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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.



    Dr Chia's Calibration of the ARUP Lab Tests for Use in ME/CFS

    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: May 14, 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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  5. scienceshea

    scienceshea

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    Would anyone be able to offer some incite to these results?

    EBV VCA IGM - 78.60 H
    < 36.00 U /mL negative
    36.00 - 43.99 Equivocal
    > 43.99 Positive

    EBV VCA IGG - 194.00 H
    < 18.00 U/mL Negative
    18.00 - 21.99 Equivocal
    >21.99 Positive

    EBV EBNA IGG - 467.00 H
    <18.00 U/mL Negative
    18.00 - 21.99 Equivocal
    > 21.99 Positive

    EBV Early Antigen IGG - < 9.00
    <9.00 U/mL Negative
    9.00 - 10.99 Equivocal
    > 10.99 Positive
     
  6. rodgergrummidge

    rodgergrummidge Senior Member

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    In J CLIN MICRO, p. 3204–3210, Klutts et al. analysed 1,846 serum specimens derived from more than 800 patients for EBV serological profiles for a total of 32 possible serological combinations. In addition to the antibodies you have had tested, Klutts et al also examined Heterophile IgM antibody test for EBV. This is because the EBV-VCA-IgM antibodies can be cross reactive and so inclusion of the Heterophile IgM antibody test for EBV is important for differential diagnosis.

    The study found that your profile, EBV-VCA-IgM+, EBV-EBV-VCA-IgG+, EBV-EBNA-IgG+ and EBV-EA-IgG-neg occurred in 56 people (thus, it is a relatively uncommon profile) in which:
    • 1 was EBV naivve
    • 0 was primary acute infection
    • 42 had past EBV infection
    • 0 were recovery or reactivation
    • 13 were inconclusive
    Of course, a proper differential diagnosis would require additional clinical details and so it is impossible to determine what your serology pattern indicates unequivocally.The potential involvement of CFS would have a large bearing on any diagnosis. Also, your lack of Heterophile IgM serology reduces the accuracy of any potential diagnosis. But, taking into account these important caveats, the most likely possibility based on this large study is that you have had a previous EBV infection. The diagnostic accuracy identified for patients with your serology profile (again, taking into account the above caveats) was 75% (42/56) with most of the remaining samples 23% (13/56) being classed as inconclusive due to lack of clinical notes. So with additional clinical details and history, it should be possible for an infectious disease clinician to determine your diagnosis (or at least further investigate) with some confidence.

    One additional note: Many CFS practitioners try and claim that high antibody titres to EBV proteins indicate that the presence of chronic active EBV infections which are responsible for CFS. This is not the case. Chronic active EBV (CAEBV) infection is a life-threatening condition that is entirely different disease to CFS. CAEBV is serious condition requiring urgent medical intervention and is characterized by persistent fevers, lymphadenopathy, hepatosplenomegaly, persisting mononucleosis, anemia and/or thrombocytopenia and is associated with abnormal patterns of antibodies to EBV. Very high EBV antibody titres to latent or lytic proteins together with detection of EBV in serum can indicate the possibility of CAEBV. In general, CAEBV patients have low or absent EBNA Abs.

    Rodger
     
  7. scienceshea

    scienceshea

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    @rodgergrummidge

    Thank you for this excellent and extremely clear response!
     
