Improving Rehabilitation of Patients with Post-COVID-19 Syndrome – Stratification Matters

Introduction: Post-COVID-19 Syndrome (PCS) is characterized as a multisystemic disorder with lead symptoms of (chronic) fatigue, decreased physical performance, dyspnoea, cognitive impairment, among various other symptoms. Current estimates indicate a prevalence of up to 10% in adults and while most patients experience a gradual healing process, the need for individualized medical rehabilitation is high.

Methods: PCS patients referred to rehabilitation (~9 months after acute infection) with lead symptoms of fatigue/exercise intolerance, shortness of breath and cognitive dysfunction underwent full clinical assessment, including symptom-limited cardiopulmonary exercise testing (CPET) and pulmonary function tests. Questionnaires were used for evaluating disease perception for up to 6 months of follow-up. Patients performed exercise-based rehabilitation including a combination of physical therapies (strength, endurance, and respiratory muscle training), cognitive exercises, relaxation techniques, and educational sessions. 

Results: Patients (N=110, 49.7±11.3 years, 37% female) exhibited significant limitation in physical exercise capacity at admission, with women demonstrating higher relative exercise capacity compared to men (82.0±14.3% vs. 68.8±13.3%, p<0.001). By contrast, women exhibited higher levels of fatigue and lower wellbeing (p≤0.027) correlating with impaired pulmonary function in terms of reduced expiratory flow and maximum inspiratory pressure (p<0.05). Overall, fat oxidation (FatOx) capacity during exercise was significantly impaired (maximal fat oxidation [MFO]: 0.35±0.12 g/min; AUC_pre: 11.3[10.7-11.9]) compared to healthy controls (MFO: 0.46±0.17 g/min; p<0.001). In particular, younger males were affected by significantly reduced FatOx capacity after correction for age and sex (p≤0.002). With rehabilitation, patients demonstrated improvements in physical capacity (VO_2peak: +1.1±2.9 ml/min/kg), maximum inspiratory pressure (+25.7±24.0 cmH₂O), fatigue (MFI-20: -10.4±15.2) and wellbeing (WHO-5: +4.1±5.5). Improvements were comparable between female and male patients when adapted to individual limitations. FatOx was significantly improved during exercise-based rehabilitation (+31.9%, AUC_post: 14.9[14.4-15.4]; p<0.001). A randomized exercise trial revealed that moderate interval training proved to be as effective as continuous aerobic training for improvement of (sub)maximal exercise capacity (+2.7±11.0% of VO₂ uptake; p=0.157).  

Conclusion: Female and male PCS patients referred to rehabilitation differed in terms of fatigue, exercise capacity and pulmonary function, indicating that examinations of PCS patients should include CPET, pulmonary function tests as well as assessments of fatigue for tailored rehabilitation programs. Aerobic continuous and moderate interval training were effective and may be used interchangeably considering patients’ preferences whereby post-exertional malaise must be considered as a limitation. Assessment of FatOx potential based on CPET data may identify patients with pronounced metabolic disturbances, which can be improved with exercise, potentially restoring mitochondrial function.