Post-Exertional Symptom Exacerbation after Sub-Maximal Exercise in Individuals with [ME/CFS] and Post-Acute Sequelae of COVID-19, 2025, Berardi et al

[forestglip]

Post-Exertional Symptom Exacerbation after Sub-Maximal Exercise in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of COVID-19

Berardi, Giovanni; Janowski, Adam; McNally, Samuel; Post, Andrew; Garg, Alpana; Sluka, Kathleen A.

[Line breaks added]

Purpose
In individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC), physical activity can exacerbate symptoms for days-to-weeks, referred to as post-exertional symptom exacerbation (PESE).

This study characterized the trajectory of PESE symptoms before and for 7 days after a sub-maximal exercise task in individuals with ME/CFS or PASC.

Methods
Individuals with ME/CFS (n=30) or PASC (n=30) and matched controls (n=30) were recruited from a university hospital and the community setting. Participants completed a 25-minute moderate intensity exercise on a whole-body cycle ergometer.

The trajectory of 8 commonly reported PESE symptoms (physical fatigue, mental fatigue, pain, physical function, flu-like symptoms, gastrointestinal symptoms, sleep dysfunction, anxiety) before and for 7 days after exercise.

Results
There was variability in the proportion of those who experienced increased symptoms ranging from 46/60 reporting physical fatigue to only 18/30 reporting anxiety. There was no change in any of the symptoms across the 7-day period when analyzed individually.

An aggregate score of 4-5 symptoms that includes physical fatigue, mental fatigue, physical function and flu-like symptoms, with or without pain, was more comprehensive in capturing maximal changes in PESE. Changes were greatest during the 72h post-exercise and for those with ME/CFS.

The aggregate score shows 8/30 of individuals with ME/CFS and 12/30 with PASC show minimal-to-no increase in PESE, while 6-7/30 show increases greater than 3/10 points.

Conclusions
PESE to a clinically relevant exercise task is variable in individuals with ME/CFS and PASC as submaximal exercise does not exacerbate symptoms for some, while modifications of intensity may be necessary to minimize PESE in others.

Web | Medicine & Science in Sports & Exercise | Paywall

 

[ME/CFS Science Blog]

Anyone has access to the paper and the main results?

 

[Hoopoe]

Maybe riding a bicycle is a form of exercise that is better tolerated than others, due to the hemodynamics?

It is something that has surprised me when I did a stress test on an ergometer.

Walking seems like it would cause greater orthostatic stress than cycling. Maybe the stronger use of leg muscles in cycling also promotes better blood flow?

An interesting question is also to what degree the symptom exacerbation associated with exertion is caused by orthostatic stress and not the activity per se. In my opinion even sitting upright causes some orthostatic stress... and maybe we tend to blame the activity that we did for the symptoms while forgetting about the orthostatic stress.

 

[Utsikt]

Results
There was variability in the proportion of those who experienced increased symptoms ranging from 46/60 reporting physical fatigue to only 18/30 reporting anxiety. There was no change in any of the symptoms across the 7-day period when analyzed individually.

How can 46/60 report increased physical fatigue while there was no change in any of the symptoms on an individual level? The whole abstract is very confusing.

 

[Creekside]

Maybe riding a bicycle is a form of exercise that is better tolerated than others, due to the hemodynamics?

I don't know if my case was unique or just exaggerated, but the form of exercise--how much muscles were pushed beyond their normal movement--was the main factor in triggering PEM. A few seconds of unaccustomed muscle usage was far more likely to trigger PEM than hours of strenuous accustomed exertion.

The form of exercise in these studies will likely be affected by differences in what activities the participants are accustomed to. Someone who walks regularly may respond differently than someone who sits or stands a lot while doing arm activities. My suggestion is that they should use an exercise that uses many muscle groups in ways that most people don't use. A rowing machine would be better than a bicycle, due to using more muscle groups. I'm unfamiliar with exercise machines, so maybe there's a better one for PEM studies.

 

[Kiristar]

Crikey 25 minutes on a bicycle. They obviously didn't recruit any severely affected or moderate to severe then. I struggle to tolerate 15 sitting upright in my wheelchair

 

[TiredMathematician]

How can 46/60 report increased physical fatigue while there was no change in any of the symptoms on an individual level? The whole abstract is very confusing.

