(Recruiting) Exercise Intolerance in Post-COVID Patients, 2022, Lundberg et al

Exercise Intolerance in Post-COVID Patients

Physiological Characterization of Functional Limitations and Exercise Intolerance in Post-COVID Patients

Tommy Lundberg, Helene Rundqvist et al
Karolinska Institutet, Karolinska University Hospital, Sweden.

"Brief Summary:

The post-COVID syndrome poses an unprecedented challenge to modern society, affecting millions of people worldwide. Persistent fatigue and exercise intolerance are among the most common complaints of these subjects.

The mechanisms of exercise intolerance in post-COVID subjects are remained yet unknown, which make the rehabilitation efforts complex and challenging.

The overall goals of this project are to:

1) improve physiological understanding of symptoms in this clinical condition,

2) elucidate plausible mechanisms to explain exercise intolerance/symptom exacerbation, and finally

3) provide knowledge that can be directly applied in the clinical setting to improve diagnosis, care, and individualized rehabilitation of subjects with post-COVID syndrome.

Post-COVID subjects and age/sex matched healthy controls will undertake a comprehensive set of physiological and functional assessments, followed by 3 experimental visits (in a randomized order), where acute exercise responses will be assessed in either continuous moderate intensity aerobic exercise, high intensity interval exercise, or strength training.

The same set of physiological assessments will also be performed after 1 year in both post-COVID subjects and healthy-matched controls to better understand the time course of the syndrome.

It is hypothesized that the mechanism responsible for exercise intolerance is linked to specific symptoms and will vary across subjects. However, it is expected that most post-COVID subjects will respond well to at least one type of exercise."

https://clinicaltrials.gov/ct2/show/NCT05445830

(ETA Helene Rundqvist)

 

"Intervention/treatment:

Procedure: High-Intensity-Interval-Exercise
Subjects will perform high-intensity-interval exercise, where the acute exercise responses will be closely monitored, including measurements of O2 saturation, blood pressure, ventilatory response, oxygen uptake, and blood lactate. In addition, blood samples will be collected before, immediately after, and 2 hours after each exercise session to describe leukocyte and cytokine release as well as systemic metabolism. After a 48-hour rest period subjects will return to the laboratory for symptom assessment, submaximal exercise response (CPET), and blood sampling.
Other Name: HIIE

Procedure: Moderate-Intensity-Continuous-Exercise
Subjects will perform moderate intensity continuous exercise, where the acute exercise responses will be closely monitored, including measurements of O2 saturation, blood pressure, ventilatory response, oxygen uptake, and blood lactate. In addition, blood samples will be collected before, immediately after, and 2 hours after each exercise session to describe leukocyte and cytokine release as well as systemic metabolism. After a 48-hour rest period subjects will return to the laboratory for symptom assessment, submaximal exercise response (CPET), and blood sampling.
Other Name: MICE

Procedure: Strength training
Subjects will perform a series of a whole-body resistance exercises, where the acute exercise responses will be closely monitored, including measurements of O2 saturation, blood pressure, ventilatory response, oxygen uptake, and blood lactate. In addition, blood samples will be collected before, immediately after, and 2 hours after each exercise session to describe leukocyte and cytokine release as well as systemic metabolism. After a 48-hour rest period subjects will return to the laboratory for symptom assessment, submaximal exercise response (CPET), and blood sampling.
Other Name: Resistance training

Procedure: Baseline assessment
Subjects will perform a series of baseline assessment including neurophysiological function, circulatory and vascular function, respiratory/ventilatory function, maximal oxygen uptake, strength, physical function and fitness, blood status, muscle biopsies, cytokine profiling, and T-cell metabolism.

