Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights... 2024 Jahanbani et al

Discussion in 'ME/CFS research' started by Andy, Mar 23, 2024.

  1. Andy

    Andy Committee Member

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    Full title: Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights into Immunopathology, and Disease Severity

    Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents significant challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. To address these complexities, we employed a comprehensive approach, integrating longitudinal cytokine profiling with extensive clinical, health, textual, pharmaceutical, and nutraceutical data, and performed personalized analyses using AI.

    Focusing on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) and marginal symptom improvements, our study highlights the dynamic nature of symptoms, severity, triggers, and modifying factors. As part of this study, we introduced an updated platform and two applications, ME-CFSTrackerApp, and LexiTime, facilitating real-time symptom tracking and enhancing physician-patient communication.

    Our longitudinal cytokine profiling underscores the significance of Th2-type cytokines and synergistic activities between mast cells and eosinophils, leading to skewing of Th1 toward Th2 immune responses in ME/CFS pathogenesis, especially in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major comorbidities. Additionally, our data reveal potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasize the importance of investigating low-dose drugs with partial agonist activity in ME/CFS treatment. Our analyses underscore the patient-centered care approach for better healthcare management.

    Abstract only at time of posting, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1369295/abstract
     
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  2. Hutan

    Hutan Moderator Staff Member

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    Fereshteh Jahanbani1*, Justin C. Sing2, Rajan D. Maynard1, Shaghayegh Jahanbani3, Janet Dafoe4, Whitney Dafoe4, Nathan Jones1, Kelvin J. Wallace1, Azuravesta Rastan1, Hannes Rost2, Holden Maecker5, Michael P. Snyder6, Ronald W. Davis4

    Presumably Whitney Dafoe is the patient. A few red flags and a lot of vagueness in that abstract. I've liked Jahanbani's work in the past though, I'll wait to see the full paper.
     
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  3. Hubris

    Hubris Senior Member (Voting Rights)

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    I think this part could be interesting. My worst symptom by far is cognitive impairment and eosinophil activation is one of the most consistent markers in my illness. Eosinophilic cationic protein is consistently elevated in my blood (10x over normal values) and eosinophils are found in my gut biopsy also consistently.

    I think for very severe patients this kind of longitudinal analysis is the way to go.
     
    Last edited: Mar 24, 2024
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  4. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Now published. (Though someone didn't do a good job on the proofing as there's a long duplicated passage.)
     
    Last edited: Apr 8, 2024
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  5. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    The application they created for symptom tracking is at https://me-cfstrackerapp.su.domains/

     
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  6. Dolphin

    Dolphin Senior Member (Voting Rights)

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    Figure 3
    Proposed Framework for Personalized Severity Assessment in ME/CFS to Capture Variation in ME/CFS Severity and Life Impairment across Patients and Time. (A)Illustrates the dynamic range of the ME/CFS severity scale based on the disease’s impact on all aspects of the patient’s life, including occupational, educational, social, and personal spheres. (B) Depicts the impact of mild to severe ME/CFS on the patient’s life. Mild: maintained about 80% of pre-ME/CFS functional capacity, as well as full-time employment with limitations due to post-exertional malaise (PEM). Moderate: pre-ME/CFS functional capacity, unable to hold part-time work, with increased limitations in activity, progressing to severe: inability to hold any job, primarily house and bedbound. (C) Shows the patient’s functioning ability significantly degrading from extremely severe A to D, highlighting ME/CFS’s profound impact at this level. Severe nutritional deficiencies led to Gastrostomy tube (G-tube) and Peripherally inserted central catheter (PICC Line) Line use. Sensory intolerance intensified, making it impossible for the patient to tolerate others in his room. At stage D, communication loss and internet access loss intensified social isolation.

     
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  7. Hutan

    Hutan Moderator Staff Member

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    Severity levels
    Figure 3 gives an interesting definition of severity levels, with additional sub levels added for extremely severe. I like the definitions of the milder levels. I'm not sure about the difference between Very Severe and Extremely Severe A, which seems to have a lot to do with being able to speak and write and being able to get to the bathroom for toileting and washing. To me, there's a big leap between those two levels; I think some people might not be able to get to the bathroom but can still speak, and that's a pretty fundamental difference. I think you'd need to do a study on the capabilities of a lot more people who are bedridden than just one to determine if the levels at the worst end of the spectrum apply more generally. Of course, I understand why the authors wanted to differentiate levels for this particular individual, in order to correlate health variables, but just noting that they may not be generalisable.


    Blog word analysis
    There's quite a lot of content about analysing the patient's blogs, in terms of word frequency and so on. I find it a bit irrelevant - basically, they had some new tools to do it, and so they did it. They say:
    I think, however, if you want to find out how someone is feeling about their health status, there are easier ways to find out, so I question the idea that this 'holds significant implications for ME/CFS research'.
    Edit to add - for example, when I am feeling better, I am more likely to write more complex things, often critical things, and have a bit more strength to be angry about things that should be better. I don't think there is a clear correlation about the sentiment of my written words and my health status.
     