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  8. SunMoonsStars

    SunMoonsStars Senior Member

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    I have had all 4 EBV antibodies positive for 4 years along with HHV-6 1:1280 and CMV 19 and Parvovirus 8.
    I have symptoms to match as attack to spleen and liver and lymphs as organs as well CNS as Meningoencephalitis.
    Horrid horrid. I used to me a typical CFS patient with the fatigue and severe post exertion malaise and such and then after a trip to Europe I was literally attacked by these viruses it seems at once like a monster. So scary. Ivig was used to keep me from just going inpatient. At the hospital. Symptoms are 80 prevent or more controlled but virus tests remain the same year after year.
    I have to get these down as they are trying to break through the ivig every day and we have had to increase it. Anti viral trial of Valtrex no good but trying valcyte and maybe Artensuate.
    IV ozone helped a ton until I slowed down and didn’t do it weekly and i needed higher and higher doses and veins said no more. And bank too.
    These viruses are strong !!!
    Once they surged so strong it’s been extremely hard to get back to Even pre attack typical CFS I was dealing with.
    Now I’m in a battle. It’s no joke. Doing ad many immune supports as I can and liver and nutritional injections and mushrooms and inosine and gcmaf and those things too all on top of ivig. I have derived like crazy prior to this and it worked really well and I resolved all my pain and other things. But these viruses are still on front line and not backing away. HHV6 May have been a bigger player than anyone caught onto as I read it can be the leader of the pack.
    Anyone agree with that ? I’ve read articles on HHV6 site and two experts say of HHV6 is not addressed the other viruses won’t calm.
    I am a total believer now that all the years of typical CFS was these viruses in a low grade flare but not to point of full attack which makes docs Leary to believe. Now that I have been full on with acute symptoms and even that acute attack is years long. It’s veey real ! I feel the virus attack all of me from organs to nerves to brain to skin to lymphs and it’s a scary feeling. I hate that t took getting so severe to get attention of doctors that it’s real that these viruses are serious players.
     

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  9. JES

    JES Senior Member

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    I agree that viruses may be a factor in CFS, but it's likely not the viruses themselves that are the issue, more likely the immune dysfunction. As you mentioned HHV-6, it's a virus that nearly 100% of the population are infected with, and once a herpesvirus enters the body, it will stay there forever. A normal immune response manages to keep these viruses in latency without any issues. But for example if you catch something like HIV, your normal immune response doesn't work as well and suddenly these herpes and respiratory viruses may become an issue. I believe a bit of the same thing is going on in CFS, but for now there isn't very strong evidence to support the case for herpesviruses being the prime issue, actually there is more evidence for enteroviruses. Many people here on PR have tried antiviral treatments like Valtrex and they don't seem to be of much help. I reckon one or two regular users that have had moderate improvements. Anyway, wish you the best and hopefully you will find something that works for you.
     
    Last edited: Mar 1, 2018
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  10. rodgergrummidge

    rodgergrummidge Senior Member

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    Antivirals dont work in CAEBV so why would they work in post-EBV CFS? Its interesting that even in serious cases of Chronic Active EBV (CAEBV) infections where there is clearly detectable viremia in the peripheral blood (as well as in some tissues) that antiviral therapy is usually ineffective and patients develop progressive immunodeficiency, and usually succumb to opportunistic infections or lymphoproliferative disease (Blood. 117:5835). Thus, it would be extremely unlikely that antiviral therapy for those with post-EBV CFS (where there is no detectable viremia in the peripheral blood) would provide any significant clinical improvement.

    In fact, this is what the clinical trials indicate.

    Two independent placebo-based clinical trials by Montoya et. al. showed no improvement in physical or cognitive functions in CFS patients.
    1. In a 2012 trial publication, Montoya et. al. showed no difference in physical or cognitive symptoms (J. Med. Virol. 84:1967)
    2. In a 2013 trial publication, Montoya et al. showed that valganciclovir (1.8g/day for 21 days followed by 0.9g to complete 6 months) in CFS didnt provide any statistically significant improvement in the MFI-20 fatigue score in CFS patients when compared to placebo controls (J. Med. Virol. 85:2101–2109, 2013) There was a statistically significant improvement in the FSS fatigue scale, but it was miniscule (-0.06). Cognitive functions improved in both valganciclovir- and placebo-treated patients suggesting that valganciclovir provided no cognitive benefits. Furthermore, no significant improvements were found in valganciclovir patients according to CDC fatigue scores. Thus, according to several independent fatigue/cognitive measurement tools, valganciclovir did not improve CFS symptoms compared to placebo.
    So why are the Montoya et. al. trials so widely used to support the use of antivirals in post-EBV CFS patients (BTW, I'm not suggesting that Montoya et. al. are using the trials to beat their own 'anti-viral drum')?

    Well the devil is in the detail.

    Although the authors clearly indicated in their abstract that the "difference was not statistically significant", they proposed that the trajectory of their improvement was significantly better than the placebo patients. It is the "trajectory of the improvement" that the antiviral therapy proponents have latched onto to argue that antiviral therapies have clinical benefit in post-viral CFS.

