Safety of cardiopulmonary exercise testing in patients with severe post-COVID-19 condition: a matched case-control study

Abstract Patients severely affected by post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) exhibit reduced physical capacity, hyperventilation, and a high susceptibility to post-exertional malaise (PEM). Cardiopulmonary exercise testing (CPET) is considered the gold standard for objectively assessing physical capacity and for exploring underlying physiological limitations. However, evidence regarding the safety and PEM-associated symptoms following CPET remains limited. This study aims to objectively assess physical capacity using CPET, and to systematically investigate changes in the duration and severity of ten PEM-associated symptoms before and after CPET. A total of 18 PCC patients and 18 healthy controls (matched for sex, age, and body mass index) completed a single maximal, symptom-limited CPET on a cycle ergometer. Ten PEM-specific symptoms were assessed daily for 7 days before and 14 days after CPET (scale 0–10). For clinical characterization, the Canadian Consensus Criteria (CCC) were applied, and the Bell Disability Scale and DePaul Symptom Questionnaire Short-Form-PEM (DSQ-PEM) were completed once before the CPET. Among PCC patients, 61% fulfilled ME/CFS criteria, 67% screened positive for DSQ-PEM, and the mean Bell-Score was 37.8 ± 19.3. Physical capacity was markedly reduced compared with healthy controls (Peak power output: 1.1 vs. 2.4 W/kg, p < 0.001; VO 2peak : 16.0 vs. 26.5 mL/min/kg, p < 0.001). In the PCC group, a significant increase in mean symptom severity was observed across all measured symptoms from baseline to the acute period (1–3 days after the CPET; Δ = 0.56, p = 0.002), but after 4–7 days, levels returned to baseline. Two out of ten symptoms increased significantly after the CPET: general fatigue (Δ = 0.99, p = 0.018) and joint pain (Δ = 0.69, p = 0.036). However, after 4–7 days, no significant differences remained. No significant group-by-timepoint interaction was found when stratifying PCC patients by DSQ-PEM status ( p = 0.187), Bell-Scores (≤ 30 vs. >30, p = 0.276), or ME/CFS status ( p = 0.523). Severely affected PCC patients showed markedly reduced physical capacity compared with healthy controls. A single maximal symptom-limited CPET induced only a transient, clinically non-relevant symptom increase (1–3 days) without prolonged exacerbation. Furthermore, the results of the CPET can be used to provide individualized objective cut-off values aimed at minimizing PEM during exercise therapy and/or activities of daily living. Trial registration: DRKS, DRKS00032394. Registered 28 July 2023, https//drks.de/search/de/trial/DRKS00032394.