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

[EndME]

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

 

[EndME]

Cohort characteristics:

Patients were considered eligible for the study if they had self-reported exercise intolerance and fatigue that developed during or after an acute COVID-19 infection (confirmed by SARS-CoV-2 PCR testing), which persisted for ≥12 weeks, and which was not explained by an alternative diagnosis.

Thirty cases had been managed at home during their acute SARS-CoV-2 infection, and 2 had required hospitalisation, one received dexamethasone and tocilizumab and the other received dexamethasone and remdesivir.

Cases were investigated in our study, on average, 14±6 months post-acute SARS-CoV-2 infection. On average participants with Long COVID reported 10±4 symptoms, and all were experiencing fatigue and exercise intolerance (supplementary Figure S1).

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):

In total, 32 participants with Long COVID (10(31%) men, 44±12 years old) and 19 healthy controls (6(32%) men, 40±13 years old) were recruited (Figure 1). Cases had higher BMI, waist-to-hip ratio, body fat (%) and calf adipose tissue thickness than controls (Table 1). Amongst cases, 26(81%) of participants self-reported a pre-existing condition including: hypertension, asthma, type 2 diabetes mellitus and mental health conditions (supplementary Table S1).

They used NIRS, previously discussed here

Continuous wave (CW) NIRS (Portamon, Artinis Medical Systems, Netherlands) was used to assess skeletal muscle oxidative capacity and microvascular PORH.

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

The gold-standard non-invasive method for assessing oxidative capacity is to directly measure PCr recovery using 31P-MRS, confirmation of these findings via this method would be useful.

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".

 

[wabi-sabi]

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.

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

 

[DokaGirl]

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.

 

[SNT Gatchaman]

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.

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.

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

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 —

After a further recovery period, the leg-cuff was inflated again to >250 mmHg for at least 2 minutes. We aimed to have a 5-minute arterial occlusion in all participants, however, this measure was poorly tolerated in our study. Based on prior work demonstrating an association between flow and vessel dilatation as measured by flow mediated dilatation (FMD) with 1.5 minutes arterial occlusion, we set a threshold of 2 minutes for inclusion in the results [8]. The cuff was then released, and the PORH response was recorded for a minimum of 3 minutes.

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

 

[SNT Gatchaman]

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)