Trial Report Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition A Randomized Crossover Clinical Trial, 2024, Tryfonos et al

[RaviHVJ]

Importance Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration.

Objective To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC.

Design, Setting, and Participants In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited.

Interventions After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise.

Main Outcomes and Measures The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC.

Results Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: −6.8 mL/kg/min; 95% CI, −10.7 to −2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: −37 Nm; 95% CI, −67 to −7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, −26.5 minutes/d; 95% CI, −42.0 to −11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing.

Conclusions and Relevance In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2817149

 

[RaviHVJ]

And here is an accompanying commentary that concludes with a hint that exercise therapy should be prescribed for ME/CFS (though they somehow omit any discussion of the vast literature on ME/CFS and exercise therapy). Tiresome.

https://jamanetwork.com/journals/ja...y's findings,–COVID-19 rehabilitation service.

 

[rvallee]

Inability to question absurd results is one hell of a problem. They have some discussion of PEM, minimal, it's listed as a required criterion, and find that exercise is well-tolerated in people who have PEM. This is obviously nonsensical. Not everyone with LC has PEM or intolerance to exercise. In those, say in people who have lost their ability to smell or other issues, it's expected that it would be well-tolerated, but then exercise makes no sense as a treatment anyway.

Plus it doesn't even produce meaningful benefits, all they report is that they find people with exercise intolerance who tolerate exercise, therefore it should be used as a treatment. This is several layers of not making sense.

But to find that people who have intolerance to exercise tolerate high-intensity exercise is blatantly absurd. It's a complete contradiction, simply cannot be true. It's like finding a group of people who are more thirsty after drinking plenty of water.

This really looks more like an advert, a trial designed to produce a desired result, and the accompanying commentary only adds to this.

 

[rvallee]

This is from accelerometer data from 7 days:

Accelerometry revealed similar total physical activity and sedentary behavior.

Patients with PCC spent 43% less time on moderate to vigorous physical activity

This has led many health care professionals to be reluctant to incorporate exercise into rehabilitation programs for patients with PCC

Obviously not.

SF-36 shows quite significant physical impairment, and yet the 6 MWT shows only a slight difference. I don't know how total physical activity, sedentary behavior and 6-MWT can be similar to controls in a group with an average of 13 in SF-36 physical function.

There was no difference in fatigue worsening between patients with PCC and controls after any of the exercise types

Table 2 shows quite significant differences and worsening, in fact zero worsening for controls and a significant worsening for patients, but in Supplemental data they disappear those difference, showing deltas of 0:

Those figures do not reflect the data above:

Those graphs are supposed to show no differences. OK, then:

I don't know what the hell is going on here. But managing to publish an advert in JAMA will no doubt lead to solid evidence-based evidence, or whatever. What an incredible disaster this industry is.

 

[SNT Gatchaman]

Of those included following initial physiological characterisation, 5 out of the 31 PCC patients dropped out. 3 after the first exercise session, 1 after the second (and 1 before the first session). 2 HCs dropped out, both after the second session.

 

[SNT Gatchaman]

PCCs are 13 minutes more sedentary per day than HCs (571 vs 558), with 11 minutes more total physical activity per day (317 vs 306).

 

[Hutan]

Swedish study, Karolinksa, does anyone recognise the names?

I think it could be an ok study in broad concept - if people with PEM want to maintain fitness and muscle tone, what is the least damaging way to go about it?

But, this is why the definition of PEM matters. If you take my experience with the CPET trial, I did the CPET in the afternoon and felt fine, but that night I felt as though I had been crushed under a steam roller. It was horrible, and it took a long time to get to sleep. The next day, and 48 hours later, I felt fine again. With this particular study design, they would not capture my episode of PEM.




Fatigue
It's true that there doesn't seem to be much that is different here, apart from underlying fatigue levels
Pre exercise: The PCCs are already at a high level of fatigue before exercise. There may be a ceiling effect going on there?
Post exercise: Both groups feel more fatigued after the exercise by around 2 steps on the VAS score.
48 h: the means go back to baseline, more or less.

Muscle pain

Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04)

The controls are pretty much 0 throughout
Pre-exercise: The PCCs already have some muscle pain before exercise.
Post-exercise: Some increase for the PCCs. An increase of 2 in both High intensity training and strength training.
48 hr: The muscle pain heads back to baseline in HIIT and MICT, but for strength training, the mean pain gets worse.
So, why does the abstract not mention strength training? It's an interesting result. And look at the median and interquartile range for the PCC - median of 5, interquartile range of 1 to 6. The scale was 0-10, so 5 is quite significant pain. So, lots of the PCC participants had muscle pain a couple of days after strength training. Is that just the result of muscle deconditioning?

