Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

It has been that way for a long time it seems.

As a side note, I've gone back to the daily mail article and finished reading to the end - which includes a description of the illness. I will paste it on the thread to do with the NHS stuff because this seems pretty 'simple English' as much as that was. But due to including certain aspects seems that bit more appropriate.


"Symptoms of CFS vary per patient and over time.

The most common include an extreme physical and mental tiredness that doesn't go away with rest as well as problems sleeping and with thinking, memory and concentration.

Other symptoms include muscle or joint pain, a sore throat, headaches, flu-like symptoms, dizziness and nausea as well as a fast or irregular heartbeat.

At its mildest, CFS sufferers can perform everyday activities with difficulty but may have to give up hobbies and social activities to rest.

The most severe CFS patients are essentially bed-bound and may full-time care unable to feed or wash themselves or even go to the toilet unassisted.

One of the greatest challenges with CFS is getting a diagnosis due to a lack of a tests that can show a patient has it.

With no such test currently available, patients are forced to undergo diagnosis by process of elimination, with medics progressively ruling out other conditions until CFS is the only one remaining.

There is currently no cure for CFS. Treatment instead revolves around therapy, lifestyle changes and the use of some medications to alleviate symptoms."

 

I just remember someone saying how arduous it was to be part of this trial and do hugely feel for the patients who went through all of this

I guess at the moment you can’t stop people riffing on what they want but it didn’t always used to be this way? The data itself is supposed to almost lead to conservative discussions of everything that could mean in the old days? Or am I imagining days the didn’t exist but should?

 

Why were the healthy controls reporting such high cognitive complaints? These scores are way higher than I would have self-reported prior to 2021 (which would have been zero on PHQ15 and I'm sure zero-equivalent on anything else).

 

From Brian Vastag Mastodon

https://sciencemastodon.com/@brianvastag/111978289834885835


Avi Nath at NIH tells me UCSF is trying to launch a clinical trial of a class of drugs called checkpoint inhibitors in ME/CFS.

The paper he published yesterday mentions these drugs as a target for testing in the disorder, on the theory that they can help clear persistent antigens.

They're cancer drugs & I don't know much about them.

 

Datasets from this study have been added to the mapMECFS portal, https://www.mapmecfs.org/dataset/?organization=nih-intramural

 

https://twitter.com/user/status/1760597750679552250


Declines in submaximal CPET measures corresponding with PEM symptoms and signs on the second day of a two day CPET have nothing to do with effort preference in people meeting accepted physiological criteria for maximal exertion. You can’t choose or fake your anaerobic threshold.

 

https://twitter.com/user/status/1760745328981233999


Effort Preference is a way to test for anhedonia, the core symptom of Major Depressive Disorder. The unsupported introduction of Effort Preference to the ME world may well be laying the groundwork for more destructive studies, characterizing ME as a somatoform illness. FN 15

 

No doubt it doesn’t help. Likely it will damage us in all sorts of ways. Can’t eat/swallow? You can prefer your way out of that.

 

Autonomic dysfunction in ME/CFS

Tilt table testing found no POTS or OI differences with controls. However, they also found reduced baroslope, which I think means that regulation of blood pressure when it changes is slower than optimal.

A wearable 24-hour ECG showed reduced heart rate variability (HRV). This is an indicator of ill-health and might well be normal in chronic illness. There were some specific HRV differences that I don't understand:

They also found increased daytime heart rate suggesting increased sympathetic activity and a reduced drop in nighttime heart ratee in PwME, suggesting reduced parasympathetic activity [consistent with observed
HRV changes in rMSSD, HF power, pNN50, and SD1].

Note that for the Hr & HRV studies they only had data on 13 or 14 subjects. I'm not sure how they failed to get 24-hour ECG data (which is easy to set up and easy to wear) on all subjects. Apart form 2 HRV measures (lnHF&LF), the p values are modest and not corrected for mulitple comparisons.

Do you think these findings are significant, @Jonathan Edwards?

