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Positive EBV VCA-IgM for at least six months. false positive?

Discussion in 'Diagnostic Guidelines and Laboratory Testing' started by .jm., Jan 15, 2018.

  1. Hip

    Hip Senior Member

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    @rodgergrummidge, what I am saying is that chronic high titers are often found in ME/CFS patients, but nobody knows what these high titers signify.

    If you believe that the high titers simply reflect a past infection, that's a valid interpretation, but it is only an interpretation, not a fact as such.

    However, an equally valid interpretation is that there is an ongoing infection in the tissues of ME/CFS patients that causes the high titers. This is usually how the ME/CFS specialist doctors interpret the high titers.

    Here are Dr John Chia's validation tests for enterovirus antibody titers of 200 ME/CFS patients versus 150 healthy controls:
    Enterovirus antibody titers of ME/CFS patients versus healthy controls
    Dr Chia Invest in Me 2009 Conference- Antibody Titers.png
    Source: Dr John Chia, Invest in ME London Conference 2009​

    The healthy controls were typically healthy spouses or relatives of the patients who came into Dr Chia's clinic with the ME/CFS patient.

    As you can see, although lots of ME/CFS patients have antibody titers no different to those of healthy controls, there is an overall trend for ME/CFS patients to have higher titers than the controls. Several of the British research papers on enterovirus-associated ME/CFS found similar raised titers in ME/CFS.

    I agree that if an ME/CFS doctor finds high titers in his patients, this is not diagnostic of ME/CFS; but given Dr Chia's data above, high titers do help support the ME/CFS diagnosis.

    More to the point, high titers help indicate which antivirals/immunomodulators would be appropriate for the patient. If a patient has high enterovirus titers, then you would want a treatment that fights enterovirus. Whereas if the patient has high herpesvirus titers, then a herpesvirus antiviral will be needed.

    I believe that's the main reason ME/CFS doctors test for viruses; it's more to help select the right antiviral treatment, rather than for diagnostic purposes.



    But what evidence is there for ongoing infection in the tissues of ME/CFS patients? As I mentioned, in the case of enterovirus-associated ME/CFS, there is plenty of evidence of ongoing infection. If you look at this post listing the early British ME/CFS enterovirus research, and do a find on the word "muscle," you will pick up all the studies in that post that found enterovirus RNA in the ME/CFS patients muscles.

    In spite of there being enterovirus RNA in the muscles in ME/CFS, no virus could be cultured from the patients' muscle samples. Thus this shows the muscle infection in ME/CFS is not an ordinary productive infection, as it does not produce viral particles.

    We now know that this muscle infection is a non-cytolytic enterovirus infection, which is an abortive infection of sorts (non-cytolytic enterovirus infections are ongoing, but produce no new viral particles).

    Enterovirus researchers think that this non-cytolytic infection may be the cause of ME/CFS in the enterovirus subset. I started this thread to explain a bit about the non-cytolytic enterovirus.


    As regards evidence for abortive EBV, HHV-6 and cytomegalovirus infections in ME/CFS, there is very little at this stage. But I think you will agree that for enterovirus, there is good evidence.



    I believe in the case of coxsackievirus B dilated cardiomyopathy, which involves non-cytolytic infection of the heart muscle, high titers to CVB are often found. So this suggests that non-cytolytic infection can lead to high titers.
     
    Last edited: Feb 4, 2018
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  2. rodgergrummidge

    rodgergrummidge Senior Member

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    I wouldnt consider a slide from a talk provides strong evidence that high Ab titres reflect ongoing abortive infections. If CFS specialists were basing their diagnosis of ongoing infections on high Ab titres, surely there must be a publication?

    I went through these papers. Most were correlating viral titres (not antibody titres) to CFS which is not the argument here. The key claim is that ongoing abortive viral infections could lead to CFS and that diagnosis could be determined by high titres of antibodies to the virus in the absence of Virema.

    Some of your cited papers examine antibody titres to cocksackie viruses in CFS patients. However, they fail to compare antibody titres in CFS patients with a control group (eg this paper). High antibody titres in CFS compared to what? It is simply not possible claim that high antibody titres to Cocksackie are associated with CFS from such studies when control comparisons cannot be made.

    However, This paper includes a control group of patients but their key finding is: "A total of 12.5% had significantly raised CBV titres compared with 4-5% of 'well' control groups; the percentage positive was greatest (21%) in those aged 30-39 years." Clearly, based on these findings, raised antibody titres are simply not diagnostic for abortive replication in CFS.

    This is an interesting paper. However, the authors make no claim that high antibody titres were associated with persistent infection. They correctly associate specific serology profiles with either recent or distant infections (which serology can identify). Their interpretations were consistent with accepted diagnostic profiles that allow recent or past viral infection as I described earlier: that is, i) naive, ii) active infection, iii) past infection.
    "CBV serology The sera of 205 patients with diagnostic features of ME seen before 1985, were tested by NT: 68/205 (33%) had titres indicative and 35/205 (17%) suggestive of recent CBV infection. Subsequently, 124 patients were additionally tested by the enteroviral IgM ELISA system. Applying the diagnostic criteria established by McCartney et al.,7 38/124 (31%) had evidence of recent/active enteroviral infection. Sixteen patients in our study, who were retested annually for three years, showed persistently raised CBV NTs and intermittently positive enteroviral IgM."

