Preprint Long-COVID Postural Tachycardia Syndrome: A deep phenotyping study, 2025, Larsen et al.

Seems like a study that one should have a closer look at. Lots of negative results that have sometimes appeared positive elsewhere. @ME/CFS Skeptic, this seems worthy of a deeper dive.

The different experiments have different cohort sizes (summarized in the tables in the end appendix). For the skin biopsy it's 23 patients from the LC-POTS group.

This part I find unusual as well. Seems like they are claming the presence of SFN in LC-POTS when their experiments have seemingly only showed the absence of it.

 

Some of the authors had previously published a small case series (8 patients) on phosphorylated α-synuclein in Long-COVID POTS, titled: A case series of cutaneous phosphorylated α-synuclein in Long-COVID POTS
(funded by Dysautonomia international where one of the authors M. G. Miglis is a board member). Would be interesting to know whether any of those patients were included in this study.

I'm not sure what a percentage of 8% would tell us? In studies for other conditions controls have a rate close to 0% whilst certain conditions (Parkinsons, dementia with Lewy bodies) seem to be close to 100%. I suppose it's possible that some LC patients have an early onset of such a condition without the usual signs yet, but are there studies to suggest that such people also have positive results on such a test?

 

Regarding increases in heart rate, which apart from the logical observation @Hutan and the authors mention is the reason for them being in the study in the first place, it doesn't seem like there is a mention of BMI or (in)activity which can also drive said results?

In this cohort one wouldn't necessarily have to expect lower activity levels in LC-POTS patients, especially since Dysautonomia international recommend exercise as treatment to this group of patients.

Edit: The authors mention group differences in BMI and that patients report lower physical activity levels due to symptoms, but these weren't quantified.

 

@EndME

 

The SFN null results (or higher rate in controls) is even more striking given that the controls were well age and gender matched.

Though to be fair, n=10 for HC leaves a lot of room for randomness to fuzzy up the results. (Although I’m questioning how 38% of HC could have had SFN, given there were 10 people. How do 3.8 people have SFN. I thought having SFN was binary?)

Anyways — this study might bolster the suggestion that HR increase isn’t a useful clinical marker for OI.

 

Thanks, I did miss that. I suppose those differences are not too large, I guess one maybe would still want to know whether differences are driven by certain individuals (a small portion of higher BMI patients causing the differences) rather than just group differences in general.

 

Thanks for tagging me. Interesting that cerebral blood flow and small fiber neuropathy showed no significant differences. The sample size was really small though.

Almost as if the added the conclusions of a different paper, it doesn't match what the study actually found.

 

One would think so but on the other hand I wonder whether there is something that makes interpreting this study quite hard: All patients that are part of this study are so because they:
1. Experience a certain increase in heart rate upon standing.
2. Have symptoms consistent with POTS (but without saying what those symptoms might be and the list can be rather long).

The patients are all from the Stanford Autonomic Disorders Clinic based on POTS symptoms that were present after a Covid infection but not before (I think it's a strong part of the study that they chose patients that can be pre-Covid be described as healthy, even if it can't be proven that their ill health was caused by Covid). So they basically say the patients have "autonomic dysfunction" and POTS. Unfortunately, they don't mention any other symptoms as part of the study (although they seem to have recoded them somewhere as they sometimes mention them) so it's not really clear to me what the symptoms here are and if there are large differences in symptom profiles or not? Maybe the authors can add those somewhere since this information seems to have been recorded.

Maybe one can expect that people reporting to such a clinic and being part of such a trial are precisely those that experience problems that can be described as orthostatic intolerance, but it needn't necessarily have to be so since the list of possible POTS and Long-Covid symptoms is very long (for example they might just have an increase in heart rate and continous brain fog, which probably isn't what would be considered OI).

 

Regarding the seemingly only difference in the groups (phosphorylated α-synuclein) the authors report that these findings might be transient:

 

They used transcranial doppler. Maybe extracranial doppler would be more sensitive:

Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography (van Campen et al, 2020, Clinical Neurophysiology Practice)

Cerebral Blood Flow in Orthostatic Intolerance (Khan et al, 2025, Journal of the American Heart Association)

Edit: What the thread's study said about hypocapnia being involved:

 

I don’t understand the bolded sentence. Why do they believe that the findings are abnormal? Compared to what?

 

1. If 38% of your HC have "reduced" IENFD on skin biopsy, doesn't this make the definition quite useless? n=10 but still...
Does anyone know how it is in the Fibromyalgia studies with roughly 50% positive in meta reviews? Unfortunately, I can't find a positive rate for HC there.

2. +31.1±20.3 bpm at HUT (end-tilt to supine) and 42.7+-16.7 (max-tilt to supine) for LC-POTS seems...weirdly low? Here the precise definition of POTS comes into play, is it >30bpm *once* within the 10min HUT? Or did they previously fulfill POTS criteria (>30 average over HUT?) and for the study measurement a significant portion did not?

Could only skim the paper though!

If these points and other issues already mentioned here persist, it makes it hard to derive anything of value.

 

Especially in younger adults, the HR will vary naturally. So you probably need a sustained >30 BPM increase. Although the increase can take many minutes to appear, so I don’t think it’s based on an average.

And many will not be able to stand for 10 minutes, so their average would be lower than those that can stand for 10 minutes.

A bit like how the average pace of a 200 meter sprint is higher than for the 100 meter sprint because the acceleration phase is a smaller part of the total duration.

 

In that case it should be even more weird that the negative SD of LC-POTS significantly goes into the non-POTS regime (<30bpm), right? And that's only 1 sigma.

For me it was actually quite simple at TTT: it nearly instantly went to a value of >40bpm at tilt and was stable at +-2 bpm over 10 mins (max difference, not SD). The curve looked very satisfying

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Looking at the not-possible percentage values my trust in the study is a bit damaged.
EDIT: Only 8 of 10 HC were tested for SFN, so need to retract this (and the other related comment from above), 3/8 were positive then, i.e. 37.5%

 

There’s some data missing for certain measurements, which might explain why the percentages don’t match up with the original cohorts.

Good point!