antibodies. However, I believe antibodies are created when virally-infected infected cells present some of the viral protein fragments (antigens) manufactured inside the infected cell to the immune system, by means of the major histocompatibility complex (MHC), which is located on the surface of the cell, and whose purpose is to present microbial antigens to the immune system.

@Jonathan Edwards will know much more about this.

I have only recent understood the significance of Dr Martin Lerner's abortive viral infection theory of ME/CFS, and this theory seems able to explain some of the observed phenomena of ME/CFS, such as the fact that many ME/CFS patients have high antibody titers, but very little virus is found in the blood, when you do PCR blood tests.

These two apparently contradictory facts have always been a paradox in ME/CFS; but an abortive infection can resolve the paradox.
 

Gingergrrl

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I just did phone consult w/my doctor and a good portion of it was re: EBV. I will post about it later in my Rituximab thread but he confirmed that the PCR is the "gold standard" test b/c it confirms that DNA particles of the EBV virus are in your blood and the result should be zero or negative.

If it is positive, unless it is a false positive, then you have viremia that should be treated with an anti-viral. But on the flip-side, he said that a negative PCR is not always accurate. My case is more complex b/c of having 1.5 yrs of IVIG so antibody titers are no longer reliable for me, but the PCR is unaffected by IVIG and is reliable. We are going to re-test the PCR and still check the IgM (b/c technically someone with IgM+ EBV should not be an IVIG donor) but in theory they could be so even the IgM is not fully accurate in my case.

There is a 1-100 score (at LabCorp) that is considered the "grey zone" but my doctor said that truly the PCR should be "undetectable" which mine is not at 110. Hoping this helps someone!
 

Hip

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According to the virologist, there is nothing to be done because the virus is not detected in the blood.

This makes sense to me because the antiviral drugs circulate in the blood and, if that's not where the virus is, they can't do much to kill it off.
From the ME/CFS perspective that virologist is not correct, because in ME/CFS it is believed the virus is in the cells of the body tissues, rather than the blood. In the case of enteroviruses, numerous studies taking muscle tissue or stomach tissue biopsies have demonstrated the presence of a chronic enterovirus infection in these tissues in ME/CFS patients, even though very little enterovirus is found in the blood in ME/CFS.



Regarding how antiviral drugs work: these circulate in the blood (there's about 5 liters of blood in the body), in extracellular fluids which bathe the cells of the body (about 15 liters of extracellular fluid in the body), and intracellular fluids which are found inside cells (about 30 liters in the body).

Not many antivirals have a direct killing effect (virucide) on the viral particles themselves; most antivirals work by mechanisms other than direct virucide of the viral particle. Antivirals typically work by thwarting the virus in its attempts to enter and replicate inside human cells. Viruses can only replicate inside cells, so if you block this, you fight off the infection.

Antivirals may work for example by preventing the virus from attaching and entering the cell; they may work by preventing the virus from uncoating once the virus has entered the cell; they may work by preventing the virus from replicating itself inside the cell. All of these mechanisms fight off the infection.
 
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ljimbo423

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@Hip Do you understand this?

Dr. Lerner seems to be saying two things here. That the HV leads to host cell dysregulation and host cell apoptosis without lytic replication.

Also that "Specific antiviral nucleosides, which alleviate ME/CFS, namely valacyclovir for EBV ME/CFS and valganciclovir for HCMV/HHV6 ME/CFS, inhibit herpesvirus DNA polymerases and/or thymidine kinase functions, thus inhibiting lytic virus replication.

New host cell recruitment thus ceases. In the absence of new herpesvirus, nonpermissive herpesvirus replication stops, and ME/CFS recovery ensues."