    The above paper does make an interesting finding though. They found persistently elevated IgMs in a small subgroup of patients. A persistent EBV IgM was also reported by @.jm. at the beginning of this thread. As I mentioned earlier, such a finding might be simply due to nonspecific antibody cross reactivity (pasted table). But it could also point to other pathologies which i discussed and suggested the importance of followup additional investigations.

    So, if ME/CFS specialist docs interpret high antibody titres as indicating an ongoing active infection, there would be scientific publications to support such a diagnosis? I couldnt find any. Can you cite them?

    This is not true. Failure to generate viral particles may simply mean that the viral infection in the muscle cells is latent. Viruses have multiple latent programs that allow viral persistence in the absence of viral replication. Thus, such findings doesnt provide any evidence for abortive infection.

    how do you exclude latent infections? I agree that its an interesting idea, but I havent been able to find any studies that provide any evidence for such an idea.

    Again, nice idea, but its doesnt seem to be supported by any scientific evidence. At least from my searches.

    But I'm happy to be proved wrong

    Rodger
     
  3. Hip

    Hip Senior Member

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    In the case of enterovirus, they are not actually called abortive infections, but non-cytolytic infections. Non-cytolytic infections are technically not abortive infections, but are very similar in certain respects to abortive infections.

    So when we are dealing with enterovirus, non-cytolytic is the correct terminology to use.

    Non-cytolytic enterovirus infection is a complex subject. It took me many, many years of reading to get some understanding of it (and my understanding is still quite shallow).

    If you want to understand more, you really need to do some background reading. Getting hold of some of the excellent video presentations made by Dr Chia at the Invest in ME London conferences might be a start.

    The idea that non-cytolytic infection is the cause of ME/CFS is a hypothesis at this stage, but a viable one. If you have no interest in hypotheses, but only a fully proven theory of ME/CFS, then non-cytolytic enteroviruses are not for you.



    I did not say that the slide provides conclusive evidence that high antibody titers are due to the non-cytolytic enterovirus infection. The slide simply shows that ME/CFS patients tend to have high titers. How we interpret that fact is the question here.

    You seem to prefer to take the conservative standard view, that these high titers only reflect past infection; but that's just an opinion, and other interpretations are also possible. The other interpretation I have pointed out is that the non-cytolytic infection may be the cause of the high titers.

    Non-cytolytic enterovirus infections are a new discovery, shown to exist only in the last 15 or 20 years. Most doctors or medical researchers I don't think have even heard of them.

    If you want to read the background to the discovery of the non-cytolytic enterovirus, and how this virus relates to ME/CFS, I suggest this very good article by Prof Steven Tracy in the Invest in ME magazine.



    I've looked at many of these papers, and looked again at some of them just now, and all the ones I saw refer to antibody titers. Can you point me to any paper in which you saw viral titers?

    You are not going to have high viral titers at all, because in ME/CFS, there is very little enterovirus to be found in the blood.



    In some of the papers I listed, they did the groundwork of finding the typical CVB titer level of the general population. One of the studies in that list (can't remember which) examined 1000 blood samples of the general population, in order to determine typical titer level for CVB.

    Once you have this information, provided you use the same testing lab or testing technique, you don't need to use controls every time, you can refer back to older studies.



    Studies are often only published when you prove something (although medical hypothesis are also sometime published), and no ME/CFS doctor has been able to prove that the high titers represent an ongoing infection; but these doctors work on that assumption, which works well in a clinical setting.

    In other words, they get good results by treating ME/CFS patients with high titers with antivirals and immunomodulators, which is what doctors are all about: making patients better. When patients respond to such treatment, and their ME/CFS improves, you find that enterovirus high titers go down. Likewise, if treatment is stopped and the patient gets worse, then concomitantly enterovirus titers will go up. So in clinical practice, changes in titer levels correlate to the ME/CFS patient's changes in health level.

    And that fact that titers go down as a result of various antivirals or immunomodulators suggests that the high titers are due to an ongoing infection (which the antivirals will reduce), rather than just due to past infection. If the high titers were due to past infection, they would not be reduced by an antiviral.

    Dr John Chia is the only doctor that currently has major expertise in enterovirus-associated ME/CFS. He uses both antibody blood tests (by the gold standard micro-neutralization method provided by ARUP Lab) to diagnose chronic enterovirus infection in ME/CFS, as well as stomach tissue biopsy testing (immunohistochemistry) for enterovirus using the VP1 stain.

    More info on the Enterovirus Foundation website: Clinical laboratory tests for chronic enteroviral infections.



    Enterovirus is an RNA virus, and RNA viruses cannot undergo latency by the normal episomal mechanism:
    I have never heard of CVB being shown to enter latency, although I believe there is some debate about whether the non-cytolytic enterovirus might be a form of latency, but I don't fully understand that debate.



    See here where it says:
     
    Last edited: Jan 23, 2018
  4. .jm.

    .jm.

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    There was a paper published 10 years ago that identified a correlation of false positive for EBV IgM in patients with Parovirus B19. I suppose it makes sense to test for Parvovirus B19.
    http://cvi.asm.org/content/16/3/372.full

    What other viruses cause false positives for EBV IgM?
     
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