Decreased physical performance despite objective and subjective maximal exhaustion in post-COVID-19 individuals with fatigue

Abstract:

Introduction: Fatigue is a common symptom in post-COVID-19 patients. Individuals with fatigue often perform less well compared to healthy peers or without fatigue. It is not yet clear to what extent fatigue is related to the inability to reach maximum exhaustion during physical exercise.

Methods: A symptom-based questionnaire based on the Carruthers guidelines (2003) was used for reporting the presence of fatigue and further symptoms related to COVID-19 from 85 participants (60.0% male, 33.5 ± 11.9 years). Cardiopulmonary exercise testing (CPET) and lactate measurement at the end of the test were conducted. Objective and subjective exhaustion criteria according to Wasserman of physically active individuals with fatigue (FS) were compared to those without fatigue (NFS).

Results: Differences between FS and NFS were found in Peak V̇O2/BM (p < 0.001) and Max Power/BM (p < 0.001). FS were more likely to suffer from further persistent symptoms (p < 0.05). The exhaustion criterion Max. lactate was reached significantly more often by NFS individuals.

Conclusion: Although the aerobic performance (Max Power/BM) and the metabolic rate (Peak V̇O2/BM and Max. lactate) of FS were lower compared to NFS, they were equally able to reach objective exhaustion criteria. The decreased number of FS who reached the lactate criteria and the decreased V̇O2 peak indicates a change in metabolism. Other persistent post-COVID-19 symptoms besides fatigue may also impair performance, trainability and the ability to reach objective exhaustion.

Trial registration: Trial registration: DRKS00023717; date of registration: 15.06.2021 (retrospectively registered).

Source: Vollrath S, Matits L, Schellenberg J, Kirsten J, Steinacker JM, Bizjak DA. Decreased physical performance despite objective and subjective maximal exhaustion in post-COVID-19 individuals with fatigue. Eur J Med Res. 2023 Aug 26;28(1):298. doi: 10.1186/s40001-023-01274-5. PMID: 37633931; PMCID: PMC10464445. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464445/ (Full text)

Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome

To the Editor:

After acute infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many individuals experience a range of symptoms including dyspnea, exercise intolerance, and chest pain commonly referred to as “post–COVID-19 syndrome” or as post-acute sequelae of SARS-CoV-2 infection (PASC) (). Exertional dyspnea and physical activity intolerance in PASC can be debilitating despite mild acute coronavirus disease (COVID-19) and normal resting pulmonary physiology and cardiac function (). There is an urgent need to understand the pathogenesis of PASC and find effective treatments. The cardiopulmonary exercise test (CPET) is commonly used to investigate unexplained exertional dyspnea; as such, it could provide insight into mechanisms of PASC. CPET data can be used to calculate rates of β-oxidation of fatty acids (FATox) and of lactate clearance, providing insight into mitochondrial function (). Fit individuals have better mitochondrial function and a higher rate of FATox during exercise than less fit individuals (). Our results suggest that patients with PASC have significant impairment in fat β-oxidation and increased blood lactate accumulation during exercise, regardless of previous comorbidities.

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Source: de Boer, E., Petrache, I., Goldstein, N. M., Olin, J. T., Keith, R. C., Modena, B., Mohning, M. P., Yunt, Z. X., San-Millán, I., & Swigris, J. J. (2022). Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome. American journal of respiratory and critical care medicine205(1), 126–129. https://doi.org/10.1164/rccm.202108-1903LE  I https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865580/ (Full text)

Enterovirus related metabolic myopathy: a postviral fatigue syndrome

Abstract:

OBJECTIVE: To detect and characterise enterovirus RNA in skeletal muscle from patients with chronic fatigue syndrome (CFS) and to compare efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients.

METHODS: Quadriceps muscle biopsy samples from 48 patients with CFS were processed to detect enterovirus RNA by two stage, reverse transcription, nested polymerase chain reaction (RT-NPCR), using enterovirus group specific primer sets. Direct nucleotide sequencing of PCR products was used to characterise the enterovirus. Controls were 29 subjects with normal muscles. On the day of biopsy, each CFS patient undertook a subanaerobic threshold exercise test (SATET). Venous plasma lactate was measured immediately before and after exercise, and 30 minutes after testing. An abnormal lactate response to exercise (SATET+) was defined as an exercise test in which plasma lactate exceeded the upper 99% confidence limits for normal sedentary controls at two or more time points.

RESULTS: Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET- patients. PCR products were most closely related to coxsackie B virus.

CONCLUSIONS: There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients.

Comment in: Enteroviruses in chronic fatigue syndrome: “now you see them, now you don’t”. [J Neurol Neurosurg Psychiatry. 2003]

 

Source: Lane RJ, Soteriou BA, Zhang H, Archard LC. Enterovirus related metabolic myopathy: a postviral fatigue syndrome. J Neurol Neurosurg Psychiatry. 2003 Oct;74(10):1382-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1757378/ (Full article)

 

Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle

Abstract:

It has been shown previously that some patients with chronic fatigue syndrome show an abnormal increase in plasma lactate following a short period of moderate exercise, in the sub-anaerobic threshold exercise test (SATET).

This cannot be explained satisfactorily by the effects of ‘inactivity’ or ‘deconditioning’, and patients with abnormal lactate responses to exercise (SATET +ve) have been found to have significantly fewer Type 1 muscle fibres in quadriceps biopsies than SATET -ve patients. We performed phosphorus magnetic resonance spectroscopy on forearm muscles of 10 SATET +ve patients, 9 SATET -ve patients and 13 sedentary volunteers.