    Last edited: Apr 8, 2024
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  8. Hutan

    Hutan Moderator Staff Member

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    Cytokines
    Levels of cytokines that were different between two disease levels, Extremely Severe A and Extremely Severe D (the difference being largely in the capability to listen to speech, read and write on a keyboard):
    The comparison is only between the two disease levels, with no reference to normal ranges for humans. Using values relating to being more than one standard deviation away from the mean, 24 cytokines were different, with only 9 of those also having significant p values. I think there is a significant typo in this section, because they then talk about 14 cytokines, when I think they mean the 9 cytokines. Only three of the cytokines that were more than one SD different and statistically significant and that survived a false discovery rate (taking into account the fact that 80 cytokines that were measured): HGF, Leptin and MIF.

    HGF - increased 4.8 SDs, p value 1.6E-06
    Leptin - increased 3.61 SDs, p value 0.0002
    MIF - increased 3.08 SDs, p value 0.002
    It is noted that all of these three were correlated with improvements in the health of the subject
    They note in the discussion:

    HGF - Hepatocyte Growth Factor - info from wikipedia
    It is involved in the response to tissue damage.
    Interestingly,
    I'm surprised that the authors of this study didn't note that association. The authors say:
    I'm not sure what they mean by 'inconsistencies across studies' - none of the studies cited seem to be about ME/CFS.

    Leptin
    - info from wikipedia
    The authors of this paper say:
    So, they are noting that higher levels of leptin were correlated with better health here, whereas others have found that they are associated with worse health in ME/CFS. They don't quote Jarred Younger's studies, I can't remember what he found. Given leptin's association with satiety and BMI, possibly the leptin finding is a downstream result of increasing BMI from previous very low levels, and so not really much to do with the underlying disease process.


    MIF -
    basically it looks to be a pro-inflammatory molecule, involved in a range of acute and chronic inflammatory conditions. Quotes below from a paper about it:
    The authors of this study say:
    So, again, there are all sorts of confounders, and it's hard to know what to make of it.


    There's a lot of talk about mast cells and eosinophils, based on differences in cytokine levels that did not reach statistical significance. It would have been very helpful if there had been some analysis of levels against normal ranges in healthy people. There is also a lot of talk about connective tissue disease. Hopefully the authors have some clues that will inspire further research, but I'm not sure that there is much we can take from this study for now, given the n=1 nature of it, and the enormous amount of confounding there will have been.
     
    Last edited: Apr 8, 2024
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  9. Murph

    Murph Established Member (Voting Rights)

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    I'm always pleased when I see Whitney Dafoe posting online because it suggests he's feeling a bit better. His blog is chugging along recently and he keeps popping up on my instagram. He does seem to have had a big improvement then setback at some point recently because he registered a small business a little while ago but i'm not sure it has continued. Mostly i just want him to be better but there's wider implications for the rest of us - if he is suddenly up at and at em it could be random - or it could hint that Stanford has some good ideas.
     
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  10. alex3619

    alex3619 Senior Member (Voting Rights)

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    If there is a Th2 skew, and it turns out to be important, and replicable, then there are ways to treat that, including Th1 vaccinations. Its all too speculative at this point but its worth a longer look I think. I have still to read most of this and probably wont this month.
     
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  11. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    One of the authors, Whitney Dafoe, provided some background on the creation of the severity scale that is in this paper. See post #6 by @Dolphin for the image of the scale.
    Text:
    New Severity Scale for ME/CFS

    I wrote this new severity scale for ME/CFS about 2 years ago.
    I really wanted to express how severe the illness can actually get which is not at all reflected in our current mild-moderate-severe-v.severe scale. And I wanted to make it more accurate to our lives. It’s not perfect, I know, mostly because every ME/CFS patient is so different.

    It’s not possible to reflect everyone’s situation perfectly or account for and all the millions of particular circumstances all ME/CFS patients face in one scale because every category would need a 50 pages long description. But I tried my best to make it as useful and inclusive as possible.

    It has been changed for publication in a few ways that I don’t like, mostly making the Extremely Severe categories labelled with A, B, C, D etc because it doesn’t mean anything without having to look at the scale and read it. A more descriptive Extremely Severe category name would be more useful to us I think so you would know what it meant from the words alone or could at least remember what they meant. But there is always room for improvement and change down the road.

    Also, I am now a twice published author! My MDPI manuscript - "Extremely Severe ME/CFS—A Personal Account"" and now this! Woo! I never thought any of my writing would ever be published, it’s amazing how ME/CFS changes our lives and also how we must change to adapt to the life ME/CFS imposes on us.