Those figures do not reflect the data above:

Fig 2 charts - the caption says that they are differences in changes from baseline to 48 hours.
I agree rvallee, I can't work out what is going on there. I thought they might have been standardised somehow, given all the PCC HIIT scores have a mean of zero. The y axis is 48-hr VAS score. I don't know why they didn't just chart the actual values.


Myopathy

Electromyography was performed in 29 patients with PCC (94%) and 28 control participants (90%). Myopathic findings were observed in 18 patients with PCC (62%) (13 [45%] had myopathic findings in ≥2 muscles and 5 [17%] in 1 muscle) compared with only 1 control participant (4%), who had myopathic indices in 1 muscle.

 

[Hutan]

2 to 4 weeks between each trial of exercise

All participants completed 3 exercise sessions (HIIT, MICT, and ST) in a randomized, balanced order with an approximately 2- to 4-week washout between sessions. Maximal workload from the baseline cardiopulmonary exercise testing (CPET) was used to determine exercise intensity for HIIT: 5 × 1-minute cycling at 90% maximal workload and a Borg Rating of Perceived Exertion (RPE) score higher than 16,15 with 1-minute passive rest between intervals. Moderate-intensity continuous training consisted of 30-minute continuous cycling at 50% maximal workload (RPE score, 12-14). Strength training included 3 exercises: dead lifts (Kbox; Exxentric AB), push-ups, and knee extensions using flywheel technology (nHance), each with 3 sets of 10 repetitions and a 3-minute rest between sets.

At the 48-hour follow-up, participants also performed CPET.

 

[Hutan]

Myography method:

(4) needle electromyography (EMG) of 6 muscles using a 35-mm concentric needle (20 Hz to 10 kHz filter). The EMG data were analyzed qualitatively and quantitively for the duration, amplitude, and number of phases of more than 20 motor unit potentials (MUPs). Spontaneous activity was assessed at rest and interference pattern during slight and maximal contraction.

The EMG outcomes were classified as (1) normal (MUPs without significant myopathic or neurogenic characteristics), (2) myopathic (>50% of displayed MUPs with short duration, small amplitudes, and polyphasia [≥5 phases]; the outcome was considered definitive myopathic if these characteristics were present in ≥2 muscles), (3) borderline myopathic (myopathic findings observed in only 1 muscle), (4) neurogenic (overrepresentation of MUPs with increased duration and amplitudes with or without increased polyphasia), or (5) mixed (both myopathic and neurogenic indices coexisted).30

 

[Kalliope]

Cidrap No need to avoid exercise with long-COVID diagnosis, researchers say

quotes:

Surprisingly, there were no differences in the two groups on self-ratings of fatigue. Patients with PCC had greater exacerbation of muscle pain after HIIT, however.

"What we can generally see is that the post-COVID patients do just as well as the controls, even though they had more symptoms to begin with. By equally well, I mean that they did not worsen their symptoms or negatively affect their body during the 48 hours we observed them," said Andrea Tryfonos, PhD, first author of the study, in a press release from the Karolinska Institutet.

....

In a commentary on the study, Peter Ladlow, PhD; Alexander Bennett, PhD; and Oliver O’Sullivan, MBChB; all United Kingdom-based researchers, said the findings are reassuring and should help guide clinicians treating post-COVID patients.

"The ability of individuals with PCC to tolerate various exercise activities, particularly hard-intensity activities … without major escalation of symptoms, fatigue, or exercise capacity is important for advancing rehabilitation," they write.

 

[Ebb Tide]

@rvallee the PCC SF 36 PF score is 49.9, I think you've quoted the Physical role score below

 

[Kalliope]

Professor Karl Lauterbach, the German Minister of Health comments the study on X:

Neue Studie aus Stockholm zu Exercise mit Post-COVID Symptomen ist sehr relevant. Eine Studie kann Frage der gezielten Belastung #Post-COVID nicht beantworten. Trotzdem ein wichtiger Hoffnungsschimmer. Werden wir mit Experten ⁦@BMG_Bund besprechen

Auto translation:
New study from Stockholm on exercise with post-COVID symptoms is very relevant. A study cannot answer the question of targeted exercise #Post -COVID. Nevertheless, an important glimmer of hope. We will discuss it with experts ⁦@BMG_Bund

https://twitter.com/user/status/1776549467866431747

⁩

 

[Eleanor]

This sort of mess just emphasises how utterly pointless it is to go on treating everyone who comes under the umbrella of Long Covid as if they had the same needs and conditions. Ridiculous categorical pronouncements that mean absolutely nothing to individuals in practice.

