Post-Exertional Malaise in Long COVID: Subjective Reporting Versus Objective Assessment, 2025, Stussman, Nath, Walitt et al

Hutan

Hutan

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https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1534352/abstract

Background:
Post-exertional malaise (PEM) is a central feature of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and has emerged as a prominent feature of Long COVID. The optimal clinical approach to PEM is inconclusive and studies of the impact of exercise have yielded contradictory results.

Objective:
To examine PEM in Long COVID by assessing the prevalence of self-reported PEM across study cohorts and symptom responses of Long COVID patients to a standardized exercise stressor. Secondarily, Long COVID symptom responses to exercise were compared to those of ME/CFS and Healthy Volunteers (HV).

Methods:
Data from 3 registered clinical trials comprised 4 cohorts in this study: Long COVID Questionnaire Cohort (QC; n=244), Long COVID Exercise Cohort (EC; n=34), ME/CFS cohort (n=9), and Healthy Volunteers (HV; n=9). All cohorts completed questionnaires related to physical function, fatigue, and/or PEM symptoms. EC also performed a standardized exercise test (cardiopulmonary exercise testing, CPET) and the PEM response to CPET was assessed using visual analogue scales and qualitative interviews (QI) administered serially over 72 hours. EC PEM measures were compared to ME/CFS and HV cohorts. A secondary analysis of QI explored positive responses to CPET among EC, ME/CFS and HV.

Results:
Self-reported PEM was 67% in QC and estimated at 27% in EC. Only 2 of 34 EC patients (5.9%) were observed to develop PEM after a CPET. In addition, PEM responses after CPET in Long COVID were not as severe and prolonged as those assessed in ME/CFS. Twenty-two of 34 EC patients (64.7%) expressed at least one of 7 positive themes after the CPET.

Self-report of PEM is common in Long COVID. However, observable PEM following an exercise stressor was not frequent in this small cohort. When present, PEM descriptions during QI were less severe in Long COVID than in ME/CFS. Positive responses after an exercise stressor were common in Long COVID. Exercise testing to determine the presence of PEM may have utility for guiding clinical management of Long COVID.
 
I haven't read this paper yet, but those last lines
Positive responses after an exercise stressor were common in Long COVID. Exercise testing to determine the presence of PEM may have utility for guiding clinical management of Long COVID.
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make it sound as if these researchers don't really understand PEM. People with ME/CFS may be able to do a CPET without PEM. After all, it's just 8 minutes of cycling, some of it at an easy pace. They are less likely to be able to do that, together with all the other activities of daily living, every day for a month without PEM.

Triggering PEM is usually not as simple as
1. do exercise,
2. 24 hours later, suffer PEM
Maybe we have to be careful not to give the impression that PEM is such a mechanistic certainty.

The clearest example I can give is my son returning to school after a year off after ME/CFS onset. The first week in February was fine. Thereafter, he had to miss more and more days due to PEM. By May, after an indoor football game, for a month he was in bed most of the day and sleeping 20 hours a day. ...But, if you had asked my son how he was after that first week, he would have told you 'great!'.

So, you can't really give a person with LC a simple exercise test and then ask them how they are for the next two days to identify the presence of PEM.

Contrary to the claim in the first sentence of this paper,
abstract said:
The optimal clinical approach to PEM is inconclusive and studies of the impact of exercise have yielded contradictory results.
Click to expand...
studies of the impact of exercise have not yielded contradictory results. Reported benefits are pretty uniformly within the likely range for a placebo response.
 
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Hutan said:
I haven't read this paper yet, but those last lines

make it sound as those these researchers don't really understand PEM. People with ME/CFS may be able to do a CPET without PEM. After all, it's just 8 minutes of cycling, some of it at an easy pace. They are less likely to be able to do that, together with all the other activities of daily living, every day for a month without PEM.

Triggering PEM is usually not as simple as
1. do exercise,
2. 24 hours later, suffer PEM
Maybe we have to be careful not to give the impression that PEM is such a mechanistic certainty.

The clearest example I can give is my son returning to school after a year off after ME/CFS onset. The first week in February was fine. Thereafter, he had to miss more and more days due to PEM. By May, after an indoor football game, for a month he was in bed most of the day and sleeping 20 hours a day. ...But, if you had asked my son how he was after that first week, he would have told you 'great!'.

So, you can't really give a person with LC a simple exercise test and then ask them how they are for the next two days to identify the presence of PEM.