Procedure: 1 year follow-up
Subjects will perform the same series of baseline assessment in 1-year time, including neurophysiological function, circulatory and vascular function, respiratory/ventilatory function, maximal oxygen uptake, strength, physical function and fitness, blood status, muscle biopsies, cytokine profiling, and T-cell metabolism."

https://clinicaltrials.gov/ct2/show/NCT05445830

 

"Primary Outcome Measures :

1. Post-exercise malaise symptoms of post-COVID subjects and age/sex matched controls in response to different exercise trials. [ Time Frame: Three exercises trials & 48 hours follow-ups of each trial ]
   The score in DePaul Symptom Questionnaire-Post-Exertional Malaise (DSQ-PEM) will be used to assess exercise intolerance (immediately after, 2 hours and 48 hours post) in response to different exercise trials (high intensity interval training, moderate intensity continuous exercise and strength exercise) across the post-COVID subjects and age/sex matched controls.
   

Secondary Outcome Measures :

1. Absolute immune cell count in blood samples of post-COVID subjects and age/sex matched controls in response to different exercise trials. [ Time Frame: Three exercises trials & 48 hours follow-ups of each exercise trial ]
   Absolute immune count will be assessed via BD TruCount in collected blood samples (before, immediately after, 2 hours and 48 hours post) in response to different exercise trials (high intensity interval training, moderate intensity continuous exercise and strength exercise) across the post-COVID subjects and age/sex matched controls. PBMCs will be analysed for distribution of B cells, NK cells, monocytes, CD4+ T cells, CD8+ T cells, with additional panels to capture plasma, effector and memory cells.
   
   
2. Exploratory metabolomic and cytokine profiling using blood samples of post-COVID subjects and age/sex matched controls in response to different exercise trials. [ Time Frame: Three exercises trials ]
   Metabolomic and cytokine profiling will be explored in collected blood samples (before, immediately after, and 2 hours post-exercise) in response to different exercise trials (high intensity interval training, moderate intensity continuous exercise and strength exercise) across the post-COVID subjects and age/sex matched controls. Olink PEA platform and GC-MS at the Swedish Metabolomics Centre in Umea will be used and targeted analysis will include IL-6, TNF-a and IFN-g profiling.
   
   
3. Exercise (in)capacity of post-COVID subjects and age/sex matched controls in response to different exercise trials. [ Time Frame: Three exercises trials ]
   O2 saturation, blood pressure, ventilatory/VCO2 response, oxygen uptake, and blood lactate will be thoroughly and continuously monitored during each exercise trial (high intensity interval training, moderate intensity continuous exercise and strength exercise) to be used towards exercise (in)capacity assessment across different exercise types in the post-COVID subjects and age/sex matched controls.
   
   
4. Exercise (in)capacity of post-COVID subjects and age/sex matched controls at 48 hours post different exercise trials. [ Time Frame: 48 hours follow-ups after each exercise trial ]
   Submaximal exercise response (CPET), including ventilation and VE/VCO2 ratio, O2 saturation, VO2, heart rate, blood lactate, and rating of perceived exertion (RPE) will be used to assess exercise capacity in all participants at 48 hours following each exercise trial (high intensity interval training, moderate intensity continuous exercise and strength exercise).
   
   
5. Physical Fitness in post-COVID subjects and age/sex matched controls [ Time Frame: Day 1 (Baseline) & at 1-year follow-up ]
   The validated 6-minute walk test or the Short Physical Performance Battery (SPPB) test will be used to assess physical fitness of post-COVID subjects and age/sex matched controls at baseline (Day 1) and at 1-year follow-up.
   
   
6. Muscle strength in post-COVID subjects and age/sex matched controls [ Time Frame: Day 1 (Baseline) & at 1-year follow-up ]
   Handgrip dynamometer and isokinetic dynamometry (Biodex) will be used to assess muscle strength of upper and lower body respectively in post-COVID subjects and age/sex matched controls at baseline (Day 1) and at 1-year follow-up.
   
