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Is ME an immunological disease?

Discussion in 'Immunological' started by Jonathan Edwards, Oct 7, 2018.

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  1. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    This thread has been split from here.
    As issues were quite intertwined, a number of posts have been copied. In copied posts, text not related to this topic has been greyed.



    This makes sense to me, but I am a bit more optimistic. CCC is probably not ideal for clinical classification but I think the IOM proposal at least indicates a fresh look with PEM as a focus. My impression from talking to scientists in the UK (as apposed to babblers of various sorts) is that CCC is seen as good for research and IOM as good for the clinic. We should expect the two to require different criteria. (No scientist is going to use NICE fortunately.)

    I agree that CFS has the disadvantage that it conflates with CF. But ME for me also has the disadvantage that it is conflated with the 'outbreak illnesses' that are the source of the spurious 'encephalomyelitis' word.


    A lot of competent research is now being done on the immunology and pretty much all the original immunological claims for ME, as a chronic disabling illness, have failed to stand up. The best experiment done recently was the Norwegian phase 3 trial which came out negative. We have some evidence of microglial activation but that is nowhere near 'encephalomyelitis' and even if it is confirmed I doubt it merits being called 'inflammation' or even 'immunological'. So the ICC idea of 'neuroimmune exhaustion' looks to me very much like a fantasy.


    I also doubt that the criteria are of any practical use because almost all the categories have a soft option that you can tick if you want to.

    So I see SEID as a potentially useful way of getting away from CFS=CF and ME=a neuroimmune disease that never existed. I still like ME as a name because it is widely accepted and it will do fine if the focus is on PEM. But I don't see a code for SEID along side it doing any great harm.
     
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  2. strategist

    strategist Senior Member (Voting Rights)

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    Is sore throat seen as evidence for some immunological process? I think it could also could also be a form of gastric reflux (presumably resulting from autonomic dysregulation). Which would align more with the idea that autonomic dysregulation is really to blame for a lot of symptoms.
     
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  3. Colleen Steckel

    Colleen Steckel Established Member (Voting Rights)

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    The immune issues in ME go far beyond the sore throat mentioned in SEID. There are multiple studies showing B cell, Th1 Th2, NK cell function issues to name a few.

    The support group I run created a cheat sheet for the immunological issues to look for. Here is a bit from that cheat sheet.

    IMMUNE ABNORMALITIES:
    · Chronic Immune Activation (5, 6, 14) · Increased inflammatory Cytokines (5, 7) · B cell abnormalities · Increased rate of active HHV-6, HHv-7 and B19 infection (15) · Immune Functional Defects (8, 9, 10, 12) · Th1 shift towards Th2 dominant response (11) · TRPM3 activity and function in NK cells in CFS/ME patients is impaired (16) · Decreased NK cell signaling, function, & cell cytotoxicity (8, 14) · Chronic enterovirus of the stomach (13) · Intestinal dysbiosis (18) · Sensitivities to food, medications, alcohol or chemicals · Bad reactions to vaccines (IC Primer page 20) · impairments in CD8+ T cells (17)

    If you want to see the full sheet go to here, I can get you the link. (It won't post here).
     
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  4. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I discuss the detailed situation with immune abnormalities in ME with Jo Cambridge in the lab on a more or less weekly basis. None of these findings has held up so far. There are some new findings in MAIT cells and B cells that again need replicating but the ones in the literature have failed to replicate. We need a scientific basis for ME but not a phoney scientific basis built on weak data.
     
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  5. Colleen Steckel

    Colleen Steckel Established Member (Voting Rights)

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    Can you clarify for us which of these listed below have failed to replicate?
    Is there an assurance you can give that the people who these did not replicate in would fit the ICC?

    Could it come down to we are talking about 2 different patient populations. As the IOM states CFS and ME are two different conditions. We need to make absolutely sure when making blanket statements like "none of these findings held up" that we are all on the same page about which patient population is being discussed.

    When I say "ME" I am specifically referring to those who have immune system abnormalities as described in the ICC. I definitely have multiple immune system abnormalities - which is why I identify with the ICC (Please ignore the numbers - this is taken from a list of immune studies from a cheat sheet from my support group.)