    The Lerner trial using valacyclovir and/or valganciclovir is also sometimes proposed as evidence that antivirals may benefit post-viral CFS patients (Virus Adaptation and Treatment 2:47). However, this paper has a number of serious flaws that make it uninterpretable including the complete omission of a placebo control group! It is somewhat bizzare that the authors obtained ethical approval to conduct such a trial with no placebo group (OR a 'Standard of Care' treatment arm if the inclusion of a placebo arm was determined to be unethical:- which in this case it would not as there is no accepted Standard of Care for CFS). The paper claims to have cured CFS in most Group A patients (EIPS score >=6) but the claim is simply not supported by the data. It is probably because of these major flaws that the Lerner et al paper failed to be accepted for publication in a scientifically credible ISI Journal and was published in the DovePress magazine, Virus Adaption and Treatment. Certainly, clinicians should never use such 'easy-ride' publications to justify antiviral therapy for CFS (although some do!).

    Overall, there is little actual clinical evidence that antivirals provide significant improvements in physical or mental CFS symptoms. But it is probably not surprising given that antivirals dont even work in CAEBV where there is pathogenic ongoing active EBV replication.

    Rodger
     
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  11. Learner1

    Learner1 Forum Support Assistant

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    @scienceshea. I hope you are not dissuaded by rodgergrummidge's commentary which might lead one to the unfortunate and wrong conclusions.

    Your EBV results have several high values. They might suggest a past infection or they might suggest a reactivated and chronic infection. EBV is funny, especially in ME/CFS patients. It messes with the immune system, which doesn't always behave in a predictable way. Some patients have a deficient response, which has been confirmed in studies...

    http://simmaronresearch.com/2014/03/1591/

    The conclusion in the study was:

    And, if your immune system isn't working normally, studies have shown it won't respond properly either.

    I was in such a situation and, though I was tested several times my EBV infection was missed as I got sicker, my immune system became less able to fight infections, and I developed autoimmune POTS.

    Unfortunately, what you don't have is a PCR test which could help by showing that you have the DNA of EBV. My doctor found I had a high PCR and high VCA titers and found I ddefinitely had it.

    I started on Valcyte, and my brain fog began to clear and my fatigue lessened.

    This is not accurate. Montoya recommends that people stay on Valcyte for a long time. He has found it works and discusses it around 22:00 and 44:00 here.



    I think a lot of people suffer needlessly when their lab results are dismissed as past infections when they indeed have a chronic infection treatable with an antiviral.

    I'm sure glad my ME/CFS specialist found my EBV infection and treated it after many other MDs scoffed at my results.

    Best wishes...
     
  12. Dan_USAAZ

    Dan_USAAZ Senior Member

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    @rodgergrummidge , please clarify. Your conclusions appear to be in stark contrast to those in the published papers.

    Below is the abstract from the first paper you reference. Fifty-nine (59%) reported at least a 30% physical improvement and eighty-one (81%) reported at least a 30% cognitive improvement. How does this align with your conclusion of “no improvement in physical or cognitive function/symptoms”?


    Abstract
    Valganciclovir has been reported to improve physical and cognitive symptoms in patients with chronic fatigue syndrome (CFS) with elevated human herpesvirus 6 (HHV-6) and Epstein–Barr virus (EBV) IgG antibody titers. This study investigated whether antibody titers against HHV-6 and EBV were associated with clinical response to valganciclovir in a subset of CFS patients. An uncontrolled, unblinded retrospective chart review was performed on 61 CFS patients treated with 900 mg valganciclovir daily (55 of whom took an induction dose of 1,800 mg daily for the first 3 weeks). Antibody titers were considered high if HHV-6 IgG ≥1:320, EBV viral capsid antigen (VCA) IgG ≥1:640, and EBV early antigen (EA) IgG ≥1:160. Patients self-rated physical and cognitive functioning as a percentage of their functioning prior to illness. Patients were categorized as responders if they experienced at least 30% improvement in physical and/or cognitive functioning. Thirty-two patients (52%) were categorized as responders. Among these, 19 patients (59%) responded physically and 26 patients (81%) responded cognitively. Baseline antibody titers showed no significant association with response. After treatment, the average change in physical and cognitive functioning levels for all patients was +19% and +23%, respectively (P < 0.0001). Longer treatment was associated with improved response (P = 0.0002). No significant difference was found between responders and non-responders among other variables analyzed. Valganciclovir treatment, independent of the baseline antibody titers, was associated with self-rated improvement in physical and cognitive functioning for CFS patients who had positive HHV-6 and/or EBV serologies. Longer valganciclovir treatment correlated with an improved response. J. Med. Virol. 84:1967–1974, 2012. © 2012 Wiley Periodicals, Inc.
     