 

[Trish]

Fatigue
It's true that there doesn't seem to be much that is different here, apart from underlying fatigue levels
Pre exercise: The PCCs are already at a high level of fatigue before exercise. There may be a ceiling effect going on there?
Post exercise: Both groups feel more fatigued after the exercise by around 2 steps on the VAS score.
48 h: the means go back to baseline, more or less.

I think there's a huge problem with using comparisons between sick and healthy people with a visual analogue scale for fatigue. Two points increase in fatigue on top of 2 points already there, ie an increase in fatigue by 2 points is likely to mean something completely different to a 2 point increase from zero in healthy people.

I'm imagining it's something like this:

For the sick people, they are already feeling drained and unwell before exercise, but know it can get a whole lot worse, so they rate the increase as 2 on the VAS. After the exercise they may be utterly exhausted and feeling a lot sicker, but they only move it up two places on the scale because they know it can get a lot worse, to the extent of being bed bound.

For the healthy people, they start not tired/fatigued, and after the execise they feel it's nice to have a sit down, they are tired, their muscles feel a bit achy and fatigued, but it's healthy fatigue and they don't feel ill. They rate this as a 2 point increase.

So numerically comparing sick person's fatigue with healthy person's fatigue is ridiculous.

 

[Eleanor]

I think there's a huge problem with using comparisons between sick and healthy people with a visual analogue scale for fatigue. Two points increase in fatigue on top of 2 points already there, ie an increase in fatigue by 2 points is likely to mean something completely different to a 2 point increase from zero in healthy people.

I'm imagining it's something like this:

For the sick people, they are already feeling drained and unwell before exercise, but know it can get a whole lot worse, so they rate the increase as 2 on the VAS. After the exercise they may be utterly exhausted and feeling a lot sicker, but they only move it up two places on the scale because they know it can get a lot worse, to the extent of being bed bound.

For the healthy people, they start not tired/fatigued, and after the execise they feel it's nice to have a sit down, they are tired, their muscles feel a bit achy and fatigued, but it's healthy fatigue and they don't feel ill. They rate this as a 2 point increase.

So numerically comparing sick person's fatigue with healthy person's fatigue is ridiculous.

exactly! - and even these sick people were capable of repeatedly doing enough tiring physical exercise to be included in the study, while other Long Covid patients can't even leave their beds. Yet these researchers think they've "comprehensively investigate[d] the physiologic mechanisms underlying PCC."

 

[Kalliope]

Professor Carmen Scheibenbogen on X:

Solche methodisch unsauberen Studien zu verallgemeinern ist für Erkrankte mit #MECFS und #PCS mit #PEM sehr gefährlich. Diese Patienten hatten offensichtlich keine #PEM!

Auto translation:

Generalizing such methodologically flawed studies is very dangerous for patients with #MECFS and #PCS with #PEM . These patients obviously had no #PEM !

https://twitter.com/user/status/1776583270047564069

 

[SNT Gatchaman]

These patients obviously had no #PEM !

16% (5/31) of PCC dropped out of the study after the initial CPET (1), first (3) or second (1) exercise sessions. In comparison 2 HCs (6%) dropped out after the second exercise session. The paper does not tell us why they dropped out. If it was due to exertion intolerance or PEM crash that needed to be reported as an outcome, otherwise this data is meaningless. It might simply be saying if we ignore the people with PEM, no-one has PEM.

 

[SNT Gatchaman]

The body of the report also glosses over the first drop-out occurring after physiologic characterisation including bicycle ergometer CPET. They write —

This study included 62 participants (47 women [76%]; 15 men [24%]), with a mean (SD) age of 47.0 (9.4) years. Specifically, the study cohort consisted of 31 patients with PCC (mean [SD] age, 46.6 [10.0] years; 7 men [23%], 24 women [77%]) and 31 age- and sex-matched healthy controls (mean [SD] age, 47.3 [8.9] years; 8 men [26%], 23 women [74%]).

