Mechanisms underlying exercise intolerance in Long COVID: an accumulation of multi-system dysfunction, 2023, Jamieson et al

Now published - final abstract here

Preprint
Mechanisms underlying exercise intolerance in Long COVID: an accumulation of multi-system dysfunction

The pathogenesis of exercise intolerance and persistent fatigue which can follow an infection with the SARS-CoV-2 virus ('Long COVID') is not fully understood.

Cases were recruited from a Long COVID clinic (N=32; 44± 12y; 10(31%)men), and age/sex-matched healthy controls (HC) (N=19; 40± 13y; 6(32%)men) from University College London staff and students. We assessed exercise performance, lung and cardiac function, vascular health, skeletal muscle oxidative capacity and autonomic nervous system (ANS) function. Key outcome measures for each physiological system were compared between groups using potential outcome means(95% confidence intervals) adjusted for potential confounders. Long COVID participant outcomes were compared to normative values.

When compared to HC, cases exhibited reduced Oxygen Uptake Efficiency Slope (1847(1679,2016) vs (2176(1978,2373) ml/min, p=0.002) and Anaerobic Threshold (13.2(12.2,14.3) vs 15.6(14.4,17.2) ml/Kg/min, p<0.001), and lower oxidative capacity on near infrared spectroscopy (τ: 38.7(31.9,45.6) vs 24.6(19.1,30.1) seconds, p=0.001). In cases, ANS measures fell below normal limits in 39%.

Long COVID is associated with reduced measures of exercise performance and skeletal muscle oxidative capacity in the absence of evidence of microvascular dysfunction, suggesting mitochondrial pathology. There was evidence of attendant ANS dysregulation in a significant proportion. These multi-system factors might contribute to impaired exercise tolerance in Long COVID sufferers.

https://www.medrxiv.org/content/10....1?rss=1&utm_source=dlvr.it&utm_medium=twitter

 

Cohort characteristics:

Matching isn't perfect with LC patients having quite a few pre-existing conditions (as they mention in the limitations section these pre-existing health conditions make it harder to draw conclusions):

They used NIRS, previously discussed here

They also mention that apparently there is a better method available, perhaps this could be interesting as well?

There appears to be a discrepancy in the physical activity data when comparing the actigraph data to self-reported data, is as the data suggests the threshold of the actigraph a completely different one for being sedentary then what one commonly believes to be sedentary and only "Average activity counts" is a meaningful measure?

Great to see such work coming from UCL. I'm not familiar with any of the authors but Hughes, Hamer, Treibel and Scully seems to be somewhat "bigger names".

 

This is new, isn't it? I thought most papers were pointing to microvascular and clotting problems.

 

I don't know if a study using all these tests has ever been applied to pre-COVID PwME. Does anyone know?

Some of these tests have of course been done for PwME; it would be good to see this more comprehensive investigation carried out with PwME, whose chronic illness did not follow a COVID infection.

As well, a comparison between PwLC and PwME using these tests would be interesting.

 

The self-report has patients less sedentary, doing more light physical activity, a little more moderate physical activity, with both LC and HC doing a little vigorous physical activity. Not much difference between groups on objective actigraphy, but as @EndME points out above there is a large discrepancy between what's counted as sedentary vs any activity between self-report and actigraphy. (I'd be nowhere near this level of daily activity).



Single CPET, with contemporaneous measurements, so no PEM component in the evaluation.

There were technical constraints with the reactive hyperaemia assessment, so possibly the ability to demonstrate group differences was affected. They referred to previous data from flow-mediated dilation (FMD) which looks at medium-sized / conduit arteries and settled on 2 minutes instead of 5. I don't know whether this reduced occlusion time could impact the microvascular assessment using the NIRS post-occlusion reactive hyperaemia (PORH).

From supplementary materials in the NIRS section —

For more on PORH*, see Reactive hyperemia: a review of methods, mechanisms, and considerations (2020, American Journal of Physiology-Regulatory, Integrative and Comparative Physiology) and Reproducibility and normalization of reactive hyperemia using laser speckle contrast imaging (2021, PLOS ONE)

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* Also when googling, search using "post-occlusive reactive hyperemia". Searching for "PORH" will give you less relevant results

 

Published in Physiological Reports as —

Mechanisms underlying exercise intolerance in long COVID: An accumulation of multisystem dysfunction
Alexandra Jamieson; Lamia Al Saikhan; Lamis Alghamdi; Lee Hamill Howes; Helen Purcell; Toby Hillman; Melissa Heightman; Thomas Treibel; Michele Orini; Robert Bell; Marie Scully; Mark Hamer; Nishi Chaturvedi; Hugh Montgomery; Alun D. Hughes; Ronan Astin; Siana Jones

The pathogenesis of exercise intolerance and persistent fatigue which can follow an infection with the SARS-CoV-2 virus (“long COVID”) is not fully understood.

Cases were recruited from a long COVID clinic (N = 32; 44 ± 12 years; 10 (31%) men), and age-/sex-matched healthy controls (HC) (N = 19; 40 ± 13 years; 6 (32%) men) from University College London staff and students. We assessed exercise performance, lung and cardiac function, vascular health, skeletal muscle oxidative capacity, and autonomic nervous system (ANS) function. Key outcome measures for each physiological system were compared between groups using potential outcome means (95% confidence intervals) adjusted for potential confounders. Long COVID participant outcomes were compared to normative values.

When compared to HC, cases exhibited reduced oxygen uptake efficiency slope (1847 (1679, 2016) vs. 2176 (1978, 2373) mL/min, p = 0.002) and anaerobic threshold (13.2 (12.2, 14.3) vs. 15.6 (14.4, 17.2) mL/kg/min, p < 0.001), and lower oxidative capacity, measured using near infrared spectroscopy (τ: 38.7 (31.9, 45.6) vs. 24.6 (19.1, 30.1) s, p = 0.001). In cases, ANS measures fell below normal limits in 39%.

Long COVID is associated with reduced measures of exercise performance and skeletal muscle oxidative capacity in the absence of evidence of microvascular dysfunction, suggesting mitochondrial pathology. There was evidence of attendant ANS dysregulation in a significant proportion. These multisystem factors might contribute to impaired exercise tolerance in long COVID sufferers.

Link | PDF (Physiological Reports)