   
7. Postural orthostatic tachycardia syndrome (POTS) in post-COVID subjects and age/sex matched controls. [ Time Frame: Day 1 (Baseline) & at 1-year follow-up ]
   Head-up TILT test will be used to examine the differences in POTS of post-COVID subjects and age/sex matched controls at baseline (Day 1) and at 1-year follow-up.
   
   
8. Cardiopulmonary function in post-COVID subjects and age/sex matched controls [ Time Frame: Day 1 (Baseline) & at 1-year follow-up ]
   VO2max on an electronically braked cycle ergometer using an online gas collection system will be performed to assess the differences in cardiopulmonary function of post-COVID subjects and age/sex matched controls at baseline (Day 1) and at 1-year follow up.
   
   
9. Pulmonary function in post-COVID subjects and age/sex matched controls [ Time Frame: Day 1 (Baseline) & at 1-year follow-up ]
   Spirometry will be used to examine the differences in pulmonary function of post-COVID subjects and age/sex matched controls at baseline (Day 1) and at 1-year follow up.
   
   
10. Cardiac function in post-COVID subjects and age/sex matched controls [ Time Frame: Day 1 (Baseline) & at 1-year follow-up ]
    Echocardiography will be used to examine the differences in cardiac function of post-COVID subjects and age/sex matched controls at baseline (Day 1) and at 1-year follow up.
    
    
11. Vascular function in post-COVID subjects and age/sex matched controls [ Time Frame: Day 1 (Baseline) & at 1-year follow-up ]
    A non-invasive ultrasound test, flow-mediated dilation (FMD) will be used to examine the differences in vascular function of post-COVID subjects and age/sex matched controls at baseline (Day 1) and at 1-year follow up.
    
    
12. Neurophysiological function in post-COVID subjects and age/sex matched controls [ Time Frame: Day 1 (Baseline) & at 1-year follow-up ]
    To examine the differences in neurophysiological function of post-COVID subjects and age/sex matched controls at baseline (Day 1) and at 1-year follow up, as assessed by electroneurography of motor and sensory nerves in the upper and lower extremities (large nerves), standardized quantitative sensory test including a thermal threshold test in the feet and hands (small nerves), sympathetic skin response (SSR) and heart rate variability (HRV) testing (autonomic nervous system), and needle EMG in proximal and distal muscles (integrity of motor units).
    
    
13. Skeletal muscle alterations in post-COVID subjects and age/sex matched controls [ Time Frame: Day 1 (Baseline) & at 1-year follow-up ]
    A small muscle biopsy (approximately 200 mg) will be taken from the vastus lateralis muscle at baseline and at 1-year follow-up under local anesthesia using the Bergström needle technique in all participants. Histochemical analyzes of fiber size, fiber type, myonuclear content, and gene/protein expression of markers involved in energy processes, muscle atrophy, endothelial dys(function), angiogenesis and mitochondrial biogenesis will be performed in all participants to investigate for any differences across post-COVID subjects and age/sex matched controls."

https://clinicaltrials.gov/ct2/show/NCT05445830

 

https://news.ki.se/help-us-to-uncover-the-physical-limitations-of-post-covid

Same article in Swedish:
https://nyheter.ki.se/hjalp-oss-att-avsloja-de-fysiska-begransningarna-av-postcovid

 

So is it the usual shit ---- avoid assessing physical activity using objective criteria i.e. actimetry (FitBit type devices) so that you can claim the intervention works using the un-objective questionnaire "assessment"?

If so then anyone who can warn the log covid community?

If it's the usual [unblinded & subjective outcome criteria] then I suppose you could say that they know how to get the right answer ("prove" the intervention works)/avoid the wrong answer ---

Who is funding the study?

 

Come on. It's embarrassing that an entire profession is incapable of handling basic facts that make them look bad, simply default to pretending otherwise even though it's a freaking blatant lie. And then they go right ahead and do the exact same thing like it's some giant coincidence and not because this is what they were already doing.

