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

They don't say that 40% have excessive orthostatic tachycardia. They say that 3/17 (17.6%) HVs had that. 7/17 (41%) HVs had symptoms - this would be any symptom at all reported during the head-up tilt test, which could be unconnected with the test, or they may have only counted prodromal symptoms like dizziness, nausea, blurred vision, odd sensation in chest, maybe neck pain as symptoms.

I think the reason you don't meet people with significant orthostatic symptoms is that normal life prevents them even in those who would have a surprise positive tilt test. You're walking around, you're sitting but moving your arms etc. So it tends to happen to a small number of people in more unusual situations like a long wait in a queue on a hot day, or standing in a choir, or standing or sitting still in a church. My sister used to faint with exercise for a few years as a teenager. She has absolutely no orthostatic symptoms as an adult. She would definitely qualify as a healthy control. Who knows what would happen on a tilt.

Looking back I've always had OI issues, I just didn't know what they were. I knew that I felt crap if I had a bath or got in a jacuzzi or played tennis (picking up the balls and lots of standing around, I think) or stood on the train in the morning. All easily sidestepped. I would have been a healthy control until I got ME/CFS. I'm now someone with really debilitating OI that does not get easily captured in these tests. I've had a negative 20 minute tilt and a positive-at-32-minute tilt. In real life can I stand still for 32 minutes? No, not even close, standing still at all is problematic. Sitting still is problematic. My guess is that the stress of the testing situation is enough to counteract what my BP would otherwise do - a bit like white coat hypertension in the doctor's surgery vs 24-hour BP monitoring at home (the latter also misses my issues). Or that, as @Jonathan Edwards has pointed out, the problems ME/CFS people without POTS have with being upright may not be not about blood pressure and heart rate.

Edited to change "are" to "may not be" in final sentence to accurately report my understanding of JE's view.

 

Addendum: The 17.6% HVs with excessive tachy on this test would not be considered to have POTS. Some will have other reasons for that tachy eg a cardiac issue. They can see from the pattern of what happens when whether it's POTS or some other issue.

 

There's no autonomic data in the supplementary material, apart from the thing I mentioned above (i.e. stating there were negative results for OH) and I haven't looked through all the source data yet. I'm assuming if there's data it has to be in the source data.

 

The paper has Figures 1-10. The source data has data for Figures 1-20D. Has anybody found out what is going on there?

 

There are supplementary figures labelled S1, S2 etc in the Supplementary Information file. So the source data has data for figures 1-9 from the published paper, and S1-S20 from the Supplementary Information file.

 

Someone affiliated with the study from the NIH messaged me today saying "We will be holding a research symposia in the next month or so where questions will be addressed.” - was this already known by the community, if you know @B_V ?

(full disclosure I’m sure everything will be code speak)

 

Given the intensity of the testing at NIH for this study (lumbar puncture, CPET (even if one day instead of two), tilt test, the metabolic chamber, the blood work and so on) what are the chances that study participants adjudicated to have ME were in PEM the entire time they were there because of the study requirements - and the intensity of the second time also (for those who managed that week).... ?

This was a really select group of people with ME that they were able to tolerate such an intensive study....

 

Are there any more sleep data in the various appendices?

I ask because lots and lots of data are generated with sleep tests—e.g. see here https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886429/

Although I’m not a data junkie, I would have rather seen a quantitative analysis of the various sleep components e.g. time spent in various sleep stages for pts vs HC rather the assessment that “Polysomnography did not reveal clinically relevant findings”

Also, although sleep tests in sleep labs are expensive, the at home sleep test are inexpensive (and quality is thought to be pretty good) and usually you get more normal-ish sleep at home. So they could have done the sleep lab test plus several more nights per patient at home.

 

Is there a way to know
How many study participants were referred by ME specialists, by PCPs, other?
How many were self-referred?

If referred by ME specialists, it would be really interesting to know which specialists felt they had PwME on their roster who could undertake such intensive activity to take part in this study.
It would also be interesting to know how many ME specialists considered this study too arduous for the PwME in their care to take part in this study.

 

One of the 17 participants has publicly shared her experience which sounds pretty harrowing. I hope she suffered no long term damage.