    2. Why (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. https://www.ncbi.nlm.nih.gov/pubmed/20038921
    3. Elevated brain natriuretic peptide levels in CFS associate with cardiac dysfunction: a case control study http://openheart.bmj.com/content/openhrt/4/2/e000697.full.pdf
    4. Decreased oxygen extraction during cardiopulmonary exercise test in patients with CFS. https://www.ncbi.nlm.nih.gov/pubmed/24456560
    5. A formal analysis of cytokine networks in CFS. https://www.ncbi.nlm.nih.gov/pubmed/20447453 (2010)
    6. CFS: clinical condition associated with immune activation. https://www.ncbi.nlm.nih.gov/pubmed/1679864 (1991)
    7. Cytokine signature associated with disease severity in CFS patients https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576836/ (2017)
    8. Immunologic abnormalities in CFS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC267940/ (1990)
    9. Elevation of bioactive transforming growth factor-beta in serum from patients with CFS. https://www.ncbi.nlm.nih.gov/pubmed/9083892 (1997)
    10. Immune and hemorheological changes in CFS https://www.ncbi.nlm.nih.gov/pubmed/20064266 (2010)
    11. Evidence for T-helper 2 shift and association with illness parameters in CFS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018761/ (2011)
    12. Immunological abnormalities as potential biomarkers in CFS/ME. https://www.ncbi.nlm.nih.gov/pubmed/21619669 (2011)
    13. CFS is associated with chronic enterovirus infection of the stomach. https://www.ncbi.nlm.nih.gov/pubmed/17872383 (2007)
    14. CFS: inflammation, immune function, and neuroendocrine interactions. https://www.ncbi.nlm.nih.gov/pubmed/18177602 (2007) also found at: https://link.springer.com/article/10.1007/s11926-007-0078-y
    15. ME/CFS and GWI patients exhibit increased humoral responses to the herpesviruses-encoded dUTPase: Implications in disease pathophysiology. https://www.ncbi.nlm.nih.gov/pubmed/28303641 (2017)
    16. Impaired calcium mobilization in natural killer cells from CFS/ME patients is associated with transient receptor potential melastatin 3 ion channels http://onlinelibrary.wiley.com/doi/10.1111/cei.12882/full (2016)
    17. A Preliminary Comparative Assessment of the Role of CD8+ T Cells in CFS/ME and Multiple Sclerosis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736227/ (2016)
    18. Increased D-lactic acid intestinal bacteria in patients with CFS. http://iv.iiarjournals.org/content/23/4/621.long (2009)
     
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  6. strategist

    strategist Senior Member (Voting Rights)

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    But is it true to say that "the IOM specifically states there is no brain involvement for those who fit SEID"?

    This study is included in the IOM report, which says: "Spin-echo magnetic resonance imaging (MRI) revealed midbrain white matter and gray matter volume changes in these patients at fatigue onset, which the authors found to be consistent with an insult to the midbrain affecting multiple feedback control loops (Barnden et al., 2011)."

    I checked a few more studies that you listed (and which I avoided quoting for brevity) and many but not all of them are included. There could be other explanations for the omissions besides bias, such as these studies not being particularly interesting and the necessity to summarize (e.g. one omitted study was EEG in patients vs healthy controls, which I wouldn't consider particularly important). Are there any studies that are important yet missing?


    The reason that the report doesn't attempt to define the illness in terms of specific brain, immune, cardiac, etc abnormalities is because there isn't sufficient evidence to do so. Many of these studies are small and unreplicated, and scientists don't consider them sufficient evidence (this is not bias against ME/CFS, it's just how things are done). It appears that you are interpreting this as a failure by the IOM report to acknowledge the reality of ME (because you're not familiar with reviewing and interpreting scientific evidence).
     
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  7. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Dear @Colleen Steckel,

    I am not sure I can put it better than @strategist does: It appears that you are interpreting this as a failure by the IOM report to acknowledge the reality of ME (because you're not familiar with reviewing and interpreting scientific evidence).

    For a condition like rheumatoid arthritis there are thousands of papers like these, 95% of which get forgotten because they are not done well enough or never stand up to repetition. Of the studies you mention the only one that I would consider worth just keeping an eye out for replication of is the natriuretic peptide one. Most of the others lots of other people have tried to repeat and found nothing consistent.

    I spent my life working on rheumatoid arthritis. I was lucky enough to make enough progress with understanding the disease to introduce a novel treatment (rituximab) for RA and a range of autoimmune diseases. I learnt to scrutinise research papers to see if they were well executed and whether they made any sense in terms of building an understanding.

    I got interested in ME because I could see it was a degree more difficult than RA because there were no accepted pathological findings. There was nothing you could see down a microscope or on a biochemistry read out that you could build a theory around. What I did see was a scattered collection of researchers producing very unconvincing and mostly uninterpretable findings. Amongst that there were maybe half a dozen solid research groups who had done epidemiology or physiology studies - most of whom nobody had heard of. I thought it was worth trying to see whether I could contribute towards getting some real research going. I am not sure I have much to offer but I have tried because it all seems such a mess and PWME clearly need something better.

