Background
The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents the greatest global public health crisis of the last decades. Most of the knowledge about COVID-19, including its clinical manifestations and early evolution comes from studies focusing on the acute infection phase [
1,
2] or short-term convalescence phase [
3]. Whilst pulmonary sequelae have been extensively analyzed, few studies focused on factors contributing to impaired exercise capacity.
Indeed, pulmonary alteration such as reduction of diffusing capacity and restrictive pattern have been reported in up to one third of COVID-19 survivors, as previously described in other coronavirus pneumonia such as severe acute respiratory syndrome (SARS) or middle east respiratory syndrome (MERS) [
4‐
9]. Recently, exercise capacity limitation has also emerged as a frequent complication leading to long-term disability in the context of COVID-19 infection [
10,
11]. The diagnosis of altered exercise capacity and the understanding of the underlying factors are crucial for patients since they may benefit early from a personalized rehabilitation program. Clinical symptoms and 6-min walk test (6-MWT) may fail to detect such a reduced exercise capacity, whilst cardiopulmonary exercise test (CPET) may unmask exercise limitation.
To decipher the mechanisms underlying the exercise capacity limitation, we conducted a comprehensive prospective evaluation in severe COVID-19 pulmonary infection survivors 3 months after hospital discharge in COVulnerability cohort. More specifically, we performed in addition to CPET and 6-MWT, lung function test, echocardiography, skeletal muscle mass and function evaluation, and measured circulatory inflammatory biomarkers.
Results
Among the 220 survivors for COVID-19 severe acute pulmonary infection included in COVulnerability cohort, 105 agreed to benefit from a follow-up evaluation three months after hospital discharge. The mean age of patients was 59.2 years and 79 (75.2%) were male. The most common comorbidity was hypertension (41.9%), followed by diabetes (27.6%), and dyslipidemia (20%). Forty-five patients (43.3%) had been admitted to the intensive care unit (ICU) during the acute phase. During hospitalization, 16 patients (15.7%) required high flow nasal cannula (HFNC) and 26 (25.2%) invasive mechanical ventilation (IMV). Other patient’s characteristics and clinical outcomes are shown in Table
1.
Table 1
Patient’s characteristics and comparison of clinical factors between patients with a normal and reduced exercise capacity
Age, years | 59.21 ± 11.81 | 59.68 ± 12.16 | 58.35 ± 11.26 | 0.585 |
Male (%) | 79 (75.2) | 46 (67.6) | 33 (89.2) | 0.015 |
BMI before COVID-19, kg/m2 | 29.11 ± 5.51 | 30.29 ± 5.64 | 27.16 ± 4.74 | 0.009 |
BMI, kg/m2 | 27.92 ± 4.98 | 29.07 ± 5.24 | 25.79 ± 3.68 | 0.001 |
Change in BMI before-after COVID-19, kg/m2 | − 1.16 ± 1.93 | − 0.90 ± 1.59 | − 1.59 ± 2.35 | 0.105 |
Tobacco history (%) | 48 (45.7) | 34 (50) | 14 (37.8) | 0.232 |
Smoking, pack-years | 11.69 ± 16.29 | 11.5 ± 15.22 | 12.06 ± 18.38 | 0.874 |
mMRC dyspnea scale (0/ 1/ 2/ 3/ 4) | 67/ 31/ 5/ 2/ 0 | 46/ 21/ 1/ 0/ 0 | 24/ 12/ 1/ 0/ 0 | 0.61 |
Comorbidities | | | | |
Hypertension (%) | 44 (41.9) | 25 (36.8) | 19 (51.4) | 0.148 |
Diabetes (%) | 29 (27.6) | 12 (17.6) | 17 (45.9) | 0.002 |
Dyslipidemia (%) | 21 (20) | 13 (19.1) | 8 (21.6) | 0.759 |
Ischemic cardiomyopathy (%) | 17 (16.2) | 12 (17.6) | 5 (13.5) | 0.583 |
Obstructive sleep apnea (%) | 15 (14.3) | 8 (11.8) | 7 (18.9) | 0.317 |
