Analysis of Fat Oxidation Capacity During Cardiopulmonary Exercise Testing Indicates Long-lasting Metabolic Disturbance in Patients With Post-COVID-19 Syndrome

Post-COVID-19 Syndrome (PCS), also known as post-acute sequelae of COVID-19, manifests following an acute infection with the SARS-CoV-2 virus (COVID-19 infection). PCS is characterized by the persistence of symptoms beyond 12 weeks from the onset of infection and/or the emergence of new symptoms within this time. Although recent guidelines offer specific criteria to diagnose PCS, ambiguity persists due to the complex nature of its symptomatology and the lack of definitive diagnostic tools. PCS is a multisystemic disorder characterized by symptoms such as (chronic) fatigue, diminished physical performance, muscular weakness and pain, dyspnea, cognitive impairments and alterations of the autonomous nervous system, as well as mental and psychological distress. The severity of symptoms varies widely among patients, from mild impairment to significant restrictions in daily activities, potentially leading to partial or complete incapacity to work. Of note, the severity of the acute infection does not predict the onset or severity of PCS. Even though many patients experience gradual recovery without specific treatment, there is a substantial need for effective medical rehabilitation, especially for those with persistent PCS. To this respect, exercise-based programs have been shown to induce significantly exercise capacity as well as higher quality of life, reduced fatigue, and less depression. Despite ongoing investigations, the mechanisms contributing to the onset and severity of PCS remain largely unknown. Factors may include endothelial dysfunction and detrimental effects on the microvasculature, as well as a "cytokine storm" associated with excessive oxidative stress and subsequent mitochondrial dysfunction which has emerged as a significant potential contributor.

Notably, detrimental effects on mitochondrial function have been described as a result of severe acute infections triggering an excessive immune response, systemic inflammation and oxidative stress. Recent studies suggested that impaired mitochondrial function in PCS may be associated with impaired fatty acid oxidation (FatOx) which can be identified using cardiopulmonary exercise testing (CPET). Currently, the number of PCS patients characterized for changes in FatOx using CPET is low and associations with signs and symptoms of PCS such as fatigue have not been reported in detail. Moreover, reports on the potential of exercise-based rehabilitation to restore FatOx capacity in PCS are not available. Thus, the current study aimed to investigate if analysis of breath-by-breath spirometric data followed by an estimation of individual FatOx capacity can be used for the stratification of PCS patients. The investigators hypothesized that a lower FatOx potential would be associated with PCS-specific signs and symptoms such as mental and physical fatigue. In addition, the investigators sought to analyze if exercise-based rehabilitation would be effective in restoring PCS patients' FatOx capacity as a sign of improved mitochondrial function.