    As far as I am aware there is no group of people with an illness called ME that includes demonstrable immunological abnormalities. Every normal healthy person has quirks of this or that level of antibodies or lymphocytes. That does not mean they have an immune disease. Moreover, there are plenty of labs that make money out of finding things wrong when there isn't. It is circular to say that the people with the immune tests out of line are the ones with ME because ME has immune tests out of line on criteria. We have no reason to think that there is any consistent immune abnormality that is part of the causation of any ME type illness. I realise that there are physicians who tell their patients this but I would call that miseducation rather than education.

    We had much the same thing for RA in a slightly different way. Vast numbers of researchers claimed that the illness was based on autoimmune T cells and that there must be an autoantigen in joints. They thought it must be true because it had been published in the Lancet! It did not make sense of the pathology anyway. When we worked out what was actually going on it was clear why these ideas made no sense. Unfortunately this sort of herd behaviour where researchers all follow the same dead end ideas has got much worse in the last twenty years with the proliferation of trash journals.

    What PWME need is science that actually stands up to scrutiny. There is a degree of enthusiasm for that now but people need to be aware that there is still an awful lot of hot air being produced. And high profile researchers are very often not the ones who actually know what they are doing.
     
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  8. Medfeb

    Medfeb Senior Member (Voting Rights)

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    There's a lack of replication and some inconsistencies but the IOM report concluded "Sufficient evidence supports the finding of immune dysfunction in ME/CFS.

    Of course, this doesn't mean that the immune system is the ultimate driver of the pathology but I think there's solid evidence its involved in some fundamental way.
     
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  9. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Do they say what? It is not clear to me what they would be referring to. I worry that people who are not familiar with the complexities of the immune system will accept that there is 'sufficient evidence' just on numbers of papers and we need something more concrete than that.
     
  10. Colleen Steckel

    Colleen Steckel Established Member (Voting Rights)

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    And now I fully understand the crux of this miscommunication if you are sure ME does not include immune abnormalities. I have immune abnormalities.. of that there is no doubt. So are you saying I must have a different disease? This also explains why you would not consider the ICC a viable criteria for ME as that criteria clearly describes a disease that has immune dysfunction.

    My immune symptoms fit the Th1 Th2 imbalance exactly. Having been at this 29 years... and living in a body that does NOT have any normal immune responses, I am absolutely positive I do have immune abnormalities. I don't have a normal response to colds and flus that go around. I don't tolerate vaccines... attributed to immune dysfunction. I had EBV reactivated... attributed to immune dysfunction.

    I could go on, but it sounds like you have set your mind that ME is not an immune dysfunction disease.
    So I either have a different disease. Or you and I think ME is something very different.

    I'm in many groups with patients who have immune dysfunction and consider themselves to have ME.
    If this group does not agree that ME includes immune dysfunction, I'm clearly in the wrong place.
     
  11. Trish

    Trish Moderator Staff Member

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    I think perhaps you misunderstand what 'this group' is. We are a diverse group of hundreds of people most of whom have been diagnosed with ME or CFS or think we may have a condition that fits with one or other definition of ME, CFS, SEID, PVFS etc. along with lots of carers, scientists, doctors and anyone else interested in ME and its variants however they are described.

    Here are our forum Core Purposes and Values

     
  12. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    I'm not sure this document:
    [​IMG]
    ...is any more helpful than this:
    [​IMG]
    ...in isolation.

    Both documents on their own are ripe for misinterpretation and abuse. That's why each has a report attached to it which explains in detail what each criterion means. We should judge the entirety of each criteria, not just a cheatsheet that vastly summarises an approach.

    For instance, the ICC summary doesn't explain whether each characteristic of PENE is needed or just one. Each of the symptom domains also include things which may not be anything to do with the domain they're included under (is pain always neurological, for instance?) and offer 'soft' options that are too generic (headaches, GI problems, dizziness) without qualification. All it takes is a person with lots of non-specific issues and a doctor who doesn't understand PENE from that document, and hey presto! Misdiagnosis!

    The ICC document also has a lot of things to check off, so there's a danger that in trying to fill it out doctors will 'fish' for answers. The longer you're asked to recall symptoms, the more you start to remember.

    So a person who went in complaining of fatigue might be provoked to recall the headaches they occasionally get, the bloating they had the other week, or the dizziness they got that one time in the supermarket. Yet these things may have been caused by dehydration, a bad curry and an inner ear infection, respectively.

