Preprint Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID, 2023, Liu, Prusty et al

Discussion in 'ME/CFS research' started by Andy, Jun 29, 2023.

  1. Andy

    Andy Committee Member

    Messages:
    22,066
    Location:
    Hampshire, UK
    Abstract

    Myalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease development is largely unknown for both clinical conditions.

    Here we show antibody response to herpesvirus dUTPases, particularly to that of Epstein-Barr virus (EBV) and HSV-1, increased circulating fibronectin (FN1) levels in serum and depletion of natural IgM against fibronectin ((n)IgM-FN1) are common factors for both severe ME/CFS and long COVID.

    We provide evidence for herpesvirus dUTPases-mediated alterations in host cell cytoskeleton, mitochondrial dysfunction and OXPHOS. Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients.

    Our findings provide mechanistic insight into both ME/CFS and long COVID development. Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities.

    https://www.medrxiv.org/content/10.1101/2023.06.23.23291827v1
     
  2. Andy

    Andy Committee Member

    Messages:
    22,066
    Location:
    Hampshire, UK
  3. RedFox

    RedFox Senior Member (Voting Rights)

    Messages:
    1,254
    Location:
    Pennsylvania
    I don't see how this paper is so groundbreaking. It's a mishmash of different measurements that are claimed to be causally connected, but not by any means proven. Closer to an initial hypothesis than proving anything.
     
    Last edited: Jun 30, 2023
    sebaaa, Ariel, cfsandmore and 8 others like this.
  4. Hutan

    Hutan Moderator Staff Member

    Messages:
    27,203
    Location:
    Aotearoa New Zealand
    Simon M, Trish, EndME and 1 other person like this.
  5. DMissa

    DMissa Established Member (Voting Rights)

    Messages:
    99
    Location:
    Australia
    "Autoimmunity is considered as a key causal factor for diseases like ME/CFS."

    Is it? I didn't know that we figured out what's causing the disease yet.

    About the literature: "Chronic post viral illnesses like ME/CFS and long COVID affect multiple body systems and may lead to development of overlapping clinical features with other known health conditions making the diagnosis and treatment difficult for clinicians. No biomarker has been identified for either of the conditions to date."

    About the results: "Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities."

    The list of studies finding other differences with ~90-100% classification accuracy (or useful predictive power for severity), true, are not yet validated diagnostic biomarkers and many (if not all?) of the studies testing this, including my own, have not been independently replicated. Absolutely. However, if one says that there are no biomarkers with all of this in mind, how is it fair to then say that this one more study, adding to our pile of novel but not yet replicated studies, is a biomarker with immediate ramifications, in the same paper? I do not know whether this is just a language issue.

    It would be more apt to say that there is no validated diagnostic test, or validated or reproduced or replicated biomarker. There are many prospective biomarkers continually emerging in recent years. This is now another of them. They're all potentially promising, they all need validation, and this is no different.

    I applaud and welcome more work in this space but the language needs to be careful not to downplay the work of many other hard-working groups around the world.

    Prusty seems like a really nice guy and I really want to meet him to hear his ideas though. I think this is probably a matter of excitedness or English language.

    edit: also nice to see more evidence that ME/CFS and LC, molecularly, are somewhat overlapping but distinct. I think this is becoming clear. Nice to see things in alignment across many groups and biological angles. I think we really need to start designing studies that factor in mode of onset/triggering circumstances from the beginning because it seems likely to me that the cellular or molecular phenotypes are going to very a lot depending on how somebody's ME/CFS is actually initiated. That's what the body of ME/CFS-LC comparison work is telling me anyway.

    Oh and also congratulations to them on their recent MEResearch funding, Very keen to see more research from this group, with so much data in one paper!
     
    Last edited: Jun 30, 2023
  6. Hoopoe

    Hoopoe Senior Member (Voting Rights)

    Messages:
    5,258
  7. Simon M

    Simon M Senior Member (Voting Rights)

    Messages:
    912
    Location:
    UK
    This is very interesting work, but I wanted to red flag the conclusions :
    Based on Bhupesh Prusty‘s recent conference presentation and accompanying slides about the work behind this paper, the results do not come close to supporting such strong conclusions.

    I wrote a commentary about the conference presentation (which I imagine quite a few people here have already read).
    https://www.s4me.info/threads/research-news-from-bhupesh-prusty.13416/page-18#post-478145
     
    Last edited: Jul 2, 2023
  8. Trish

    Trish Moderator Staff Member

    Messages:
    52,714
    Location:
    UK
    Thank you @DMissa and @Simon M. I find it very helpful to read experts' comments like both of yours to help me gauge how excited to be about this work. It does seem to be a useful step towards better understanding, but as @DMissa says, this team, along with some others we could name, seem too quick to claim to have found the first definitive biomarker. I hope funding can be found to replicate all such claims.
     
  9. chillier

    chillier Senior Member (Voting Rights)

    Messages:
    194
    Not much more to say I think that hasn't been discussed already, but we now have the full data so can finally see if what we've heard him claim about differences in natural IgM levels stacks up. This I think is the key figure, where he has measured immunoglobulin levels with ELISA in a decently sized cohort (HC = 83, ME = 106 Covid+no long covid = 149, mildLC = 107 severeLC = 23)
    upload_2023-6-30_10-59-15.png
    So basically a negative result of IgM and IgG with FN1 affinity between controls and ME, which unfortunately contradicts his earlier finding from the pull down proteomics. The big difference between controls and long covid is also seen in the No long covid group who have tested positive for covid - so the difference is probably primarily driven by covid infection rather long covid.