Malignancy (%) | 14 (13.5) | 8 (11.9) | 6 (16.2) | 0.541 |
Chronic kidney disease (%) | 11 (10.5) | 3 (4.4) | 8 (21.6) | 0.006 |
COPD (%) | 1 (1) | 1 (1.5) | 0 (0) | 0.459 |
During COVID-19 hospitalisation | | | | |
ICU stay (%) | 45 (43.3) | 26 (38.8) | 19 (51.4) | 0.216 |
HFNC (%) | 16 (15.7) | 10 (15.2) | 6 (16.7) | 0.841 |
IMV (%) | 26 (25.2) | 14 (21.2) | 12 (32.4) | 0.209 |
Tracheotomy (%) | 2 (1.9) | 1 (1.5) | 1 (2.7) | 0.675 |
ECMO (%) | 4 (3.9) | 1 (1.5) | 3 (8.1) | 0.097 |
Pulmonary embolism (%) | 8 (7.8) | 7 (10.6) | 1 (2.7) | 0.150 |
Acute kidney injury (%) | 23 (22.1) | 11 (16.2) | 12 (33.3) | 0.045 |
Cardiogenic shock (%) | 2 (1.9) | 2 (3) | 0 (0) | 0.289 |
Despite no major symptoms of dyspnea and 6-MWT in normal range, more than a third of patients (37 patients, 35%) had an impaired CPET with a VO
2peak under 80%. Interestingly, patients with a reduced exercise capacity did not complain of dyspnea and had similar 6-MWT as compared with those having normal exercise capacity. Compared to patients with normal exercise capacity, patients with reduced exercise capacity were more often men (89.2% vs. 67.6%, p = 0.015), with diabetes (45.9% vs. 17.6%, p = 0.002), renal dysfunction (21.6% vs. 17.6%, p = 0.006) and lower BMI (25.79 ± 3.68 vs. 29.07 ± 5.24, p = 0.001). Of note, smoking habits was similar between groups. The severity of acute COVID-19 disease was not different between groups in terms of ICU admission, HFNC, IMV and ECMO (Table
1). During the exercise test, patients with altered exercise capacity compared to the others reached a lower maximal work, a lower maximal heart rate and had a higher breathing reserve (Table
2). We do not observe desaturation between groups, at the peak of exercise the saturation was 98.4 ± 3.2% in the normal group vs. 99 ± 1.42% in the impaired group (p = 0,239).
Table 2
Comparison of pulmonary function, skeletal muscle parameter and transthoracic echocardiography between patients with a normal and reduced exercise capacity
Exercise capacity assessment (CPET) | | | | |
Wrmax, W | 116.14 ± 51.67 | 130.74 ± 53.39 | 89.32 ± 35.55 | 0.0002 |
HRmax, bpm | 139.43 ± 25.80 | 143.51 ± 26.38 | 131.92 ± 23.21 | 0.013 |
Breathing reserve, % | 25.49 ± 19.13 | 21.14 ± 18.38 | 33.14 ± 18.23 | 0.009 |
V'O2max, ml/min | 1523.89 ± 552.69 | 1718.90 ± 540.20 | 1165.49 ± 368.13 | < 0.0001 |
V'CO2max, ml/min | 1764.03 ± 696.62 | 1991.90 ± 700.66 | 1345.24 ± 458.19 | < 0.0001 |
RER | 1.15 ± 0.11 | 1.15 ± 0.09 | 1.15 ± 0.13 | 0.979 |
V'O2max/BW, ml/min/kg | 18.28 ± 5.34 | 20.15 ± 5.16 | 14.84 ± 3.75 | < 0.0001 |
VO2max/kg leg muscle mass (ml/kg leg/min) | 86.4 ± 21.8 | 95.7 ± 18.5 | 68.5 ± 16 | < 0.0001 |
Anaerobic threshold %VO2 max predicted | 62.7 ± 19.8 | 71.1 ± 17.4 | 45.96 ± 12.2 | < 0.0001 |
Respiratory frequency, breathe/min | 38.98 ± 8.87 | 39.76 ± 8.56 | 37.55 ± 9.36 | 0.319 |
VO2/HR, ml/beat | 11.12 ± 3.30 | 12.18 ± 3.27 | 9.02 ± 2.17 | < 0.0001 |
VO2/HR, % predicted | 86.32 ± 19.59 | 96.62 ± 14.69 | 66.03 ± 9.58 | < 0.0001 |
Hemoglobin, g/dl | 13.57 ± 1.54 | 13.99 ± 1.39 | 12.77 ± 1.52 | < 0.0001 |
6-min walking distance, m | 485.18 ± 111.08 | 494.02 ± 109.47 | 469.22 ± 113.72 | 0.285 |
Pulmonary function | | | | |
FVC, L | 3.49 ± 1.11 | 3.67 ± 1.18 | 3.17 ± 0.88 | 0.026 |
FVC, % predicted | 84.90 ± 18.08 | 90.54 ± 16.69 | 74.54 ± 15.99 | < 0.0001 |
FEV1, L | 2.78 ± 0.82 | 2.91 ± 0.83 | 2.55 ± 0.76 | 0.030 |
FEV1, % predicted | 87.45 ± 18.62 | 93.26 ± 16.38 | 76.76 ± 17.92 | < 0.0001 |
