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Vol. 76. Issue 3.
Pages 206-209 (March 2023)
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Vol. 76. Issue 3.
Pages 206-209 (March 2023)
Scientific letter
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Ventilatory efficiency in response to maximal exercise in persistent COVID-19 syndrome patients: a cross-sectional study
Eficiencia ventilatoria en respuesta al ejercicio máximo en pacientes con diagnóstico de COVID-19 persistente: un estudio transversal
Robinson Ramírez-Véleza,
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Corresponding autor.
, Nora García-Alonsoa, Gaizka Legarra-Gorgoñóna, Sergio Oscoz-Ochandorenaa, Julio Oteizab, Mikel Izquierdoa
a Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Navarra, Spain
b Servicio de Medicina Interna, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Navarra, Spain
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To the Editor,

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).

Table 1.

Clinical characteristics and ergospirometry parameters of the study population by group

  COVID-19 (n=95)  Control (n=95)  Cohen's d  P 
Sex (male/female), No.  73/22  51/44  −  − 
Age, y  47.37 (45.45-49.31)  52.21 (49.84-54.60)  0.441  <.001 
Height, m  1.66 (1.64-1.68)  1.66 (1.63-1.68)  0.026  .303 
Weight, kg  74.52 (71.30-78.42)  71.27 (69.30-75.13)  0.159  .185 
Body mass index  27.12 (25.99-28.26)  26.03 (24.85-26.65)  0.262  .063 
Total fat, %  38.93 (37.35-40.51)  33.01 (31.13-34.88)  0.686  <.001 
Lean mass, %  58.9 (57.44-60.36)  64.55 (62.80-66.31)  0.707  <.001 
PA, MET-min/week  983.59 (754.73-1212.47)  1732.77 (1395.45-2070.11)  0.517  <.001 
Physical activity levels (low/medium/high), %b  56/42/4  37/40/23  −  <.001 
Calorimetry at restc
Caloric expenditure at rest, kcal/d  1511.13 (1450.75-1571.52)  1544 (1484.87-1605.01)  0.150  .434 
Caloric expenditure per kg, kcal/d/m  20.37 (19.78-20.96)  21.52 (20.99-22.04)  0.349  .005 
VO2, mL/min  222.97 (207.87-238.07)  223.74 (214.99-232.50)  0.014  .932 
VCO2, mL/min  177.80 (170.65-184.95)  180.73 (173.21-188.26)  0.054  .575 
Respiratory quotient  0.82 (0.80-0.83)  0.81(0.80-0.82)  0.175  .396 
Risk factorsc, %
Overweightb  33  47  .006 
Obesityb  29  10  .006 
Systolic blood pressure, mmHg  128.35 (125.26-131.44)  133.18 (130.04-136.32)  0.321  .031 
Diastolic blood pressure, mmHg  83.83 (81.89-85.77)  90.90 (77.68-104.13)  0.138  .280 
Blood pressure> 135/85mmHg, %b  60  63  .721 
Coronary score  214.68 (105.30-324.05) 
Cardio-ankle vascular index  6.86 (6.60-7.12)  6.81 (6.38-7.24)  0.340  .848 
Ankle-brachial index  1.11 (1.09-1.13)  1.06 (1-1.13)  0.123  .248 
Cardiovascular responsec
VO2 at VT1, mL/kg−1·min−1  9.55 (8.96−10.14)  11.02 (10.37−11.68)  0.488  .002 
VO2 at maximum load mL/kg−1·min−1  21.30 (20.17−22.43)  26.24 (25.01−27.48)  0.825  <.001 
O2 pulse at VT1, mL/beat  6.83 (6.34-7.32)  8.42 (7.71-9.14)  0.601  <.001 
O2 pulse at maximum load, mL/beat  10.92 (10.17-11.67)  12.76 (11.56-13.97)  0.505  .007 
Watts at VT1  42.73 (39.24−46.22)  46.16 (42.33−49.98)  0.199  .203 
Watts at maximum load  125.31 (118.12−132.50)  140.81 (132.94−148.69)  0.436  .006 
HR at VT1, bpm  105.83 (102.82−108.84)  98.90 (95.36−102.25)  0.472  .004 
HR at maximum load, bpm  148.15 (143.76−152.53)  155.26 (150.21−160.30)  0.257  .042 
METs at VT1  2.73 (2.56−2.90)  3.15 (2.97-3.34)  0.504  .001 
METs at maximum load  6.08 (5.76−6.40)  7.71 (7.36−8.06)  0.836  <.001 
Ventilatory efficiencyc
VE/VCO2 slope  34.37(33.18-35.56)  31.44 (30.58-32.30)  0.737  <.001 
Baseline PECO2, mmHg  21.65 (20.72-22.58)  23.11 (22.33-23.88)  0.463  .021 
PECO2 at VT1, mmHg  25.18 (24.26-26.10)  26.79 (25.84-27.73)  0.432  .017 
PECO2 at maximum load, mmHg  25.23 (24.37-26.09)  27.48 (26.57-28.38)  0.663  <.001 
VEVCO2 at VT1  33.24 (31.89-33.59)  30.89 (30.04-31.74)  0.491  <.001 
VEVCO2 at maximum load  34.64 (33.64−35.64)  31.12 (30.02−32.22)  0.708  <.001 
VEVO2 at VT1  36.59 (35.50−37.67)  33.73 (32.54−34.92)  0.531  .001 
VEVO2 at maximum load  36.59 (35.50−37.67)  33.73 (32.54−34.92)  0.531  .001 
VE at VT1, L/min  21.72 (20.41−23.03)  20.94 (19.50−22.37)  0.121  .439 
VE at maximum load, L/min  60.93 (57.33−64.52)  65.50 (61.56−69.44)  0.330  .101 
OUES at maximum load  2097.36 (1933.54-2261.18)  2301.02 (2081.40-2520.63)  0.244  .134 
Effort exerteda
Exercise time, min  13.05 (11.99-14.11)  16.11 (14.69-17.53)  0.594  .001 
VO2(≥ 85% predicted)b  68.13 (64.92-71.35)  85.02 (80.33-89.72)  0.869  <.001 
HR (≥ 85% predicted)b  86.29 (84.11-88.47)  91.92 (89.54-94.33)  0.314  .005 
Respiratory quotient at maximum load  1.05 (1.04-1.07)  1.08 (1.07-1.10)  0.329  .010 