There were no differences in resting spectra between these groups but at the end of exercise, intracellular pH in the SATET +ve patients was significantly lower than in both the SATET -ve cases and controls (P < 0.03), and the SATET +ve patients also showed a significantly lower ATP synthesis rate during recovery (P < 0.01), indicating impaired mitochondrial oxidative phosphorylation.

These observations support other evidence which indicates that chronic fatigue syndrome is a heterogeneous disorder, and confirms the view that some chronic fatigue syndrome patients have a peripheral component to their fatigue.

 

Source: Lane RJ, Barrett MC, Taylor DJ, Kemp GJ, Lodi R. Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle. Neuromuscul Disord. 1998 May;8(3-4):204-9. http://www.ncbi.nlm.nih.gov/pubmed/9631403

 

Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome

Abstract:

OBJECTIVES: To examine the proportions of type 1 and type 2 muscle fibres and the degree of muscle fibre atrophy and hypertrophy in patients with chronic fatigue syndrome in relation to lactate responses to exercise, and to determine to what extent any abnormalities found might be due to inactivity.

METHODS: Quadriceps needle muscle biopsies were obtained from 105 patients with chronic fatigue syndrome and the proportions of type 1 and 2 fibres and fibre atrophy and hypertrophy factors were determined from histochemical preparations, using a semiautomated image analysis system. Forty one randomly selected biopsies were also examined by electron microscopy. Lactate responses to exercise were measured in the subanaerobic threshold exercise test (SATET).

RESULTS: Inactivity would be expected to result in a shift to type 2 fibre predominance and fibre atrophy, but type 1 predominance (23%) was more common than type 2 predominance (3%), and fibre atrophy was found in only 10.4% of cases. Patients with increased lactate responses to exercise did have significantly fewer type 1 muscle fibres (p<0.043 males, p<0.0003 females), but there was no evidence that this group was less active than the patients with normal lactate responses. No significant ultrastructural abnormalities were found.

CONCLUSION: Muscle histometry in patients with chronic fatigue syndrome generally did not show the changes expected as a result of inactivity. However, patients with abnormal lactate responses to exercise had a significantly lower proportion of mitochondria rich type 1 muscle fibres.

 

Source: Lane RJ, Barrett MC, Woodrow D, Moss J, Fletcher R, Archard LC. Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 1998 Mar;64(3):362-7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2169994/ (Full article)

 

Exercise responses in the chronic fatigue syndrome. Objective assessment of study is difficult without knowledge of data

Comment on: Exercise responses and psychiatric disorder in chronic fatigue syndrome. [BMJ. 1995]

 

EDITOR,-In their study of exercise responses and psychiatric disorder in the chronic fatigue syndrome Russell J M Lane and colleagues claim to have detected abnormal lactate responses to subanaerobic threshold exercise in 31 of 96 patients. As no data are offered to support this statement, however, objective assessment of the validity of their findings is difficult.

The authors’ definition of an abnormal response is “lactate concentrations exceeding the upper 99% reference limit for normal control subjects at two or more time points.” However, only three samples were taken (before, immediately after, and 30 minutes after exercise), and a raised lactate concentration in the sample obtained before exercise began cannot be described as an abnormal response to exercise. Neither the method used to measure lactate nor its precision is given; assessment of the importance of the “abnormal” lactate concentrations could not be guessed at without this information, even if the authors had given details of the patients’ concentrations.

You can read the full comment along with the authors’ reply here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2551191/pdf/bmj00618-0070a.pdf

 

Source: Hutchison AS. Exercise responses in the chronic fatigue syndrome. Objective assessment of study is difficult without knowledge of data. BMJ. 1995 Nov 11;311(7015):1304. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2551191/pdf/bmj00618-0070a.pdf

 

Lactate responses to exercise in chronic fatigue syndrome

Comment on: Exercise performance and fatiguability in patients with chronic fatigue syndrome. [J Neurol Neurosurg Psychiatry. 1993]

 

We were interested to read the recent account of exercise characteristics in patients with chronic fatigue syndrome by Gibson et al,’ which concluded that there was no abnormality of neuromuscular function in this condition. Patients reached the limits of exercise tolerance at lower heart rates than controls during incremental exercise to exhaustion but their peak work rates and duration of exercise did not differ significantly from the control group, although the total work done (the product of these variables) would appear to have been less; the authors had previously reported that patients with this condition showed a reduction in maximal work rate achieved in such tests.2 Despite this, plasma lactate levels at the end of exercise were as high in the patients as the controls.

In an earlier study using incremental exercise on a treadmill, Riley et a13 had found higher heart rates and increased lactate levels compared with normal controls at submaximal work rates but similarly noted no differences at peak exercise.

We have found that a proportion of patients with chronic fatigue syndrome exhibit abnormally raised lactate levels following steady state exercise at work rates below the anerobic threshold, corresponding to roughly half the peak work rates achieved in the incremental test paradigm.4 It is thus possible that lactate levels in some patients increase more rapidly than normal at lower work rates.

The cause of this apparent ‘left shift’ of the anaerobic threshold is unclear. Neither we nor Gibson et al 2 found evidence of “deconditioning” in terms of cardiac responses to exercise in our patients, and phosphorus spectroscopy of muscle in the syndrome has shown no consistent disturbance of muscle energy metabolism.5 The phenomenon may be of significance in the pathogenesis of “fatigue” in some patients, and it may be premature to conclude that neuromuscular function in all patients is normal, or that the “fatigue” is exclusively “central” in origin. Indeed, it may be presumptuous to consider chronic fatigue syndrome as a unitary entity.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1072952/pdf/jnnpsyc00035-0134b.pdf

 

Source: Lane RJ, Woodrow D, Archard LC. Lactate responses to exercise in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 1994 May;57(5):662-3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1072952/