Continuing —

During the study, there was 1 minor adverse event in 1 control participant (3%) (knee pain during isokinetic dynamometry) that resolved with [without?] sequelae, and the participant was able to complete the study.

All participants reached the targeted exercise intensity during exercise sessions (eTable 2 in Supplement 2).

However "all participants" doesn't actually seem to mean "all participants" as for PCC there are data for 27, 28 and 27, so not 31 (or even 30). So it seems to mean that all participants that did the exercises reached the targeted intensity.

eTable 9: Mean differences in variables from the 48h follow-up cardiopulmonary exercise testing (CPET) between the three exercise sessions (HIIT: high-intensity interval training, MICT: moderateintensity continuous training, ST: strength training). Data are combined patients with post-covid condition (PCC; N=31) and age-, sex- matched healthy controls (N=31). Means (SD) for each group and exercise are presented in eTable 7. Data are presented as mean difference (95% CI).

But 31 PCC didn't do the three exercise sessions: eTable 2 says 27 did. However fig 1 says only 26 did all 3.

 

[Dolphin]

Editorial on this.

Free fulltext:
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2817151
Invited Commentary
Physical Medicine and Rehabilitation
April 4, 2024
Exercise Therapy for Post–COVID-19 Condition—Does No Harm
Peter Ladlow, PhD1,2; Alexander N. Bennett, PhD1,3; Oliver O’Sullivan, MBChB1,4
Article Information

• 1Academic Department of Military Rehabilitation, Defence Medical Rehabilitation Centre (DMRC) Stanford Hall, Loughborough, United Kingdom
• 2Department for Health, University of Bath, Bath, United Kingdom
• 3National Heart and Lung Institute, Imperial College London, London, United Kingdom
• 4Academic Unit of Injury, Recovery and Inflammation Science, School of Medicine, University of Nottingham, Nottingham, United Kingdom

JAMA Netw Open. 2024;7(4):e246959. doi:10.1001/jamanetworkopen.2024.6959

 

[SNT Gatchaman]

Invited commentary largely referencing their own prior work and opinions.

Exercise tolerance, fatigue, mental health, and employment status at 5 and 12 months following COVID-19 illness in a physically trained population (2023, Journal of Applied Physiology)

Use of symptom-guided physical activity and exercise rehabilitation for COVID-19 and other postviral conditions (2023, BMJ Mil Health)

The latter opinion piece contained —

The basis of this commentary is to: (1) address the controversies surrounding GET for post-COVID-19 rehabilitation treatment; (2) provide evidence supporting PA promotion and the consequences of physical inactivity; (3) address additional population-based challenges for UK Defence Rehabilitation practitioners; and (4) propose ‘symptom guided PA and exercise rehabilitation’ as an appropriate method of exercise rehabilitation for managing individuals with multifaceted medical needs.

GET is a poorly conceived exercise rehabilitation method which does not accommodate individual needs. However, this does not imply that exercise promotion for the management of ME/CFS or post-COVID-19 syndrome should be contraindicated.

We recognise a degree of greater rehabilitation support and creativity may be warranted to elicit favourable long-term changes in physical function for individuals with complex needs. However, the authors strongly believe that PA and exercise should be carefully prescribed and managed following a comprehensive needs analysis (box 2: adapted from Ruddock et al), and proactively encouraged due to the consequences of physical inactivity and importance of resistance exercise and cardiorespiratory fitness during rehabilitation.

Given the opinions expressed above [box 1], it is the authors’ belief that individuals or advocacy groups should not conflate the omission of GET as a justification for removing ‘any’ exercise therapy as treatment option for post-COVID-19 syndrome (or any other postviral condition).

Concluding with —

Recommendations supporting ‘pacing’, but not appropriately tailored PA and exercise as a safe and effective rehabilitation intervention, for the management of post-COVID-19 syndrome are (in these authors’ opinion) suboptimal recommendations. The same principles should underpin both, with PA and exercise prescription remaining individualised and regulated by symptoms.

Correct exercise prescriptions require a comprehensive needs analysis, appropriate training volume/loads (based on energy availability), with the consideration of other factors including sleep, adequate rest, and nutrition, cognitive functioning and regular review of symptomatic response. Failure to consider these variables when designing and delivering exercise programmes will almost certainly guarantee poor rehabilitation outcomes, PESE and loss of faith in healthcare provider(s).

(Article also noted in Ravi's post #2).