Preprint Dysautonomia in long COVID is prevalent and could explain the frequency of symptoms, 2025, Tamariz, Klimas+

Dysautonomia in long COVID is prevalent and could explain the frequency of symptoms
Leonardo Tamariz; Irina Rozenfeld; Rafael Iglesias; Elizabeth Bast; Santiago Avecillas; Lina Shehadeh; Nancy Klimas; Ana Palacio

BACKGROUND
Long COVID presents with a variety of symptoms. Some of those symptoms could be related to autonomic dysfunction. Our aim is to evaluate the prevalence of autonomic dysfunction in long COVID patients.

METHODS
We conducted a cross-sectional study and included all consecutive patients enrolled in several clinical research studies. We performed the following autonomic dysfunction markers: heart rate variability, heart rate, systolic and diastolic blood pressure changes during NASA lean test, cardiopulmonary exercise testing and a COMPASS-31 scale. We used linear regression to calculate the contribution of each dysautonomia measure on symptom burden as measured by the modified COVID-19 Yorkshire scale.

RESULTS
We included 100 patients for this study. Our sample had a mean age of 56+/-11 years, included 53% minorities and 32% were women. Dysautonomia as defined by an abnormal COMPASS-31 was seen in 82%; 95% 72-89 while cardiovascular resting dysautonomia as represented by an abnormal heart rate variability was seen in 60%; 95% 48-70 of the population, orthostatic hypotension in 12% and POTS in 10%. In our adjusted analysis, we found that the beta coefficient for the COMPASS-31 score (0.37) was significant on changes in a self-reported long COVID symptom burden. The orthostatic intolerance and gastrointestinal domains of the COMPASS-31 was associated the highest long COVID symptom burden.

CONCLUSION
Dysautonomia is common in long COVID patients and contributes to the overall symptoms seen in long COVID. Identifying dysautonomia has important diagnostic and therapeutic implications.


Link | PDF (Preprint: MedRxiv) [Open Access]

 

It would be interesting to know more about that intervention study - there is no reference given for it.


I was interested to know more about how a CPET could be used to evaluate a patient for dysautonomia

Only 25 participants had a CPET. The Methods said 'We evaluate induced autonomic dysfunction in selected patients who received CPET as a part of their clinical care'. It is not clear why the 25 patients had a CPET as part of their clinical care while others did not. It is also not clear from that wording whether all the patients who had a CPET contributed data to the analysis.

It's interesting though. They call it exercise induced dysautonomia. I wonder what is normal in obese unfit people.

There's this study
Effect of obesity on cardiovascular responses to submaximal treadmill exercise in adult males

So, it looks as though people who are obese typically have a higher resting heart rate and a higher resting heart rate after exercise and attenuated HR recovery after exercise. So, the Jouven's criteria 1 and 3 are commonly met by obese people. But Jouven criterion 2 (a smaller than usual increase in heart rate during exercise) probably isn't.

I've seen it suggested that the heart has to work harder in obese individuals, in order to move the greater mass and also to keep the larger mass of tissue oxygenated. I've also seen it suggested that the heart has to work harder in unfit individuals, it has to beat faster, as the cardiovascular system is not as efficient. So, if the increase during exercise is lower than normal in these patients, then that could indeed be anomalous.

I wonder though if the testing regime is a confounder. The method suggests the patients only exercised to volitional fatigue. People who are obese and unfit may stop earlier than people who aren't. And therefore their heart rate increase may not be as high as in people who aren't obese and unfit. They may not be exercising long enough to have their heart increase more than 89 beats per minute.

 

Another possibility is that people with Long Covid may be hesitant about pushing their bodies to the extreme limit, and the researchers may also not push an ill person in their care to keep going as much as they might push a healthy person. It is common, even standard, in a CPET for the assessor to provide verbal encouragement, so it is definitely a potential source of bias.

I didn't see a report of the RER achieved in the CPET, which is one measure of physiological effort although I haven't checked all tables and appendices. Without that, I don't think we can know how hard the participants pushed themselves. To take an extreme example to illustrate the point - if a healthy control person sprints 100 metres and has a high increase in heart rate and a patient walks 50 metres and has a lower increase in heart rate, I don't think you can conclude that there is something wrong with the way the heart worked in the patient.

 

Just noting the low incidence of these.

Although, I don't think we can be sure what exactly the symptoms in the people in this Long Covid cohort are. So, it doesn't necessarily tell us about the incidence of POTS in ME/CFS.

 

I'm sorry @Turtle. It was not meant to be a judgement of the character of the participants. I think anyone with ME/CFS or LC who participates in a research trial has done a self-less thing. I just want to make sure that researchers make good use of their effort and produce information that increases our understanding of the conditions.

I probably was a bit thoughtless as I posted. I'll check my posts.

I know some people are hesitant to do a CPET, or in fact would not do one, because they know that it is likely that they would suffer for days or more. It's reasonable. So, if some of the participants did know about PEM and did have that concern, they might not have pushed themselves as hard as a person who didn't have that concern.

Also, as I noted, I think the researchers might give a different level of encouragement to their patients than to healthy people. The encouragement that is part of a standard CPET can be very 'encouraging' e.g. 'keep going!' shouted excitedly every 30 seconds or something. If you know your patient is going to be miserable for days, would you keep pushing them so strongly?

So, yes, researchers might not have the right information. The Respiratory Exchange Ratios would tell us if the participants got to the same point of physiological effort as is expected of people doing a CPET - maybe they are reported somewhere, they normally are in CPET trials.

Yes, also as @Utsikt says. People who are not used to cycling may feel they have got to the exhaustion point earlier than people who often cycle. People with orthostatic intolerance or who are exhausted from getting to the clinic might have reasons for not feeling great and wanting to stop earlier.

 

Also, even if on average the LC participants stopped at a lower RER than is usual, that does not mean that all of them did. Or that all of them are unfit.

it's getting late here, but I'll have a really good look for RER data in the paper tomorrow.