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.