That no one can even see how absurd it is to keep "testing" something that was the standard of care for LC from the start is even more embarrassing. It's been a standard for decades applied to millions of people, and they all pretend like it's some separate unheard of thing. It's like someone just going around in loops trying the same key in the same lock over and over again and every time thinking it's a genius idea. WTH, man?

 

Is this a treatment study or a symptom provocation study? If it's the latter, a HIIT workout will be harsh but effective.

 

They probably won't be needing three trials of it for people with PEM—I doubt they'll find anyone daft enough to try it more than once.

 

Don't know how to feel about this study.

A part of me is screaming "don't do it, patients will get hurt!" It doesn't help that the researchers seem to come at it with the assumption that they'll find some sort of exercise that will help LC. Nor does it inspire confidence that they're conflating PEM and exercise intolerance.

On the other hand, this is a relatively large (by ME standards anyway, n=80) provocation study with a CPET 48 hours after exercise and they're doing a lot of blood tests at several time points plus a range of other objective tests (although most of those only at baseline and the 1 year follow up which is a missed opportunity because for example a tilt test 48 hours after exercise could look interesting). But there seems to be at least a reasonable chance for some valuable findings in return for the risk patients expose themselves to.

So, like with the CPET studies in ME, I'm feeling conflicted.

 

Similar conflict, they are using a lot of objective measures, hand-grip, physiological monitoring of every description and using the DePauls questionnaire for PEM etc. It is my understanding that this is the current research standard in Australasia for pwME out of Griffith University, Gold Coast, Australia (NCNED)

Important that the study participants have proper informed consent on the risks of deterioration and the researchers have clear understanding of levels of physiological impairment. I think they do.

I believe we do need good physiological data and stress testing of cardiovascular systems to further the knowledge of ME/LC and the flow on effect of finding if this is peripheral or central or an inter-relationship etc. Electrophysiologists in New Zealand, (Hodges, Massey University), are already finding a peripheral component for ME, which further strengthens the mitochondrial dysfunction and/or how the endothelium may be affected or “becomes stiffened”. This strengthens scientific knowledge away from BPS and may give much needed data on aetiology (causation).

If I had an opportunity to be part of this study when I had mild ME or LC, I would probably have done it for the scientific community.

edit: a few additions

 

If you believe that over-exertion in people who experience PEM is potentially harmful, which I do, then I believe that the ethics of a study which asks people who experience PEM to over-exert themselves is always going to be problematic.

I doubt that this study explicitly says "we will be asking you to over-exert via CPET, and you may therefore experience harm", so to my mind the patients taking part can't possibly have given informed consent. Of course the counter argument is that we have no definitive proof that over-exertion causes harm, but then NICE, and others, have changed their treatment guidelines based on the patient survey reports of harms.

 

Why would you state that you are assuming some form of exercise will help patients when your whole study is designed in order to provoke symptoms in them via exercise?

There is no way I would have taken part in this study at any level of illness (am now severe, have been mild and different levels of moderate). Others may be willing to put themselves through it to discover something to help; as Andy says there is the issue of informed consent. But they are hardly saying, "OK, if there's a problem here let's measure and quantify it". They are stating they think this will help people and don't discuss risks.

Am I missing something? It just seems inconsistent to me.

ETA: How are they going to offset the selection bias? There is no way many people who have PEM will take part; it looks really dangerous.

 

Are they also putting the cart before the horse, trying to find a treatment through exercise before we know what PEM actually is, and without apparently developing away of distinguishing issues like reduced lung capacity and impaired cardiovascular function following the acute phase from an abnormal (physiological) response to any over exertion including cognitive over exertion?

Also it is impossible to take seriously any study that is not also controlling for activity levels overall including what happens outside the exercise setting? You need to know what other things subjects might or might not be doing during the experimental period. Surely this is only achievable by electronic monitoring of subjects activity 24/7 as well as keeping some sort of activity diary to ID cognitive or emotional exertion.