    All it takes is that doctor thinking that, like the others on the cheatsheet, PENE is a multi-option symptom, and you've got a problem. They might say they get more fatigued after exercise (who doesn't?) and that's that.


    I think you missed the 'demonstrable' part. A few cytokines here and there (sometimes conflicting ones) doesn't demonstrate this conclusively. Things like a 'Th1/Th2' shift are very woolly and may be equally due to recall bias. It's also worth pointing out that Ron Davis has found fewer viruses in patients than in controls so far. The evidence here is all over the place.

    Jo has talked numerous times about how people with lax understanding of immunology have overstated the case for immune involvement in ME (and in other diseases). That's not to say the immune system isn't involved, but it is to say that the evidence we have so far is very poor quality and full of pet theories that don't go anywhere.

    A faggot fallacy is 'a belief that multiple pieces of evidence, each independently being suspect or weak, provide strong evidence when bundled together' (see here). I think that the science around ME has been particularly prone to faggot fallacies on all sides of the debate.

    Realising that evidence is poor or lacking is not the same as agreeing with the BPS school, though, or not sticking up for ME. In fact, it's precisely because we want to stick up for ME that we want the discussion to be as accurate as possible.

    I realise that this is getting off-topic, but in short, we should discuss this based on what's actually there in the criteria, and not overstate weak evidence or cling to some sacred cow or other.
     
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  13. Colleen Steckel

    Colleen Steckel Established Member (Voting Rights)

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    Thank you for clarifying. As the name of this group is Science for ME. (Not Science for ME and CFS and SEID and PVFS) I understood the focus of this specific discussion to be about ME. For me ME is described by the ICC and at its core (the aspect of ME that has impacted my life the most) is the immune abnormalities.

    Possibly it would be helpful for posters within the group to clarify which disease they are referring to when posting? When people say "this disease" everyone "assumes" they are talking about the disease they are diagnosed with.

    This thread was specifically about the US push to designate ME, CFS, and SEID with three different codes.

    So this discussion gets at the core of the problem we are facing. If these are three different diseases. How are they diagnosed and how do we get proper treatments to go with each diagnosis? SEID treatments are based on behavior modification. ME treatments are based on the immune dysfunction so include antivirals, IVIG, etc.


    The immune system denial by Jonathan Edwards obviously shocked me. I knew that CFS / SEID as described by the CDC and IOM do NOT include immune dysfunction but I thought it was a general agreement in the ME community that ME DOES have immune dysfunction.

    Each person on any topic chooses the "input" they are going to use to hold a position on a topic. My "input" is as much about my personal immune dysfunction experience as it is the science. For those who have not lived in a body with immune dysfunction the "input" has to be based on other information.

    While I recognize that I may have a bias because of my experience, I also recognize that those who haven't had this experience are going to question my experience. That is the most insidious part of living with ME. Continuously having my experience questioned by "experts" who insist they know better because the primitive tools of science have not "seen" the proof needed to believe the patient. It took decades for the "experts" to "discover" that we have exertion intolerance. All of us with ME knew that decades ago.

    We who have ME know exactly what PENE means. The Neuro and Immune exacerbation of symptoms that occurs after overdoing are quite recognizable.

    What I meant about maybe not being in the right group is that if this group has decided that the specific disease ME does not include immune dysfunction, my input would be at odds with the group.
     
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  14. Adrian

    Adrian Administrator

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    The question is whether there is any reproducible evidence that shows consistent immune abnormalities. This is where the evidence is somewhat lacking there are small studies showing things but other studies showing different things. I think its one of the reasons why we need a large project to try to replicate potentially interesting results over a much larger population. This would establish if there is reliable evidence.

    I do wonder if there are other issues that interact with the immune system in more random ways so that perhaps there is much greater variability in the immune system and more people on the edge or over the definitions of normality but with a lack of a consistent signature.

    Rather than pushing favorite theories we need to be looking at the evidence, clues from small studies (especially finding well run and biologically plausible ones) and trying to push for clarity on these research topics and for the questions that are raised (say about immune abnormalities) to be properly investigated so we have more certainty in answers.
     
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  15. Colleen Steckel

    Colleen Steckel Established Member (Voting Rights)

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    A biomarker can't be found if vague and imprecise case definitions are used. Experts who had seen thousands of patients and had a good handle on recognizing this specific population created the CCC and then the ICC. This was done so researchers would stop looking at the wrong patient populations described by the vague Fukuda and Oxford definitions.

