Coronavirus disease 2019 (COVID-19) is a global pandemic affecting individuals to varying degrees, ranging from few days of mild symptoms to respiratory distress requiring intensive care unit (ICU) treatment, including ventilation support and death (1, 2). Most acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections are mild to moderate (3–5), but pneumonia progressing to acute respiratory failure is associated with significant morbidity and even mortality (6). The use of a minimum set of common outcome measures for COVID-19 studies (measurements of viral burden of patient survival and of patient progression) have been recommended by the International Forum for Acute Care Trialists, and the International Severe Acute Respiratory and Emerging Infections Consortium (7). It has been suggested that even patients with mild symptoms can suffer from prolonged physical impairment and reduced quality of life (QoL) (8). Although COVID-19 is a novel disease, there have been previous outbreaks of SARS-CoV, where deficits in cardiorespiratory and musculoskeletal performance (e.g., in the 6-min walking test, 6-MWT, and/or handheld dynamometry for major muscle groups), but also a reduced QoL was demonstrated in a cohort study of 171 SARS survivors (9). Besides the pulmonary involvement (10), there are increasing reports of non-pulmonary manifestations in patients with COVID-19, such as musculoskeletal abnormalities with pain and weakness in lower limbs (11–13), elevated creatinine kinase (CK), and lactate dehydrogenase (LDH) (12). Respiratory muscle's weakness and with higher ventilatory demands were reported even in patients recovering from mild COVID-19 symptoms (14). Moreover, cardiac complications like myocarditis may be the consequence of direct viral injury or cardiac damage due to the host's immune response (13, 15). These findings let us hypothesize that the majority of the patients with COVID-19 will present reduced exercise capacity and abnormal responses to cardiopulmonary exercise testing (CPET), even a few months after disease onset. Thus, the aims of this prospective study were (1) to assess exercise capacity and cardiopulmonary responses to CPET, and (2) to evaluate potentially limiting factors of aerobic exercise capacity in adult patients who had COVID-19 for 3–6 months after confirmation of infection.

This prospective study demonstrated prolonged impairment of both the predicted maximal exercise capacity (Wpeak and VO₂peak) in patients with mild and severe post-CoV, and the predicted submaximal exercise performance (predicted VT1/VO₂peak and VT2/VO₂peak) only in patients with severe post-CoV compared to controls. Impairments were more pronounced in the severe compared to the mild post-CoVG. Regression analyses (supported by the elevated NT-proBNP values) revealed that aside from impaired pulmonary function, cardiac and skeletal muscle dysfunction contributed to the limitation of VO₂peak in patients with post-CoV.

Generally, the manifestations of COVID-19 showed a wide severity spectrum from asymptomatic to most severe forms (17). Moreover, a large heterogeneity concerning the signs and the symptom duration was found in these patients (18–20). Not surprisingly, a reduced exercise capacity has been reported in 59% of 18 patients with COVID-19 at the time of hospital discharge, with a VO₂peak <70% of predicted in 61% of cases (14). In agreement with our findings, prolonged performance impairment was demonstrated in 50% of patients with COVID history, up to 100 days after infection, with impaired lung function in 42% after 60 days, and still in 36% after 100 days (21). Another study reported the persistence of at least one symptom in more than 80% of patients with COVID-19 after the onset of the first symptoms (19). Diminished physical fitness associated with persistent breathing disorder has been found even 6 months after hospitalization for COVID-19 infection (22).

To our knowledge, we presented the first study demonstrating different impairment of maximal and submaximal exercise performance, between patients with mild and severe CoV history after 3–6 months of recovery. In addition, we showed that both impaired pulmonary and cardiac function, but also a probable dysfunction of the skeletal working muscles, contributed to the explanation of the reduced aerobic exercise capacity. Although VEmax and BR, as potential indicators for ventilatory limitation, were rather normal in the patients with CoV history, multiple linear regression analysis indicated that low BR contributed to the variance explanation of relative VO2max. This is also true for the compromised resting pulmonary lung function observed, which is in agreement with other studies (23, 24). Out of the patients with history in CoV, 37% showed decreased DLCO (< LLN), but without abnormal KCO (< LLN). These observations are also in accordance with previous studies (25, 26), supporting the view that loss of alveolar units is not the primary cause for the observed DLCO impairment (27). Thus, other factors like pulmonary microangiopathy, fibrin clotting within small capillaries around alveoli, small vessel thrombosis, and thickening of alveolar capillaries might contribute to a reduced DLCO (27).

The present findings suggest that aerobic exercise capacity (relative VO₂peak) may also be limited as related to potential extrapulmonary manifestations, e.g., myopathy, autonomic dysregulation, and physical deconditioning (13, 15). Cardiac involvement is supported by the elevated NT-proBNP values in post-CoV patients. A correlation between left ventricular dysfunction, NT-proBNP, and exercise capacity has been demonstrated in patients with heart-failure (28). Cardiac abnormalities are common in survivors of COVID-19, and could be detected in 42.3% of the 97 survivors of the said illness (29), with a wide range of different manifestations including brady-tachyarrhythmia and COVID 19- related-myocarditis up to left ventricular dysfunction [12]. In our patients, cardiac arrythmia at exercise could be found in 28.3% of the patients who had CoV, without significant differences in both patient groups.

Whether it does and to what extent it can, the contribution of the dysfunction of working muscles to the observed VO2peak impairment is difficult to assess from CPET results. Severe muscle dysfunction and pain were reported in patients with COVID-19 (11, 12), and seemed also to be true in patients of the present study. This can be derived from the low HRmax values observed, likely indicating muscle dysfunction, as low maximal HR responses have also been demonstrated in patients suffering from chronic fatigue syndrome with debilitating fatigue, muscle pain, and muscle weakness (30). In addition, low VTs may also point to affected working muscles, which has been demonstrated in patients suffering from mitochondrial dysfunction (31).

There are several limitations of the current study. First, the study population consisted of a higher percentage of patients with history of COVID, with mild to moderate courses of the disease, but especially for these patients, information about cardiopulmonary limitations were missing. Secondly, cardiopulmonary evaluation prior to COVID-19 was not available, so it cannot fully evaluate the impact of pre-existing cardiopulmonary impairments. Although cardiorespiratory and musculoskeletal limitations have also been reported after previous outbreaks of SARS-CoV (9), it remains unclear that these findings are specific for COVID infections.

Three to 6 months after recovery from COVID-19, many patients are still affected by reduced maximal exercise capacity (for mildly and severely affected patients) and by impaired submaximal exercise performance (only severely affected patients). Our findings reveal that pulmonary, cardiac and skeletal muscle dysfunction contributed to the limitations of aerobic exercise performance in patients with CoV history. These findings may have important implications on rehabilitation programs for the said patients, with a need for multidisciplinary collaborations to assess the optimal structure of rehabilitation programs.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the Ethics Committee of Medical University of Vienna. The patients/participants provided their written informed consent to participate in this study.

KV designed the study, had full access to all of the data used, acquired data, analyzed and interpreted data, searched literature, wrote, and reviewed and edited original draft. AL, DB, MG, and SS performed study examination and acquired data. AS and MB had full access to all data in the study, analyzed and interpreted data, wrote, and reviewed and edited original draft. MI and DG designed the study, had full access to all data in the study and verified the underlying data, and reviewed and edited original draft. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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