    I really hope I did you all justice and that this may be useful for us if nothing else, for a template for moving forward to make a scale that is even better. I have already read some great ideas for improvement.

    I love you all. Whitney :heart:
     
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  12. Trish

    Trish Moderator Staff Member

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    I think it is a good idea to expand the severity scale to include more detail at each severity level. I always seem to fall between levels, whatever scale is used.

    I had a quick attempt to fill this in. I couldn't make sense of how it worked, and how one retrieves saved data for comparison over time. The questions didn't seem to relate to the words in the coloured strip sometimes, and I'm not sure what I'm supposed to be writing in the white strips.
     
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  13. mariovitali

    mariovitali Senior Member (Voting Rights)

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    Regarding elevated Hepatocyte Growth Factor (HGF) and since hepatocytes are liver cells, it is interesting that there is no mention of liver involvement. The text mentions that increased HGF was associated with fewer symptoms :


     
    Last edited: Apr 11, 2024
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  14. Nightsong

    Nightsong Senior Member (Voting Rights)

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    The logic of this simply doesn't follow to the point that I'm surprised it got past peer review. The authors resurrect the Th1/Th2 "imbalance" hypothesis - if I recall correctly a decade or so ago there were various papers claiming that such an "imbalance" was implicated in the aetiology of ME, which never made much sense and which I assumed had been abandoned.
    Oh dear. And how would this "systemic mast cell and eosinophil overactivation" correlate with the actual clinical presentation of ME/CFS? There's an awful lot of spurious hypothesising based on some often very woolly immunology all throughout this paper.

    I created an account to look through some of the tracker app's questions - here's one: "How has ME/CFS symptom severity impacted your ability to hold a job?" with the possible answers being: "yes" "most of the time" "some of the time" "rarely" "no" - which isn't very clear. Also: "How would you rate your sleep quality?" with the possible answers being "not at all", "mildly", "moderately", "severely", etc - again, very unclear. And the "How do I feel compared to the last time I filled out this form" question is repeated twice and the answers are all "very restful" "restful" etc - why restfulness? There are no instructions as to what to fill in the "string" fields. There's also no privacy policy or any indication as to who will have access to the data being submitted on the site that I can see.

    I was going to look at Lexitime, but the GitHub link is broken.
     
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  15. leokitten

    leokitten Senior Member (Voting Rights)

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    What do people think about interleukin-2 inducible T-cell kinase (ITK) inhibition as a possible target for ME/CFS for an empirical drug response trial? If ME is a T-cell mediated inflammatory/immune disease with a Th2 skew this could be a promising target. Soquelitinib (formerly known as CPI-818) for example is a highly selective ITK inhibitor that modulates affected T cells back towards Th1 and has demonstrated efficacy in Th2-mediated diseases in preclinical models. I believe it’s also in early human clinical trials for certain cancers and autoimmune diseases. @Jonathan Edwards I remember you wondered if ME is a T-cell mediated disorder, and the fact that many pwME also come down with MCAS some of it seems to make sense.
     
    Last edited: Apr 12, 2024
  16. leokitten

    leokitten Senior Member (Voting Rights)

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    ITK inhibitors in inflammation and immune-mediated disorders, Sahu et al, 2009
     
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  17. leokitten

    leokitten Senior Member (Voting Rights)

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    @Jonathan Edwards do you have any thoughts or useful insight into ITK as a target and possible ITK inhibition in ME/CFS? Like everything else to get treatments to patients would require an empirical trial without direct evidence supporting this hypothesis. In addition to the other functions mentioned above, ITK inhibitors also reduce T-cell exhaustion, so there are various bits of evidence in ME research that point to a problem in the immune system where ITK inhibition might work. A company is trialing ITK inhibition for autoimmune disorders like atopic dermatitis, so I imagine the side effect profile is decent.
     
    Last edited: Apr 15, 2024
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  18. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    As Nightlong said, the Th1/Th2 balance idea was a barmy speculation with no evidence base in any disease in fact about three decades ago. I had hoped it had finally died out.

    Whatever ME/CFS is it ain't Th2 I would say. Not even Th1, but something to do with CD8s.

    To me this is all the worst sort of immunobabble.
     
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  19. leokitten

    leokitten Senior Member (Voting Rights)

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    @Jonathan Edwards

    How about ignoring for now the semantics or specific immunobabble language of Th1/Th2 balance and, I'll try my best here I'm not an immunologist, e.g. there might be some dysfunctional regulation of ITK-mediated signaling in ME/CFS which causes dysfunction in certain NK cells, mast cells and T cells resulting in them chronically producing pro-inflammatory cytokines such as IL-2, IL-9, IL-13, etc and our disease pathology?

    Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis, Lechner et al, 2020

    What I also find interesting is the ppl with genetic ITK gain of function mutations acquire a disorder which results in EBV infections and severe immune dysregulation
     
    Last edited: Apr 15, 2024

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