    Panel C and D is breaking the ME group down by severity and there's an association with severity, at least when you define the severity in this specific way. He's collected some good data but it's a pretty negative result overall for ME. Not a biomarker.
     
  10. V.R.T.

    V.R.T. Senior Member (Voting Rights)

    Messages:
    126
    Why did he have to hype this so hard? What was the point of giving desperate people false hope?
     
    JoanneS, sebaaa, Michelle and 6 others like this.
  11. EndME

    EndME Senior Member (Voting Rights)

    Messages:
    911
    The problem I have with this paper is the lack of consistency at different levels. Sometimes they use some ROC analysis to provide some statistical analysis for a certain set, sometimes they do multivariate clustering on a different tiny subset, sometimes they do something different or split the data rather arbitrarily, sometimes they do none of this. All of these things are usually done on completely different subsets, sometimes overlapping, sometimes not, but never are they consistent in their own findings or the analysis of these. It isn't clear which patients from which sets are used at what point in time and why. It feels a bit picky rather than methodological. Each result on its own isn't a biomarker, but they cannot be combined either, due to the lack of consistency.

    It's a bit like: Ok so we tested this small group of patients and found measurement A. Now instead of looking at result A in a larger group or doing a thorough analysis, we will look at measurement A* (which is sort of a bit like A but actually not really) in a completely different group of patients.

    Perhaps this is an artefact of the fact that they wanted to get this preprint out asap, rather than taking another year to write things up and doing some further tests.

    It's an interesting hypothesis paper with many different results, but is it more than that?
     
    Last edited: Jun 30, 2023
    AndroidEeyore, Tia, Michelle and 7 others like this.
  12. V.R.T.

    V.R.T. Senior Member (Voting Rights)

    Messages:
    126
    It seems to me that the ME research community cannot afford to be overhyping admittedly interesting findings like this. I have literally had a bps sympathetic doctor say that the research community is constantly claiming to have found a biomarker but nothing ever comes of this.

    Acting like this is playing into the hands of deniers/skeptics
     
  13. Shadrach Loom

    Shadrach Loom Senior Member (Voting Rights)

    Messages:
    1,052
    Location:
    London, UK

    That’s important, and revealing. I’d assumed that medics didn’t follow the twist and turns of false hope.

    My default position on anyone trying to get the bottom of ME has been tolerance - even at Prusty levels of parturient montes, nascetur ridiculus mus - but you make a good case for not crying wolf.
     
  14. Trish

    Trish Moderator Staff Member

    Messages:
    52,714
    Location:
    UK
    According to Google translate:
    the mountains will give birth, a funny mouse will be born
     
  15. Solstice

    Solstice Senior Member (Voting Rights)

    Messages:
    1,178
    There are holes to be punched in papers like this. Most of the BPS-papers would go straight to the garbage bin after writing it out if people looked at it accurately though. Your doctor being justly sceptical about biomarker claims but then buying into the bps narrative is fully down to his own biases and frankly, incompetence.
     
    AknaMontes, sebaaa, Tia and 4 others like this.
  16. RedFox

    RedFox Senior Member (Voting Rights)

    Messages:
    1,254
    Location:
    Pennsylvania
    When I saw the breakdown by severity, I suspected they did it after analyzing the results. If they compared all pwME vs controls, and got no significant result, then stratified patients by severity to get something, this paper is just a useless fishing expedition.
     
    sebaaa, Michelle, Sid and 3 others like this.
  17. V.R.T.

    V.R.T. Senior Member (Voting Rights)

    Messages:
    126
    Oh he was a terrible doctor, at least as far as I was concerned. I came to him because I had deteriorated to moderate from excercise and he tried to get me to do GET

    Edit: it wasn't my intention to pull this thread off topic so I'm going to stand back and let the scientifically minded among us speak
     
    Solstice and Trish like this.
  18. EndME

    EndME Senior Member (Voting Rights)

    Messages:
    911
    Performs a test of 120 things on a cohort of 12 patients vs 3 controls. Constructs a machine learning classifier based on these results. Says nothing about the accuracy of this classifier amongst this cohort on which is was constructed (which will probably be close to 100% due to the lacking construction). Doesn't test the classifier on an independent cohort which is the whole point of a classifier. Doesn't apply multiplicity corrections. Deduces that "these results suggest that decreased immunoglobulin against fibronectin and other proteins are key features of severe ME/CFS based".

    What?
     
    Last edited: Jun 30, 2023
  19. Sid

    Sid Senior Member (Voting Rights)

    Messages:
    1,057
    Another hyped paper bites the dust.
     
  20. Hoopoe

    Hoopoe Senior Member (Voting Rights)

    Messages:
    5,258
    I think it's also a question of funding and putting in the work of replicating and refining the candidate biomarkers. If that had been done we might have a decent biomarker by now.

    It's the same with treatments probably. The orthostatic issues are low hanging fruit and that we don't have good proven treatments for that aspect yet might just be an issue of nobody putting in the work to make it happen (or not having funding to do so).

    ME/CFS research gets so little funding that it's hard to do anything at all.

    Also, you speak to BPS sympathetic doctors?
     

Share This Page