    The concern remains that researchers are still not selecting a patient population that is recognized as ME as per the ICC. That would explain researchers seeing a lack of immune system abnormalities that are experienced by the ME community. We know that many patients need antivirals for reactivated viruses, low NK cell function is prevalent, IVIG is also needed. Many of us with immune system issues are seeing improvement using low dose naltrexone (immune system modulator).


    Here is an example of a study that used ICC as the criteria for selection of patients.

    A Preliminary Comparative Assessment of the Role of CD8+ T Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis. (2016) Brenu, Broadley, Nguyen, Johnston, Ramos, Staines, Marshall-Gradisnik https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736227/

    Conclusion from that study: "In summary, these preliminary findings provide new insight into the possibility of hyper activated inflammatory CD8+ T cell profile in untreated MS patients while CFS/ME patients may display an exhausted profile which permits viral prevalence and persistence. The above data may suggest that the differential expressions of receptors and adhesion molecules in MS patients are in response to imbalances in neuroimmune homeostasis. In comparison to CFS/ME patients, MS patients may have more severe immune dysregulation. Nevertheless it is likely that impairments in CD8+ T cells in CFS/ME patients relate to abnormal levels of adhesion and migratory molecules and these abnormalities may contribute to the persistent immune dysregulation observed and warrant further validation in a larger sample size
     
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  16. strategist

    strategist Senior Member (Voting Rights)

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    Ron Davis recently said that they were unable to find any viruses in severely ill patients. These patients have actually less viruses than healthy controls, and I'm sure they're so sick they easily fulfill all the major criteria.

    What do you make of this?
     
  17. Colleen Steckel

    Colleen Steckel Established Member (Voting Rights)

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    This is a fascinating discovery. I would, of course, be asking a lot of questions. Were they looking at antibodies that require a "normal" immune response? Does this finding show that the immune system is so revved up it is taking out more viruses than the average person?

    I'm seeing that as a significant indicator that the immune system is behaving in a different way than a normal person. Could the revved up immune system explain the "fluish" feeling we all deal with? It is a tantalizing finding... that raises a lot of questions about the immune system.
     
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  18. strategist

    strategist Senior Member (Voting Rights)

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    Here is a link to the talk by Ron Davis on viruses in his sample of 20 severely ill patients. They tested for the viruses that many of the patients think they have.


    Patients may have something going on that feels like a viral infection.
     
  19. Colleen Steckel

    Colleen Steckel Established Member (Voting Rights)

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    For those who aren't familiar with PCR testing (I needed a refresher - googled emedicinehealth)

    "PCR amplification is only part of the identifying test, however. Once the amplification is done (see below), the amplified segments need to be compared to other nucleotide segments from a known source (for example, a specific person, animal, or pathogenic organism). This comparison of unique segments is often done by placing PCR-generated nucleotide sequences next to known nucleotide sequences from humans, pathogens, or other sources in a separating gel. Electrical current is run through the gel and the various nucleotide sequences form bands that resemble a "ladder" according to their electrical charge and molecular size. This is termed gel electrophoresis. Bands or "ladder" like steps that migrate to the same levels in the gel show identity of nucleotide sequences. This method is one of the most popular ways PCR tests are completed (See Fig 1)."

    A statement in this explanation stands out to me...

    "next to known nucleotide sequences from humans"

    It's clear after decades of research into this that nothing is "normal" when it comes to ME research. This could be a serious limitation of the PCR testing. We obviously don't know what is happening with the viruses inside our bodies. It could be they are so changed they no longer are comparable to "known" sequences.

    We have ample patient stories giving evidence that antivirals produce more than a placebo affect in a patients. It is possible the antivirals are doing something other than fighting viruses, but many of us have seen high levels of viral activity which was brought down by antivirals giving us improved quality of life.

    This article lists a number of limitations and possible reasons for false negatives. https://www.co.monterey.ca.us/home/showdocument?id=16826

    I have good respect for the labs Dr. Davis is using, but there are other factors that could be affecting the results.
     
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  20. strategist

    strategist Senior Member (Voting Rights)

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    We have patient stories and yet, as far as I know, double blind placebo controlled clinical trials of antivirals have shown little to no benefit. This kind of clinical trial is designed to separate placebo from treatment effect. I am not against the idea that these could help, but so far it looks like they don't work nearly as well and often as people think. The lack of effect of antivirals is consistent with Ron Davis (and some other groups) not finding viruses.

    I am curious what you mean by "high levels of viral activity which was brought down by antivirals".
     

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