 

apparently "Avi Nath at NIH tells me UCSF is trying to launch a clinical trial of a class of drugs called checkpoint inhibitors in ME/CFS. The paper he published yesterday mentions these drugs as a target for testing in the disorder, on the theory that they can help clear persistent antigens. They're cancer drugs & I don't know much about them"
I am quite worried about this as, whilst we both disagree about how to interpret the exact data regarding the specific immune manifestations and cells that might be driving ME, wether its innate or adaptive these drugs will FUCK patients up, like they literally can CAUSE autoimmunity at worse case: https://pubmed.ncbi.nlm.nih.gov/32390537/
We know that there are likely sub-sets within ME, maybe in general between a sort of active virus VS immune system hyperactivity/autoimmunity-esque line. If the trials do not make a serious effort to work out which sub-set someone is in i strongly encourage people to stay the fuck away for their own safety frankly

 

Decided to post this on Twitter - basically @JonathanEdwards ideas - unattributed!
https://twitter.com/user/status/1760984754625953825

 

I am not sure that propping up ideology can have any impact on a review of evidence for efficacy of treatments.

And in as much as this study says anything specific it says that CBT and GET wouldn't address the problem itself.

 

I doubt it. My main concern is that PWME are bound to be in a different autonomic state because they are the ones being tested for an illness - the ones with a threat.

 

I find this very strange. As far as I know nobody as found any evidence of residual antigen and the weight of evidence in post-infective syndromes is that persistent antigen is not the problem. So there is no reason to use checkpoint inhibition on the basis of the current study.

Moreover, if ME is driven by continued immune activation checkpoint inhibitors are most likely to take it worse. I don't buy this story of immune exhaustion. If the immune system is exhausted you may be a risk of catching new infections but in inactive system is not going to be producing ME symptoms.

 

All of this is at p=0.05 and unadjusted, so it's possible every one of those genes in that venn diagram is a false positive.

To be honest I'm not too concerned that those first two PCAs (a, b) look the way they do, they're looking at global differences in gene expression and it would make sense that the vast majority of the genes would be irrelevant.

Agree that it's not informative to do those PCAs (d, f) based on the differentially expressed (DE) genes - something more relevant might have been to take the highly variable genes across everybody, then do a PCA based on that. Then you could see for example whether more variance is explained by men/woman or ME/control or BMI or whatever (maybe they tried something like that and it wasn't interesting). Really though there are better easier ways to explore those relationships. If they had a much bigger sample size maybe it would be a way to look for subgroups/types of ME.

What would have been informative instead of a PCA of the DE genes would have been to show them as a heatmap, and I think it's telling they didn't do that in this figure when they did do it in the previous figures with the same sort of data structures. It probably looked uninteresting. So we don't get a mention of any individual genes then.

The pathways analyses actually do meet multiple testing correction criteria by the looks of it (by pooling genes into groups by related annotated function and then checking if you see that pathways come up more or less than you would expect it to by chance). Problems with this kind of analysis is 1) you need to trust the ontology annotations which may actually be extremely dodgy (eg may be automated annotation based on protein sequence, instead of being described through actual experiments), and 2) it's vague.

Still, besides the concerns about mismatched groups, I don't think the fact there are big differences in the pathways between men and women is worrying in itself, and may actually be potentially interesting. After all theres a maybe 4:1 sex bias in this disease and maybe that reflects the biology. The data suggested females have downregulated fatty acid metabolism related gene pathways (which is seen in the male data only to a much lesser extent) and males have increased neutrophil related immunity pathways (not seen in women at all). In many metabolomics studies there are much greater differences found in women and very little differences men, so this could be consistent with that.

Agree with @DMissa that we want to see actual genes and their mechanisms studied, but it doesn't look like they found any genes here you could really trust is worth following. The sample size is just miles too small (maybe WASF3 actually did meet q@0.05 and they haven't mentioned it?).

It's not really much to go on but for the sake of argument here are some experiment ideas. They mention in the text they see nominal differences in growth hormone receptor signalling and ubiquitin-transferases. These genes tag proteins for destruction so could be worth investigating cell growth, protein synthesis and degradation rates. Could look at the master growth regulator mTOR and its signalling pathways for changes in phosphorylation state. If hormone receptor signalling is altered maybe that's a clue to a possible 'factor in the blood.'