    Last edited: Mar 2, 2018
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  13. rodgergrummidge

    rodgergrummidge Senior Member

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    Yes @Dan_USAAZ . I didnt go into the Montoya et al antiviral 2012 CFS trial (J. Med. Virol. 84:1967) in any detail because the more expansive follow-up Montoya et al 2013 antiviral CFS trial showed no significant effects.

    But the Montoya et al 2012 trial has a number of key problems that are worth discussing, particularly in terms of what we might consider strong versus weak evidence. As we have learnt from the failed PACE trials, proposing new treatments based on poorly controlled data or incorrect data analysis can be a disaster.

    As you correctly point out, the abstract says: "Thirty-two patients (52%) were categorized as responders. Among these, 19 patients (59%) responded physically and 26 patients (81%) responded cognitively."

    Sounds impressive, but analysis of the actual data is problematic:
    • A strong clinical trial design involves a i) prospective study that is ii) double-blinded and iii) contains a control arm (either placebo or standard-of-care). The Montoya et al antiviral 2012 CFS trial (J. Med. Virol. 84:1967) study is a retrospective, non-blinded, non-placebo-based study making the results unreliable.
    • Such trials are usually only of use in justifying the next trial (which Montoya et al did with their follow up 2013 trial report) and would never be used to support any new treatment.
    • Another serious issue with the study is how the authors have collected their key data. Everything rests on how the physical and cognitive charateristics of CFS patients was measured. This is particularly important in non-blinded, non-placebo trials where there will be a whole range of influences that can confound or invalidate the data. Very strangely, the authors elected to use unreliable self-reported questionaires to 'measure' physical and functional levels in CFS patients. A human trial that is non-blinded, non-placebo-based and which uses subjective self-reporting questionaires to collect key findings is the worst possible combination of "ifs", "buts" and "maybes".
    • Another curious feature of the trial is how the authors justified selecting the best physical and cognitive improvements to be used in their analysis. They state that only the "highest levels [of improvement] after treatment (rather than the average of all available levels) were chosen in order to capture the largest effect of treatment on functioning." Anyone who understands CFS knows that symptoms can fluctuate widely and simply plucking the best (most improved) results, while ignoring all the bad results is extremely poor methodology and does not provides a valid or reasonable way to collect clinical trial data for CFS.
    • Also worrying, is that even when they took their selected best results, ~25% of patients became worse physically and ~20% of patients became worse cognitively (estimated from the data in Fig. 2C). Note that these deteriorations are different to "herxing" where it is suggested that some CFS patients initially get worse on antivirals and then get better in the longer term. In this case, patients just got worse with no improvement. Thus, anyone wishing to pursue antiviral agents based on this paper should consider the possibility that the antivirals may have toxicities (mitochondrial?) that might make them worse in the longer term.
    • Strangely, in their follow-up 2013 placebo-based antiviral trial, they argue the opposite in terms of data collection where they acknowledge that "CFS is characterized by a highly fluctuating clinical course; symptoms vary significantly on a daily, weekly, and monthly basis. Therefore, MEL regression models that make use of all data points appear to be more suitable to determine drug effect over placebo in CFS patients." Thus, in their first trial they selected their best data while in their followup trial, they took all data points. Regardless, there was no significant overall improvement following antiviral therapy in the second more comprehensive 2013 trial.
    Overall, it is difficult to conclude much from the 2012 CFS trial (J. Med. Virol. 84:1967). Certainly, the follow up placebo-based Montoya 2013 antiviral trial made it fairly clear that antivirals did not provide a major significant improvement in CFS physical or cognitive symptoms (as i outlined in detail in my earlier post). Such a conclusion is perfectly consistent with the known poor activity of antivirals in conditions where chronic EBV reactivation is clearly detectable (eg. CAEBV).