I'm not really sure where that comes from - this is the relevant part of the results section.

Prior to exercise, average intensity of all 8 symptoms was greater in individuals with ME/CFS and PASC compared to HC, while physical fatigue, pain, physical dysfunction, and flu-like symptoms was greater in ME/CFS compared to PASC (Table 2). The trajectory data before and after exercise was highly variable with ratings ranging from 0-10 for most symptoms (Figure 1-2, Supplemental Figure 1-3, Supplemental Digital Content, http://links.lww.com/MSS/D321).

To examine effects in response to exercise, we analyzed the change in symptoms after exercise compared to before exercise – these data showed that the response to exercise was highly variable with some showing increases, some decreases and others no change in symptoms (Figure 2). Changes in mental fatigue and flu-like symptoms were greater on Day 1 in individuals with ME/CFS compared to HC; there were no changes in other individual symptoms between groups (Supplemental Material: Results, Supplemental Digital Content, http://links.lww.com/MSS/D321).

Perhaps it should say "other individual symptoms"?

With respect to the physical fatigue stuff, the proportion of participants reporting increases in physical fatigue was significantly greater in both patients with ME/CFS and PASC compared to healthy controls (Supplementary Table 1).

From the ANOVA analysis, they report that:

The change in physical fatigue following exercise was different by group (Time*Group: F(14,609)=2.923, p<0.001, ηp2=0.063), however, no differences remained with post hoc analysis (p>0.05)(Figure 1a).

 

[Utsikt]

I'm not really sure where that comes from - this is the relevant part of the results section.




Perhaps it should say "other individual symptoms"?

With respect to the physical fatigue stuff, the proportion of participants reporting increases in physical fatigue was significantly greater in both patients with ME/CFS and PASC compared to healthy controls (Supplementary Table 1).

From the ANOVA analysis, they report that:

Thank you. The link to the supplement doc works, so at least I can read that.

The change in physical fatigue following exercise was different by group (Time*Group: F(14,609)=2.923, p<0.001, ηp2=0.063), however, no differences remained with post hoc analysis (p>0.05)(Figure 1a).

Do you know what they mean by «post hoc analysis»? I’m assuming the corrected for something?

 

[Utsikt]

How active were the participants at baseline?

Also, did they do any tracking of their activity throughout the day? If I was healthy enough to participate, I would have rested a lot before and after to minimise the impact of the exercise.

 

[TiredMathematician]

Do you know what they mean by «post hoc analysis»? I’m assuming the corrected for something?

This part of the analysis is done using ANOVA.

The first part of this is testing the null hypothesis that the mean change in symptoms over time is the same in all groups. In this case, the null hypothesis is rejected, telling us that the mean change in symptoms over time is different in at least one group, but it doesn't tell us which group.

Post hoc tests are then run to determine which pairs of groups are different (e.g. compare group A to B, B to C, and A to C using separate t-tests). It's common to make some sort of correction for multiple comparisons when doing this, but I don't see any mention of that here.

Perhaps counterintuitively, it is possible to reject the null hypothesis that all group means are equal, but fail to reject the null for any of these pairwise tests, as seems to have happened here.

 

[TiredMathematician]

How active were the participants at baseline?

Also, did they do any tracking of their activity throughout the day? If I was healthy enough to participate, I would have rested a lot before and after to minimise the impact of the exercise.

I don't see anything about that - the only measurements I can during the study see are symptom questionnaires.

And this the full table of baseline characteristics.




BTW if you want the full pdf, just send me a DM.

 

[Eleanor]

Is this one of those where scores out of 10 on a questionnaire are assumed to have a linear, mathematical reality across individuals and groups? So e.g. if a control says their fatigue went from 1 to 3 and a pwME says theirs went from 5 to 7, that's interpreted as showing "no difference" because they both put their number of points up by the same amount?

 

[TiredMathematician]

Is this one of those where scores out of 10 on a questionnaire are assumed to have a linear, mathematical reality across individuals and groups? So e.g. if a control says their fatigue went from 1 to 3 and a pwME says theirs went from 5 to 7, that's interpreted as showing "no difference" because they both put their number of points up by the same amount?

