Currently, the clinical course of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains uncertain, particularly given the variety of chronic symptoms in the subsequent weeks and months.1 Parameters such as ventilatory efficiency and exercise capacity allow objective assessment of an individual's ventilatory and functional response, and also provide prognostic information on their clinical status, with important implications for treatment.2

The aim of the present study was to examine the—as yet unassessed—effect of persistent coronavirus disease 19 (COVID-19) on parameters of ventilatory efficiency and exercise capacity, in comparison with a group of patients with no history of COVID-19. The sample for this exploratory observational study included 95 individuals (77% were women) with a diagnosis of COVID-19 and mild or moderate symptoms, who had not previously been hospitalized, and had no structural heart disease or lung disease. Patients were considered to have persistent COVID-19 on the basis of compatible signs or symptoms and a positive polymerase chain reaction test for SARS-CoV-2. In addition, they were required to have symptoms persisting for 3 months after the infection, as assessed with a semistructured questionnaire previously used and validated by international expert consensus, which included self-diagnosis of 21 relevant symptoms 3 months after infection (yes/no answers).3

The group of patients with no history of COVID-19 (n=95; 54% women) had not had SARS-CoV-2 infection and were recruited from the exercise capacity and cardiometabolic risk assessment clinic in our hospital. They underwent clinical assessment and functional testing of resting calorimetry, ergospirometry, vascular function, and body composition. Patients were also asked about their physical activity level. The study was approved by the ethics committee of Hospital Universitario de Navarra, and the participants gave signed informed consent (PI_2020/140).

The most prevalent persistent symptom was chronic fatigue (96.1%), followed by headache (81.4%), memory loss (80.4%), and difficulty concentrating (79.4%), the same symptoms as observed in previous studies.4,5 The results of the univariate general linear model (ANCOVA), adjusted for age, sex, and body mass index, showed that, during exercise, the group with persistent COVID-19 had lower oxygen uptake and metabolic equivalents (METs), as well as significantly higher oxygen pulse, the ratio between oxygen uptake and heart rate (VO2/HR), at the first ventilatory threshold (VT1) and at maximum load (P < .01). Significant between-group differences were also observed at peak VO2, as well as in the pulmonary ventilation (VE)/CO2 output (VCO2) slope (d=0.708), the VE/VO2 slope (d=0.531), watts (d=0.436), VE (d=0.257), VO2/HR (d=0.424), METs (d=0.836), and heart rate (HR) as percentage of predicted (d=0.314) (table 1). Approximately 85% of the patients with COVID-19 had a moderate/severe ventilatory limitation score (table 2).

In previous studies,1 patients with COVID-19 showed peak VO2 values that were 35% lower (∼15mL/kg-1·min-1) than the control group (∼23mL/kg-1·min-1) at 30 days after hospital discharge. Debeaumont et al.4 reported on parameters of VO2 and maximum power of, respectively, ∼80% and ∼90% of predicted values for age at 6 months after discharge. Similarly, patients with persistent COVID-19 symptoms had a significant reduction in 6-minute walk test at 6 months after onset of symptoms.5 In our series, the COVID-19 group showed peak VO2 values ∼18% lower than the control group. There was also a mixed pattern of abnormalities in parameters of ventilatory efficiency including VO2 at VT1 (70% vs 54%), abnormal VE/VCO2 (46% vs 36%), and a very low VE/VCO2 ratio (COP) (11% vs 0%), indicating a higher risk of functional deterioration.

To date, the mechanisms to explain the reduced exercise capacity in patients with persistent COVID-19 are unknown, but it has been hypothesized that excess adiposity (as seen in this series) and low levels of physical activity could partly explain the findings of this study.1 The myopathic effect of SARS-CoV-2 has also not been excluded as a cause of functional deterioration in patients after COVID-19.2 However, experimental studies are needed to corroborate these hypotheses.2,4 The main limitations of our study are the number of patients included, the inclusion of a majority of women (a characteristic of persistent COVID-19 syndrome) and the lack of previous measures of exercise capacity, a limitation that is difficult to solve given the emergent nature of the pandemic.

More research is needed to better understand the long-term consequences of COVID-19 on functional capacity over the whole spectrum of the disease, especially the underlying biological mechanisms that characterize its pathophysiology. Considering the central role of exercise capacity in patients with persistent COVID-19, exercise rehabilitation could be fundamental in this new and little-known situation. Therefore, it is essential to establish strategies with multicomponent programs, to optimize recovery in these patients.