    I thought it important to highlight the PACE trials earlier because, as @jonathon edwards has correctly pointed out for the PACE trials, "..you can’t have an unblinded trial and a subjective outcome.The Montoya et al 2012 trail is, i) unblinded trial with a ii) self-reported and iii) subjective outcome. If we reject PACE for such flaws, shouldnt we also acknowledge the flaws in the 2012 Montoya et al antiviral CFS trial?

    Of course, future studies may provide convincing evidence that antiviral therapies significantly improve physical or cognitive symptoms in subsets of CFS patients either as a single agent or in combination with other drugs. But to claim that they work based on current clinical evidence is simply cherry picking the data that we agree with while ignoring any the data we disagree with. That is, our decisions would be clouded by our confirmation biases.

    A final important note: I am not suggesting that Montoya et al have made any false claims in regard to their clinical trial findings in either the 2012 or the 2013 trial papers. They interpret their data in a very responsible scientific manner. They certainly dont claim that their findings indicate that antivirals should be used in the treatment of CFS. Thus, unlike the PACE trials, Montoya et al have not embarked on an antiviral treatment program based on their un-blinded subjective outcomes in their trials (at least as far as i am aware). Unfortunately, I think the issue is that others have used the Montoya et al papers to support their antiviral treatment programs in CFS.

    Rodger
     
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  14. Learner1

    Learner1 Forum Support Assistant

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    As a patient, I am far more concerned with results than picking apart the minutiae of a trial.

    My ME/CFS doctor is part of the Stanford Center of Excellence and seems to be aware of all of the recent research.

    He put me on valganciclovir and my significant brain fog and cognitive dysfunction, which had been a debilitating factor in my life for 18 months, began to clear after 4 weeks on it. 8 months later, my head is clear, and my EBV and CMV PCRs went to 0 from being elevated last summer.

    Also, while I do value scientific studies, I haven't qualified for any myself due to the combination of drugs and supplements I'm taking which have helped me.

    Therefore, I find it impossible to compare myself to any study subjects, though my doctors and I read through the studies and make educated guesses of how they might apply.

    But, I also understand my results may be quite different, so sometimes, it takes a leap of faith to try something new, or conversely, throw out a potential treatment that worked for the study subjects which might work for me (like refusing radiation in my cancer treatment which was the standard based on much research, only to have my oncologist tell me 3 years after the fact that he's really glad I refused it, thstvid be an even bigger mess today if I'd gone ahead with it).

    So, studies will only get us so far. In the case of valganciclovir, it has been helpful for many of us, while in others, a different drug may be a better choice. There's certainly not a "one size fits all" treatment for this disease.
     
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  15. rodgergrummidge

    rodgergrummidge Senior Member

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    @Learner1 Unfortunately in your haste, you missed my key point:

    That is, "The potential involvement of CFS would have a large bearing on any diagnosis"

    Because the original post by @scienceshea only detailed serology and I made no assumptions regarding the involvement of CFS as I clearly indicated in my caveats above.

    My suggestions for interpretting the serology were based on high quality published research findings involving 1,846 serum specimens derived from more than 800 patients for EBV serological profiles for a total of 32 possible serological combinations (JOURNAL OF CLINICAL MICROBIOLOGY, Oct. 2009, p. 3204–3210). My evidence was not based on blogs or youtube videos.

    Of course persistent high IgM titres in the context of some clinical situations can be serious and should always be followed up with an infectious diseases clinician. I detailed at least some clinical scenarios to consider based on high and persistent EBV IgM titres here in an earlier post.

    Rodger
     
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  16. Learner1

    Learner1 Forum Support Assistant

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    Pacific Northwest
    You can certainly yell louder about this, but it still won't change the fact that a variety of combinations of titers have been found in patients with EBV due to a variety of issues with how the immune system is interacting with EBV.

    Unfortunately, some people may pay a high price if they're dissuaded from further investigation. I have, and it wasn't until it was found and treated that I began to improve. But, I still have the EBV autoimmunity that I didn't have 3 years ago to now deal with because the EBV wasn't found and treated sooner.
     

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  17. SunMoonsStars

    SunMoonsStars Senior Member

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    I’m with you!
     

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