Contrary to the claim in the first sentence of this paper,

studies of the impact of exercise have not yielded contradictory results. Reported benefits are pretty uniformly within the likely range for a placebo response.
Click to expand...

I think we'll have to wait for what the paper actually says. I do know of a few LC patients who suffer from shortness of breath following exercise and where this is considered to be PEM (which doesn't match what PEM is considered to be in the context of ME/CFS), so I wonder whether similar things might reflect some of the apparent disparities in the results. It's possible that the LC exercise study includes all sorts of different groups of people. I guess for LC one also has to know at what point in time the first questionnaires were filled out and when the exercise testing occured, due to natural recovery rates.

Presumably the LC patients are those that are part of the NIH exercise study, whilst the ME/CFS patients are from the intramural study?

I think what this study tell us is that people doing CPET studies have to ask about the presence of PEM (before and after) and can't just assume they are studying PEM, much like people on S4ME have been advocating for.
 
I am not able to read the full paper atm, but some contextual things about it are very important to note, I think.

Lead author, Barbara Stussman, has no background as researcher in these types of ilnesses, let alone good knowledge about PEM. She built a career on surveying the use of alternative health practises for the NIH's have-you-tried-yoga division, and her publications are important for the NCCIH's main goal of integrating these practises into medicine.

She was a colleague of Walitt when he worked there, and I think she (along with a crew of other NCCIH employees) was recruited via Walitt into the ME/CFS intramural study.
I wrote an elaborate post on her background here, which I recommend reading.

Given that she is affiliated with the NINDS for this Long Covid paper (and earlier mentioned to do questionnaires on Long Covid and GWI patients), I expect that she is now an employee of Walitt's at his new (and second!) unit for "interoceptive disorders" at NINDS, which is part of his long-time effort to treat ME/CFS as a problem of subjective perception, and which ties in perfectly with the Koroshetz-approved interoception project the NCCIH is currently running in order to expand the use of complementary medicine (like mindfulness, yoga and CBT).

What Stussman and Walitt have been doing with PEM in the ME/CFS intramural study is disturbing, especially considering the context. It got sidelined to a questionnaire paper (despite Walitt's promise that the goal of the study was "to understand exactly what the biology of post-exertional malaise is") and that paper, like now this long covid one, nudges the reader into seeing PEM as a subjective perception and patients as unreliable narrators by pitting their reports against questionnaire answers and symptom reports after a single C-PET, just like they use an "exercise stressor" here.
Hutan said:
"Self-report of PEM is common in Long COVID. However, observable PEM following an exercise stressor was not frequent in this small cohort."
Click to expand...
This all fits with Walitt's "effort preference" creation and his directorship of the unit for Interoceptive Disorders where Walitt, according to his bio, focuses on "persons with disorders characterized by aversive symptoms that develop after exposures, such as infection" by which he means ME/CFS, Long Covid and GWI.

Walitt has a long history of trying to prove patients actually have abnormal sensations, see the document attached to this post, which includes a link to a 2009 study protocol, and this addition.
I have deep worries about what is happening at the NIH with the interoception project, both the NCCIH umbrella project and Walitt's unit at the NINDS. The NCCIH-led project is currently purposefully attempting to create an as-yet unexisting scientific foundation for their own redefined "interoception" definition (which goes two ways) in order to be able to declare illnesses mind-body problems that can be treated with non-medical practises, and I think it is vital for advocates to understand the context of papers such as these, as I personally think that the red carpet is being rolled out to pull ME/CFS and Long Covid into that, possibly as springing board with stuff Walitt and other former NCCIH employees produce as part of the NINDS unit.

I made a thread where I collected a bunch of puzzle pieces on that context. (I'm sorry that I have not been able to rework it into a shorter post/doc.)

A summary of my concerns is made in this post, although there is more to be added.

(I have not been following this topic at all since earlier last year. But there is e.g. the fact that the person who played a big role in the EEfRT test part of the intramural study was part of Walitt's clique at the NCCIH, or that Walitt, when asked to explain what he meant when he said the intramural study found that there was "a mismatch between what someone thinks they can achieve and what their bodies perform" in ME/CFS, used a 2022 hypothesis paper that very much post-dates Walitt's claims of ME/CFS as a disorder of perception that can be researched with brain imaging, and his decades-long habit of fMRI-ing fibro patients to prove that their illness is based in subjective perception (2009). (Walitt has been treating ME/CFS as an "interoceptive disorder" since at least 2010, and he was preparing neuroimaging studies to prove ME/CFS was a problem of subjective perception right before he was recruited into the NIH ME/CFS intramural study.)
 