Though attempting to address an important issue, I suspect over the course of the study they will lose those with ME/CFS, but apparently come up with positive exercise recommendations because they are including those with already spontaneously recovering post viral fatigue or those experiencing one off damage that occurred during the acute phase.

 

Well, it's not research, so none of this matters. They have a popular conclusion that they want to market, it's very desirable, and they will market the hell out of it. Everything else is irrelevant. No one involved in this wants to understand anything, they already believe they do, and clearly reality is irrelevant in their ideological fanaticism.

The flaws and weaknesses aren't bugs, they're necessary features. The goal is to market the usual, cheating is the norm to achieve this and one thing has been made very clear these last few years and it's that the entire profession is OK with that, doesn't care about any of that science and ethics thing because they don't have to respect any of this when it comes to chronic illness, the profession is simply incapable of accepting they have majorly screwed up for decades, ruined millions of lives, and would rather keep the lies going than face reality.

Ironically, exactly what they accuse us of. Because it's all projection, every single damn thing they say about us is really about them, as is every accusation they make of us. In the end it's the same reason why US police officers keep murdering people in cold blood, even on camera: because they can, they're allowed to do that, they want to keep doing that and you can't make them stop.

 

Isn't it just their main tactic/strategy - so.. habitually/tactically accuse the other side of it [to distract people from that being exactly what they are doing].

And yes, whilst I also wouldn't argue with the idea those in that area have lost the plot on what research in any other world to them is supposed to be, it is deliberate on the basis of the whole aim of the game being rather different

- and you gotta blame regs and the parts of the puzzle (such as publications, those involved with peer review and hierarchy and those who keep them in jobs) for I assume asking for it

I find it astounding the whole system thinks their reputation so untouchable they are prepared to not protect the meaning of the terms 'research', 'evidence', 'significance' and so on to differentiate ideological manifestos from academic discussion anywhere in the chain - which sort of makes people just hired paper-writers, hence if this is going to be the 'environment' these things are produced in then knowing the exact financial and other interests of individuals publishing, along with their own ideologies becomes one of the most important things for any reader to be informed of? It's just pure rhetoric with everything removed isn't it?

And this is where I get puzzled by the ethics board issue - if this is recruiting people, and their participation cannot possibly change the outcome as even if the design made hypothesis rejection possible it wouldn't be published, and the primary, secondary outcome can change and different calcs get picked around for fishing expeditions without any requirement of raw data transparency is that not a major issue?

Anyone help me with putting into technical terms what that translates as for participants? Because is there not an issue if an area does have this 'different definition of research' with full transparency being given regarding these 'looser regs' needing to be made very clear prior to someone signing up e.g. 'after you sign up to this, it might change in outcomes and if you drop out you will be counted as a drop-out even if you would have refuted hypothesis, results might not be published in full etc'.

Surely there is a definitional issue here that relates quite directly to ethics in recruitment - if they aren't covered by the academic/medicine regs then surely they would be covered by market research regs or other regs and there must be transparency on how their data will be used being provided before sign-up?

And that is before you have to ask about the risk analysis side of things - and why they don't as researchers have to submit plans about how they are safeguarding not harming those who have PEM/PESE given there is enough research on that now to make that a possibility

 

Anyone here from Sweden - anyone know someone in Sweden?
Worth asking that they include Actimetry (FitBit) that way the data would be higher quality/more confidence in the result.

 

You could contact them yourself? Adding actimetry is a very good suggestion. There is contact info on the KI page, linked above. You can write to them in English.

 

Last time - Swiss study - University Zurich* - I did it myself and cc to a Swiss charity - I'd rather a local charity did it ----

*
https://www.s4me.info/threads/effec...ic-encephalomyelitis.23974/page-2#post-399838

 

You could contact the Swedish Covid Association info@covidforeningen.se, and suggest they do it? Or RME info@rme.nu?