It is a reply to this Bateman Horne Center Facebook post about the study:

https://www.facebook.com/batemanhor...Kz3VtXU8uhr8sBiqvntC7pv5qmvHwS39F2f3wcUMUzfdl

 

Giving visibility this message from Nath to another pwME today, who I don't think would mind that I'm sharing here since nothing is private here (I also think e-mailing has helped apply pressure, that they now will be hosting this supposed 'symposia' - just sharing if any here have thoughts or concerns, I would send away to him).

1. The study provides irrefutable evidence for the biological basis of the illness by finding multiple systemic abnormalities. This we think this is a major step forwards for patients with ME/CFS.
2. PEM: Of note, improving understanding of post-exertional malaise has always been part of our project. PEM was one of the inclusion criteria for all the study participants (See Supplementary Data file 1 for study inclusion/exclusion criteria). I would like to point you to two papers that have already been published from our group about post-exertional malaise based on the work that was published today:
   Focus group work we performed to develop the tool we used to measure post-exertional malaise: https://pubmed.ncbi.nlm.nih.gov/33071931/
   Implementation of the PEM tool as part of the ME/CFS cohort: https://pubmed.ncbi.nlm.nih.gov/38352048/
3. The study makes available a huge amount of data that other researchers can use and identify therapeutic targets. In fact we have already initiated a clinical trial using IVIG in patients with Long-COVID who have symptoms very similar to ME/CFS. There are multiple other clinical studies and trials in Long-COVID patients being done around the country which should benefit ME/CFS patients as well since they similar underlying pathophysiological mechanisms.
4. We have shown that the effort preference is due to a dysfunction in the integrative brain regions and thus provides a biological basis for it. And should be interpreted to say that the patients were too sick to exert the effort. At least that is what we were trying to communicate. Maybe it did not come across that way.

 

IVIG has already been tried in ME/CFS and POTS and it didn’t work. My god, do these people even bother reading work that has been done before them.

 

But has it been tried on the back of a new study with null results?

 

Statement from the Bateman Horne Centre about the study,

"But, no study is perfect. In our opinion, this one fell short by not including enough patients who are moderately to severely ill. That happens frequently in ME/CFS research, and was probably amplified by the travel, rigor and duration of the study.

Studying only early-stage, post-infection ME/CFS, may also be an important reason the findings don’t fully reflect the larger population of people chronically ill with ME/CFS.

We were particularly dismayed by use of the term “effort preference” as an explanation for the origin of fatigue when the authors subsequently go on to suggest that their data and other published data substantiate dysregulation of autonomic nervous system functioning and changes in metabolic pathways that could more readily be implicated, if not fully understood, in contributing to overall fatigue.

We were, additionally, disappointed at the lack of emphasis or evaluation placed on post-exertional malaise in this particular study. As we all know, PEM (or PESE) is a distinct and debilitating physiological phenomena that differentiates ME/CFS from other fatiguing illnesses and that can be measured (approximately) via 2-day CPET testing. PEM is not a mere “discomfort” or “symptom” for patients, and its representation and implication as a subjective symptom in this study is not in accordance with our data or practice."

Full text, https://batemanhornecenter.dm.networkforgood.com/emails/3168080

 

You know my answer, but would be curious how he’d rebuttal if any ask him. His e-mail is avindra.nath@nih.gov

Pretty sure he’s pretty over of my critiques that I e-mailed at this point..feel free to CC monica.bertagnolli@nih.gov if you think this study was not up to par.

 

Ah, I hadn't seen. Thanks for sharing this. It's definitely a canned answer they've formed then now.

 

This is nonsense but as a necessary upbeat take on a very costly study that was supposed to be groundbreaking it is excusable, and at least a good message to the world.

This I think is more problematic, not only nonsense but unhelpful. As far as I can see they have simply shown a weak correlation between some task choices and some brain signals. Those task choices may well be entirely healthy in that they may reflect a sensible learnt pacing strategy. Or maybe just rational choices. It is far from clear that the control choices were more rational.

Moreover, the brain signals simply suggest that the patients were thinking differently. Maybe they were thinking less about which bar to go to later or more about how many changes of clothes they had brought. Nobody has any detailed idea what these signals mean. A reasonable generous interpretation that allows that the signals might actually have something to do with the choices is that they show healthy rational thinking as opposed to whimsical thoughts in controls for whom none of it matters.

It is possible that the signal patterns are a tell tale sign of whatever is actually stopping PWME from doing things but if so nothing has been discovered about what that is or where it is.