Sustained Impairment in Cardiopulmonary Exercise Capacity Testing in Patients after COVID-19: A Single Center Experience, 2022, Evers et al

Abstract

Background. Following COVID-19, patients often present with ongoing symptoms comparable to chronic fatigue and subjective deterioration of exercise capacity (EC), which has been recently described as postacute COVID-19 syndrome.

Objective. To objectify the reduced EC after COVID-19 and to evaluate for pathologic limitations.

Methods. Thirty patients with subjective limitation of EC performed cardiopulmonary exercise testing (CPET). If objectively limited in EC or deteriorated in oxygen pulse, we offered cardiac stress magnetic resonance imaging (MRI) and a follow-up CPET.

Results. Eighteen male and 12 female patients were included. Limited relative EC was detected in 11/30 (36.7%) patients. Limitation correlated with reduced body weight-indexed peak oxygen (O2) uptake (peakV̇O2/kg) (mean 74.7 (±7.1) % vs. 103.6 (±14.9) %, ). Reduced peakV̇O2/kg was found in 18/30 (60.0%) patients with limited EC. Patients with reduced EC widely presented an impaired maximum O2 pulse (75.7% (±5.6) vs. 106.8% (±13.9), ). Abnormal gas exchange was absent in all limited EC patients. Moreover, no patient showed signs of reduced pulmonary perfusion. Using cardiac MRI, diminished biventricular ejection fraction was ruled out in 16 patients as a possible cause for reduced O2 pulse. Despite noncontrolled training exercises, follow-up CPET did not reveal any exercise improvements.

Conclusions. Deterioration of EC was not associated with ventilatory or pulmonary vascular limitation. Exercise limitation was related to both reduced O2 pulse and peakV̇O2/kg, which, however, did not correlate with the initial severity of COVID-19. We hypothesize that impaired microcirculation or limited peripheral O2 utilization might be causative for prolonged deterioration of EC following acute COVID-19 infection.

Open access, https://www.hindawi.com/journals/crj/2022/2466789/

 

No, they'll read the following and conclude that "professional intervention" is needed.

VO2Max/O2 pulse is determined by exercise intensity not activity levels and chances are people suffering from perceived exercise capacity impairment after COVID are not likely to exercise regularly at high intensity levels.

However it does also mean that the typical approach in GET studies where they just tell you to walk for a few minutes longer each day also won't work.

The lack of evidence of pulmonary disease in most patients shouldn't be a surprise as it isn't a cause of fatigue or exercise capacity (EC) impairment except at high intensity levels and this was a retrospective study so we have no baseline to know if the peak lung capacity declined.

Reduced O2Pulse can also be due to reduced ejection from the heart, which can be due to cardiovascular deconditioning. They examined the heart with MRI (in the sixteen patients with EC and claimed they ruled out diminished biventricular ejection fraction but they provided no quantitative data and this is a retrospective study so there was no comparison with pre-COVID data. So basically they only ruled out COVID related heart disease.

The lack of discussion of deconditioning at all in the study seems to be deliberate, presumably they justify this with a lack of evidence of improvement at the ~3 month followup CPET.

The results could well be due to microcirculation problems, but that is merely speculation given the results of this study.

 

I'm always currently worried that lack of saying it doesn't mean that is the agenda but... I actually did the whole cntrl+f on 'rehab' and found nothing suggesting this and haven't spotted anything suggesting that necessarily explicitly within it - other than the note that 'professional rehab was not offered between the first (C. 4 mnths post covid) and second CPET' (c 3.6mnths first CPET, however, they discuss that it was a real issue getting enough for this follow-up).

I quite like the scientific curiosity/humility involved with them noting their limitation was no pre-covid measure of fitness, and so their inclusion of the following reference and description of it - it seems a neat addition for what they note is primarily hypothesis-forming rather than conclusive theories:

"A relevant limitation of the study is the missing patient’s CPET data before COVID-19 manifestation. Therefore, EC limitations can only be diagnosed by comparison with healthy individuals or lower limit of normal values but do not consider a diverging individual physical fitness before infection with SARS-CoV-2. In this context, Milovancev et al. evaluated professional volleyball players three weeks after convalescence of COVID-19. While this cohort is thought to be well trained before SARS-CoV-2 infection, peak V̇O2/kg was deteriorated likewise in CPET [60], allowing for a concept of EC limitation pathogenesis after COVID-19 beyond pre-existing mitochondrial density and physical training."

