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

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

 

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.

 

Now published. (Though someone didn't do a good job on the proofing as there's a long duplicated passage.)

 

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

 

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.

 

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.

 

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.

 

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

 

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 :

 

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.

 

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.

 

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

 

@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.

 

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.

 

@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