HR, heart rate; METs, metabolic equivalents; OUES, oxygen uptake efficiency slope; PA, physical activity; PECO2, expired CO2 pressure; VE/VCO2, slope of the pulmonary ventilation and VCO2 ratio; VEVCO2, ventilatory equivalent for CO2, VEVO2, ventilatory equivalent for O2; VO2, oxygen uptake; VT1, first ventilatory threshold.


Data are presented as mean and 95% confidence intervals (95% CI) without adjustment or percentage as appropriate.


Data presented as percentage (%).


Data presented as marginal mean and 95% CI. General linear univariate model (ANCOVA), adjusted for age, sex, and body mass index. The ergospirometry test on cycle ergometer (Lode Excalibur Sport, Germany) consisted of incremental ramp increases in load, starting with 25 W with 25-W increments every 2min (pedaling cadence, 50-60 revolutions/min). The variables VO2 (mL/kg−1·min−1), oxygen pulse (VO2/HR), parameters VE and VT (L/min−1), ventilatory equivalents of O2 and CO2 (VEVO2, VEVCO2), and expiratory CO2 pressure (PECO2) were recorded at the first ventilatory threshold (VT1) and at maximum load using flow analysis and concentrations of inhaled and exhaled respiratory gases in the mixing chamber (QUARK CPET, Cosmed, Italy).

Table 2.

Comparison of ergospirometry criteria and ventilatory performance score by study group

Criteria  Categories  COVID-19 (n=95)*Control (n=95)*χ2  P 
VO2 inflection at VT1aNormal > 11, mL/kg/min  29  (30)  44  (46)  4.587.006
Abnormal < 11, mL/kg/min  67  (70)  51  (54) 
VE/VCO2bNormal < 34, slope in degrees  51  (54)  74  (77)  11.318.001
Abnormal > 34, slope in degrees  44  (46)  21  (23) 
OUEScNormal > 1550 mL  65  (68)  72  (76)  0.942.331
Abnormal < 1550 mL  30  (32)  23  (24) 
COPdNormal < 30 L  85  (89)  95  (100)  8.550.003
Abnormal > 30 L  10  (11) 
ΔVO2/HR VT2 vs VT1eNormal > 0  92  (97)  89  (94)  0.467.494
Abnormal < 0  (3)  (6) 
Ventilatory performance scorefNo limitation  14  (15)  29  (31)  9.847.007
Moderate limitation  62  (65)  58  (61) 
Severe limitation  19  (20)  (8) 

COP, cardiorespiratory optimal point; HR, heart rate; OUES, oxygen uptake efficiency slope; VCO2, carbon dioxide produced; VE, pulmonary ventilation; VO2, oxygen uptake; VT1, first ventilatory threshold; VT2, second ventilatory threshold.


Point of inflection of VO2 expressed in mL/kg/min and estimated manually on the graph of VO2 at VT1.


Ventilatory efficiency or class derived from the VE/VCO2 slope.


OUES VO2 efficiency slope.


COP estimated based on the minimum VE/VCO2 ratio.


Difference in oxygen pulse between VT2 and VT1, derived from VO2/HR ratio.


Ventilatory performance criteria score was derived from the sum of the abnormal criteria in a-e, then classified as: no ventilatory limitation (no abnormal criteria), moderate limitation (1-2 abnormal criteria), and severe limitation (more than 3 abnormal criteria).

Values are expressed as No. (%).

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.


This study was funded in part by a grant (PID2020-113098RB-I00) corresponding to the call for RD&I projects from the national programs for knowledge generation and scientific and technical strengthening of the RD&I system aimed at the challenges of society, within the framework of the National Plan for scientific and technical research and innovation 2017-2020.


All authors contributed substantially to the concept and design, data acquisition, analysis, and interpretation, as well as the writing, review, and intellectual content of the manuscript.


The authors have no conflict of interests to declare.

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Revista Española de Cardiología (English Edition)

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