I also note that their discussion includes a whole paragraph on CFS (I've split it into 2 for reading purposes) - which seems a good discussion with references (including studies including MYhill on mitochondrial dysfunction) of causes including mitochondria but also muscle findings:

"Interestingly, chronic fatigue syndrome (CFS), a debilitating disease also caused by viral infections [42], shows similar features to long COVID syndrome, such as exertional intolerance with postexertional malaise and chronic fatigue. In CFS, vascular dysfunction leading to impaired muscle perfusion and limited cerebral blood flow upon exertion is considered a key mechanism for symptomatic disease [43–46]. In addition, mitochondrial dysfunction has been considered in CFS [47, 48]."

"In this regard, previous studies with CPET demonstrated reduced peak oxygen consumption in the majority of CFS patients [49, 50], although peak V̇O2 was not attributed to reduced oxygen uptake and transport to the muscle [51]. Since we were able to exclude a cardiac genesis as the cause of limited oxygen pulse and peak V̇O2, we hypothesize, based on our observations, that persistent vascular dysfunction with reduced peripheral oxygen delivery and/or impaired peripheral oxygen consumption due to metabolic dysfunction may also be present in our patient collective."

 

I don't really think that (pre-COVID) CPET data would have added much to the study. Hypothetically, lets just say that they did and the CPET results were the same, or declined post-COVID. The former is unlikely, but we'd just conclude that there are no exercise abnormalities in patients, nothing to see here, move along. The latter and we'd still have an inconclusive result - yes there is a drop in performance, but is it due to deconditioning due to lack of intense exercise or is it something else? Measuring mechanistic biomarkers over time is what is necessary for any sort of conclusion out of a study like this, even without baseline data.

The vague discussion of mitocondrial stuff shows they don't know what they are talking about.
VO2Max occurs at well below maximal utilisation of motor units. VO2Max is almost never limited by mitocondrial capacity since there is always more muscle fibre with more capacity that could potentially use any remaining oxygen. The potential rate limiting factors are the lungs, the heart and the circulatory system.

 

No wonder, when I got sick, the most objective sign that something was wrong was my sudden reduction in cardiovascular endurance. Literally overnight I could no longer do cardiovascular activities without getting exhausted prematurely, while just a few days before that I had no problem doing those activities for extended periods of time.

 

Yes, but the key point is that measuring VO2Max on a single CPET (as per the above study) isn't the right tool for measuring that reduction in cardiovascular endurance.

 

Fair point. However I also know that as prior to ME I was an athlete then I would have seemed 'fitter' than most peers even when actually obviously seriously depleted. Sadly this meant I was still the one doing all the sports activities that noone else would have been capable of but things like it being devastatingly hard, health going downhill and the odd race where having to bow out early due to not being able to get a lungfull made it obvious to me and the very few who might have trained with me and been near the same level of fitness/performance/times (not many). That's why I think the 2-day CPET is neat.

ALso we've all had to become very tenacious (which is why the courses with certain tones and talking about personality type are so patronising but also ignorant), adaptable and tough at getting through things despite should really being on the floor - because the illness can be somewhat pernicious in how it creeps up. So comparing across rather than within participants really does rely on the cohort being 'matched' in some way. ANd what I hear about long covid is that it is the athletes/most fit that tend to be more likely to get it. Agree that 2-day CPET and looking at the 'size of PEM and the difference in their measures of indicators of this' is more scientifically accurate perhaps. They seem to be focused on some specific issue area rather than big-picture which seems to have fed into their choice of methodology and so gut says doing neither of these would make it seem naive.

You'll have to catch me up on the last para. Isn't VO2 max the indicator of aerobic threshold. And so effectively if muscles become affected by exertion causing issues with uptake of oxygen and then glucose 'could' be engaging a different 'system' anyway (we don't know where it isn't measured) certainly towards the end/limit - I don't know with those issues whether the outcome can be it presents 'during' is would mostly be something that over time exhibits as a 'side-effect' from overdoing it exertion-wise like PEM? Or something far better put and not got round my neck than that - but the point being that they seem to not be saying 'instead of' but 'as well as' or 'alongside' these issues is the vascular hypothesis ie are they saying 'the combination' explains?