That is how their questionnaires worked (example below), but I don't think it would explain any non-significant differences between groups for a given symptom, as the healthy controls didn't report any meaningful change in any symptoms following exercise.

 

[Utsikt]

I don't see anything about that - the only measurements I can during the study see are symptom questionnaires.

And this the full table of baseline characteristics.

View attachment 29104
View attachment 29105

BTW if you want the full pdf, just send me a DM.

So not very well matched then. Substantial difference in BMI, and especially gender for ME/CFS v HC. They’ve not even asked them to rate their activity level in general.

 

[Utsikt]

INTRODUCTION
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC) are complex syndromes characterized by persistent fatigue.(1-5) Both syndromes have a similar symptom presentation that includes physical and mental fatigue, localized joint pain and widespread pain, sleep dysfunction, and general malaise, all of which impact function.(6-8)

A hallmark feature of ME/CFS is the exacerbation of symptoms by physical activity, referred to as post-exertional symptom exacerbation (PESE);(2,9) exacerbation of symptoms by physical activity is also reported in individuals with PASC.(9,10)

It seems like the authors have confused PESE with PEM (the hallmark feature of ME/CFS). PESE would presumably include fatiguability, DOMS, etc.

PESE occurs during and after an exercise task, lasts for hours to weeks, and is a barrier to participation in daily activities and exercise.(11-22)

That is a not a very accurate description. PEM occurs if the person do more than their individual limit, either as a one off or as a result of cumulative activity. It’s possible for some less impaired patients to do some physical activity without any consequences.

The use of exercise in these populations is controversial, primarily due to PESE.(23-30) Systematic reviews show that routine exercise improved symptoms in PASC and possibly ME/CFS.(26, 28, 31, 32)

26 is Larun. Citing that does not give me confidence in the authors ability to assess scientific work..

Qualitative studies report long-lasting exacerbation of symptoms, while quantitative studies show differing reports for both ME/CFS and PASC that depend on intensity of exercise, symptoms examined, and time of assessment after exercise.(15, 16, 19, 33, 34)

For example, a recent study showed PESE symptoms lasting for 7 days following two serial maximal intensity exercise tests in individuals with ME/CFS.(21) In contrast, a low intensity walking task shows minimal PESE in individuals with ME/CFS.(19) Together, these data suggest intensity of exercise is critical to the PESE response.

19 is an opinion piece from 2008 about how fantastic GET is for ME/CFS.

https://medicaljournalssweden.se/jrm/article/view/18129

 

[Utsikt]

Study participants were also invited to complete the PESE survey daily for 8 days without exercise exposure to understand natural fluctuation in symptoms; this was collected a posteriori 9 to 20 months after the exercise task (HC: 6 M, 15 F; ME/CFS: 10 M, 20 F; PASC: 7 M, 15 F)

I can’t get the numbers to add up here. There were 1 male and 29 female ME/CFS patients. But here they say there were 10 male and 20 female.

There were 10 male and 20 female PASC patients, but those numbers can’t be switched around because there are too many male in the later PASC group for it to be the original ME/CFS group.

Are these new groups of patients?

I also don’t understand how data from a random week 9 to 20 months after could be relevant. Far too much could happen in that time to affect symptom fluctuation.

We’ve also discussed here that a proper study on PEM would have to follow patients for months if not years. ResetME has a 3 month run-in.

 

[poetinsf]

Yeah, 25 min of moderate cycling is A LOT. I usually ride at 10 mph or less, and 25 min nonstop is at the borderline for PEM trigger for me. And I'm supposed to be recovered. When I was moderately sick, walking 98 steps/min for 10 min was enough to trigger a bad PEM. The exercise indicates that the subjects were very mildly sick at worst. I'd dismiss this paper just on that account.

edit: 15min ->10min

 

[Utsikt]

The magnitude and duration of symptom exacerbation was less in the current study than prior reports examining the response to a maximal exercise task, suggesting lower-intensity exercises have the potential to be more tolerable in ME/CFS and PASC.(65, 66) This has clinical implications for implementation of exercise in these conditions.