The paper said:
observable PEM
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The what in the what now? And what is this "observable" PEM they are speaking of here? I guess we'll find out.

They still seem to make the classic mistake of taking unrelated measurements and thinking they must be better than subjective reports, as long as they minimize the problem, I guess. The simple reality is that they don't have instruments to assess this, not that patients overestimate their subjective experience.

And they clearly still reject the notion of PEM, unwilling to change their misguided views, and its cumulative effect. In short they appear to have learned nothing and this is simply Walitt pushing his preferred ideological interpretation.
 
Hutan said:
People with ME/CFS may be able to do a CPET without PEM. After all, it's just 8 minutes of cycling, some of it at an easy pace. They are less likely to be able to do that, together with all the other activities of daily living, every day for a month without PEM.
Click to expand...

I had no idea it was only an 8 minute cycle at an easy pace. Is this across the board for a CPET?
 
Mij said:
I had no idea it was only an 8 minute cycle at an easy pace. Is this across the board for a CPET?
Click to expand...
A normal CPET is done like this:
Procedure
  1. Attach electrocardiogram (ECG) electrodes and blood pressure cuff.
  2. If using a bicycle ergometer, adjust seat to proper height level and null bike.
  3. Obtain baseline ECG, blood pressure, and VO2/VCO2 measurements.
  4. Begin exercise period and record data.
  5. Patients are encouraged to exercise to their maximum endurance or until the nurse ends exercise due to symptoms like pain, HA, dizziness, syncope, excessive dyspnea, leg discomfort
Recovery period: 5 minutes or greater until patient returns to baseline.
https://stanfordhealthcare.org/medical-tests/c/cardiopulmonary-exercise-test.html
 
I'd agree with @EndME. The problem with LC is that it is so widely defined with ME/CFS as a subset. Since ME/CFS symptoms are part of LC, it's a possibility that some LC patients without ME/CFS could mistake other post-exertional effects as PEM, etc.

That is not to discount LC as not being as severe or disruptive. But there is no reason for them to suffer the indignities of ME/CFS if they don't actually have ME/CFS. The presence of PEM is an important indicator, so it's probably worthwhile to study the prevalence of PEM among LC population vis-a-vis ME/CFS relative to self-reports.
 
Mij said:
I had no idea it was only an 8 minute cycle at an easy pace. Is this across the board for a CPET?
Click to expand...
We have a very detailed procedure somewhere, but you start cycling with little resistance and then every minute or so it gets harder and harder. So, at least a few minutes aren't terribly taxing. I think the usual time to completion is around 8 minutes. Then you keep sitting on the bike, pedalling with no resistance for maybe a couple of minutes.

People's experiences of it differ. I was not particularly fit, but I did not find it very hard. I could have kept going for longer, but I guess my RER got to the required 1.1. I did not need to lie down after it, my legs were not wobbly. This was done at a time when I had given up work.

Contrast that with the 30 minute pilates sessions with a 10 minute walk each way that I tried to do when I was still sort of working. There my muscles were pushed to the point where they shook a lot, and I reliably experienced PEM afterwards.
 
Hutan said:
Contrast that with the 30 minute pilates sessions with a 10 minute walk each way that I tried to do when I was still sort of working. There my muscles were pushed to the point where they shook a lot, and I reliably experienced PEM afterwards.
Click to expand...

That combo would have my legs shaking too. I had a stationary bike in the earlier years and my heart rate was up within a few minutes with very little tension, my legs were shaking when I got off, but I can power walk for up to 50 minutes and climb a few flights of stairs on 'good' days w/o my heart rate going up too much. My legs don'ts shake. I find cycling much more difficult so I sold my stationary bike
 
Mij said:
I had no idea it was only an 8 minute cycle at an easy pace. Is this across the board for a CPET?
Click to expand...
It varies, I don't think there's a specific setup. I had one a few months ago for a cardiac check-up and it was a treadmill starting at a brisk pace, much faster than even the most energetic walking I did in the past 10 years.

I only made it to the 3rd step, about 4-5 minutes in, and my pulse was at 175. I'm much older now but last time I did a test (not medical, at a gym) I would be at lower than 100 for this. It was very difficult to walk afterward and it took me 3 days for the PEM to subside, but I don't think they accounted for that.

The test had a slight anomaly, and I will be having one at a hospital with a tracer, so I'll see if it's relatively standard or if each clinic has their own variation of it.
 
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