I don't fully get the vascular dysfunction bit either and can see that it is trying to 'add it into' the picture alongside all these other things then the precision with which those other aspects are understood and the impact and interaction to produce indirect aspects are therefore estimated in order to 'quantify how much of a part was left unexplained/could mean a role of vascular dysfunction'. I guess this is a hazard of the systemic stuff/conditions being done by people/methodology that is wanting a 'clean focus' on the area of interest when it could all be very interactive through all of these conditions they will have studied patients undertaking.

Shows perhaps how necessary understanding the 'stages' of ME/PEM is for any scientific research to develop a cohort that is effectively undertaking the same task in the same condition. It is nonsense if some are in PEM on arrival for some experiments and vice versa I don't know how long after the 'test' these measurements were continued for given the post-exertion physiology changes have been documented as delayed/happening over time. How do you know what you are explaining with a hypothesis if you've snapshotted a small timeslice of it only - or am I off track as to that being relevant for this vascular area (it seems relevant)?

 

No it is not.

Firstly we're talking about the anerobic threshold which itself is an artifact of the ramped power output of the exercise protocol - namely the gradual increase in required power output by the participants. When doing day to day activities or other forms of exercise, a shift to majority anerobic metabolism can occur at a wide range of heart rates and force outputs.

CPETs measure several thresholds . There are several ventilatory thresholds other than VO2Peak, the first is the gas exchange threshold (the "gas exchange threshold"). In my case when I did the testing, this occurred at around 70% of my VO2Peak. The second ventilatory threshold is the respiratory compensation point and this occurs at around 90% of VO2Max, and is the point at which exercising individuals hyperventilate to reduce CO2 in their blood and hence reduce acidity of the blood.

I prefer not to talk about "anerobic thresholds" as it is misleading as there is no clearly measurable correlate. Instead exercise physiologists should talk about ventilatory thresholds and lactate thresholds. The latter of which requires an invasive CPET to monitor the blood.

This first ventilatory threshold, sometimes suggested to be associated with an "anerobic threshold" is the gas exchange threshold. But these are not synonymous, since each of the muscle fibres in each of the motor units have actually has a range of metabolic sources and they aren't all driven into majority anerobic metabolism at exactly the same time and the shift in ventilation also also be influenced by supraspinal (brain) components as discussed below.

The reason why there is a clear ventilatory threshold however is due to feedback loops. As some of the muscle fibres increasingly rely on anerobic metabolism, they fatigue faster, requiring increased muscle drive and motor unit recruitment to sustain the same force output. This creates even more anerobic metabolites as a side effect stimulating more type 3/4 muscle afferents, which cause "central fatigue" (by inhibiting the excitability of the motor cortex) and some of the sensations associated with fatigue. But since the power output must be maintained due to the aforementioned ramped exercise protocol, the upstream drive increases, which also increases the drive to the lungs (which increases the minute ventilation of the lungs). So these feedback loops are what leads to the clear 'knee' in the graphs of VCO2 and VO2 in CPET tests, indicating the gas exchange threshold.

Side note, I have explained the basics of the various CPET parameters here (along with a summary table of results from 2 day tests). https://me-pedia.org/wiki/Two-day_cardiopulmonary_exercise_test

Problem is these tests don't really indicate PEM, but the reduction in the ventilatory threshold in ME/CFS patients on the second day does seem to be a correlate. Whether a participant is already in PEM or not can affect the results, but studies also suggest that milder levels of exercise are insufficient to lead to a clear shift in the ventilatory threshold. The studies also suggest that this effect doesn't persist at the 72 hour time point.

The reduction of the ventilatory threshold itself is indicative of central fatigue (it is a consequence of reduced motor cortex excitability) so this will also lead naive research to believe that is all in the brain, without realising that peripheral fatigue and metabolism are always coupled with central fatigue due to the afferent feedback loops I mentioned. So the place to look for the exercise intolerance component of PEM is the stimulation of those afferent nerves and their effects on the brain.