We propose that herpesvirus EBV, HCMV, and HHV6 immediate-early gene expression in ME/CFS patients leads to host cell dysregulation and host cell apoptosis without lytic herpesvirus replication. Specific antiviral nucleosides, which alleviate ME/CFS, namely valacyclovir for EBV ME/CFS and valganciclovir for HCMV/HHV6 ME/CFS, inhibit herpesvirus DNA polymerases and/or thymidine kinase functions, thus inhibiting lytic virus replication. New host cell recruitment thus ceases. In the absence of new herpesvirus, nonpermissive herpesvirus replication stops, and ME/CFS recovery ensues.
https://www.dovepress.com/a-paradig...expression-apoptos-peer-reviewed-article-VAAT

Jim
 

Hip

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Do you understand this?
Dr Lerner is saying that herpesvirus ME/CFS is caused by an abortive infection in certain cells (called non-permissive cells) which does not produce new viral particles (lytic replication), but there is also a small degree of a regular herpesvirus infection which does produce new viral particles as per normal.

As current antivirals cannot directly target the abortive infection, Lerner says the best you can do is target the regular infection. That will inhibit the regular infection from producing new viral particles, and in the absence of new viral particles, he thinks that you will not get any more abortive infections (in non-permissive cells) seeded by these new viral particles, and so eventually the abortive infections will dwindle.

So in that way, the theory is antivirals do not directly target the abortive infection, but target it indirectly.
 
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Jesse2233

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Given the contrasting opinions of doctors and researchers it may be an unanswerable from a scientific standpoint

From a practical standpoint I suppose it’s a risk / benefit decision. There’s a chance Lerner / Montoya etc are right and latent EBV / HHV are driving symptoms and may respond to antivrals. They of course could be wrong and Naviaux / Chia / Davis could be right.

From what I’ve seen Famvir, Valtrex, and even Valcyte are unlikely to cause long term harm if discontinued after side effects appear. If it were me, I’d cautiously “bet” that Lerner / Montoya are right and try the safest antiviral (likely Famvir) while monitoring labs and keeping in mind the other researchers dissenting views.

The upside is you improve substantially and possibly recover over time, the downside is you have some unpleasant side effects, spend some money / time / hope, and nothing else happens
 

Hip

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From a practical standpoint I suppose it’s a risk / benefit decision. There’s a chance Lerner / Montoya etc are right and latent EBV / HHV are driving symptoms and may respond to antivrals. They of course could be wrong and Naviaux / Chia / Davis could be right.
None of these theories about the nature of ME/CFS are mutually exclusive: you could have enterovirus-associated ME/CFS and respond to Dr Chia's oxymatrine / Epivir treatment, or you could have herpesvirus-associated ME/CFS and respond to the herpesvirus antivirals given by several ME/CFS doctors (the late Dr Lerner, Montoya, Peterson, Klimas, and others).

Or you could have both enterovirus and herpesvirus infections and thus presumably would benefit from both enterovirus and herpesvirus treatments given simultaneously.

The ME/CFS metabolic dysfunction investigated by Naviaux, Davis, Myhill, etc could conceivably be just downstream effects of the chronic abortive herpesvirus or non-cytolytic enterovirus infections, so these ideas are not mutually exclusive.

The problem with these metabolic dysfunction theories of ME/CFS though is that they have no corresponding treatment like the viral theories do.



Everyday infectious disease specialists do not understand the viral theories of ME/CFS. These specialists are taught that chronic viral infections can only exist in the form of an active infection producing viral particles, such as occurs in untreated HIV for example. HIV is a classic chronic viral infection they can understand.

But most infectious disease specialists do not know about for example the intracellular non-cytolytic enterovirus infections that smolder away slowly within cells and do not produce any viral particles, even though such infections have been shown to occur in ME/CFS, chronic coxsackievirus B myocarditis, and may also be the cause of type 1 diabetes.

So most infectious disease specialists, if they do not find any evidence of a viral infection producing actual viral particles (detected by PCR or viral culture blood tests), they will assume there is no chronic infection, which is a wrong assumption, as we know that intracellular non-cytolytic enterovirus infections exist in ME/CFS and other diseases.


Thus lack of understanding has had tragic consequences for ME/CFS, and was the reason the original British enterovirus theory of ME/CFS was discounted in the US, because of negative PCR results. Thankfully Dr Chia has taken up the enterovirus cause.
 
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