It is important to assess multiple symptoms to determine the magnitude of PESE as some individuals will have minimal to no PESE. In those with PESE, avoidance of a daily exercise routine and allowing adequate recovery time may be necessary. It also may be necessary to individualize the exercise task using lower intensities or shorter duration to prevent PESE, yet still promote increased activity.

It is telling that they never provide any reason for why pwME/CFS should exercise. And they never discus how having to exercise might have impacted how much someone were able to do in the days leading up to and following the bout of exercise.

Indeed, a recent report provided exercise recommendations for PASC that are based on the presence of no, mild/moderate, and severe PESE, thus supporting an individualized approach.(67)

67 is this, it’s not good:

https://www.s4me.info/threads/practical-recommendations-for-exercise-training-in-patients-with-long-covid-with-or-without-post-exertional-malaise-2024-gloeckl-scheibenbogen.38254/

The CDC suggests that standard exercise protocols for ME/CFS could be harmful, despite several clinical trials showing low-intensity exercise improving outcomes.(68)

And finally we’re at the reason for this paper: they want pwME/CFS to exercise. They go on to cite numerous of what’s undoubtedly highly flawed studies that supposedly found positive effect of exercise.

Future studies will need to determine the clinically relevant changes in the symptom change, determine if modification of the exercise task can reduce PESE acutely, and determine if regular exercise can reduce PESE.

Any what is the rationale for exercise being able to reduce PESE or PEM?

Limitations

The PESE experienced in this study is specific to the exercise task performed and may not be generalizable to other tasks. While we verbally encouraged study participants to not partake in additional exercise, we were not able to control for all physical, cognitive, or emotional stressors which may have confounded PESE following exercise.

Again, they seem completely oblivious to the fact that PEM can be caused by non-exercise activities and exertion, or an accumulation of those.

Individuals who volunteered in this study were willing to participate in an exercise task and those with more severe PESE may not have been willing or able to participate in our study.

Something you never brought up in the discussion where you make it very clear that you think everyone with PEM should exercise.

One limitation of the study is that we used a simple numerical rating scale to capture each individual symptom. While we did capture 8 symptoms, we recognize that this may not fully capture the full PESE experience.

So why did you not do better?

Future studies will need to further validate PESE using both the simple multi-symptom NRS surveys, as well as more complex surveys to comprehensively capture the PESE experience.

Ah, that’s for someone else to do in the future..

I do not understand why studies like these continue to be funded and published. It adds nothing of value and is clearly done by people with no real understanding of ME/CFS and PEM.

 

[Mij]

I had difficulty with moderate cycling for 15 minutes on my stationary bike years ago. I was out of breath quickly and my legs felt fatigued/unstable after, but I can power walk for an hour with no issues for the most part.

What do you mean by "sick"?

Geez, the delayed PEM was horrible when I felt 90% improvement and thought I was recovering years ago.

 

[EndME]

Given group differences in comorbidities do the authors clarify what they consider to be comorbid conditions?

It seems like the authors have confused PESE with PEM (the hallmark feature of ME/CFS).

PEM and PESE are typically used as synonyms. I don't think one can critisise the authors for that.

I think the actual question is whether these people experience the type of PEM members on here seem to report or whether they are plagued by other problems. I'm also not quite sue what the point of having a PASC group is, without seemingly characterising the nature of symptoms of this group much besides filling in some questionnaires, I guess you just have a group that also reports being unwell but don't know anything besides that.

I can’t get the numbers to add up here. There were 1 male and 29 female ME/CFS patients. But here they say there were 10 male and 20 female.

Maybe the additional 0 is a typo?

I think something we very often unfortunately see in these studies is that despite the rather small sample sizes there were seemingly no medical assessments whatsoever (they either already had a diagnosis or met criteria, but it is not clarified how that was assessed).

Looking at the material above it seems to suggest that people with ME/CFS had marginally lower average heart rates and lower maximal heart rates during the exercise tests despite having a higher BMI and whilst doing fewer RPM. I had been under the impression to only use a subjective assessment of exertion is not ideal. For example if a participant might be experiencing knee pain or another source of pain, they report a higher subjective exertion but that doesn't mean that the exertion is sufficient to trigger PEM, rather than being painful.