FEV1/FVC (%) | 80 ± 7 | 81 ± 8 | 80 ± 7 | 0.828 |
TLC, L | 5.42 ± 1.24 | 5.57 ± 1.35 | 5.13 ± 0.93 | 0.081 |
TLC, % predicted | 83.70 ± 14.72 | 87.88 ± 13.79 | 75.81 ± 13.24 | < 0.0001 |
DLCO, % predicted | 71.27 ± 19.34 | 74.66 ± 20.48 | 65.14 ± 15.53 | 0.015 |
KCO, % | 93.87 ± 17.56 | 94.79 ± 17.59 | 92.19 ± 17.62 | 0.472 |
PaO2, mmHg | 89.04 ± 9.35 | 87.82 ± 9.68 | 90.81 (8.7) | 0.173 |
PaCO2, mmHg | 37.08 ± 4.97 | 37.21 ± 2.5 | 36.84 ± 7.24 | 0.73 |
Skeletal muscle mass and function | | | | |
ASMMI, kg/m2 | 7.85 ± 1.17 | 8.13 ± 1.19 | 7.36 ± 0.94 | 0.001 |
Sarcopenia (%) | 21 (21) | 7 (10.9) | 14 (38.9) | 0.001 |
Grip test, kg | 34.42 ± 10.37 | 36.33 ± 10.71 | 31.5 ± 9.27 | 0.047 |
Pinch test, kg | 6.66 ± 2.17 | 7.04 ± 2.31 | 6.07 ± 1.82 | 0.054 |
Transthoracic echocardiography | | | | |
CO, L/min | 5.71 ± 1.37 | 5.88 ± 1.44 | 5.44 ± 1.24 | 0.182 |
LVMi, g/m2 | 84.43 ± 24.5 | 79.31 ± 18.01 | 93.43 ± 31.34 | 0.012 |
LVEF (2D), % | 60.25 ± 6.06 | 60.31 ± 5.75 | 60.13 ± 6.64 | 0.898 |
Global longitudinal strain, % | − 17.24 ± 2.45 | − 17.59 ± 2.39 | − 16.66 ± 2.49 | 0.114 |
E/A ratio | 0.89 ± 0.33 | 0.90 ± 0.34 | 0.88 ± 0.32 | 0.767 |
E/E' ratio | 7.1 ± 2.20 | 7.10 ± 2.03 | 7.12 ± 2.56 | 0.971 |
E' lateral, cm/s | 9.46 ± 3.07 | 9.54 ± 3.36 | 9.29 ± 2.44 | 0.733 |
LAVi, mL | 28.15 ± 9.78 | 27.82 ± 8.77 | 28.70 ± 11.39 | 0.697 |
RVEDs, cm2 | 17.43 ± 4.45 | 16.70 ± 4.34 | 18.65 ± 4.45 | 0.077 |
TAPSE, mm | 21.49 ± 3.33 | 21.74 ± 3.47 | 21.04 ± 3.05 | 0.389 |
S’ wave, cm/s | 12.79 ± 2.08 | 12.72 ± 2.01 | 12.95 ± 2.26 | 0.663 |
TRV, m/s | 2.32 ± 0.34 | 2.30 ± 0.32 | 2.35 ± 0.37 | 0.656 |
systolic PAP, mmHg | 25 ± 6.05 | 24.61 ± 5.65 | 25.5 ± 6.66 | 0.646 |
PAcT, ms | 119.7 ± 27.53 | 125.84 ± 25.95 | 106.6 ± 27 | 0.024 |
RA area, cm2 | 14.68 ± 4.42 | 14.35 ± 4.42 | 15.30 ± 4.44 | 0.387 |
Reduced exercise capacity was associated with a significant decrease in respiratory function at rest: compared to the normal exercise capacity group, predicted FVC was significantly lower in the impaired group (74.54 ± 15.99% vs. 90.54 ± 16.69%, p < 0.0001) as predicted FEV1 (76.76 ± 17.92% vs. 93.26 ± 16.38%, p < 0.0001) and TLC (75.81 ± 13.24% vs. 87.88 ± 13.79%, p < 0.0001). DL
CO was also significantly lower in the reduced exercise capacity group (65.14 ± 15.53% vs. 74.66 ± 20.28%, p = 0.015). K
CO was not modified in the reduced exercise capacity group, highlighting a restrictive pulmonary pattern in patients presenting an altered exercise capacity (Table
2).
Furthermore, we found a reduced skeletal muscle mass by ASMMI in the altered exercise capacity group (7.36 ± 0.94 kg/m
2 vs. 7.85 ± 1.17 kg/m
2, p = 0.001) together with a decrease in grip test (31.50 ± 9.27 vs. 36.33 ± 10.71, p = 0.047) highlighting an impairment in skeletal muscle strength (Table
2). There also was a decrease in VO
2/kg of muscle leg in the reduced exercise capacity (68.5 ± 16 vs. 95.7 ± 18.5, p < 0.0001). Notably, sarcopenia was more frequent among low exercise capacity patients compared to the others: 38.9% vs 10.9%, (p = 0.001).
We did not observe any significant cardiac dysfunction with systolic and diastolic parameters in normal range values at rest. Furthermore, LVEF and right ventricular function were similar in both groups (Table
2). Reduced exercise capacity was associated with a shorter PAcT (107 ± 27 ms vs. 126 ± 26 ms, p = 0.02) despite no argument for pulmonary hypertension (based on tricuspid regurgitation peak velocity). Predicted VO
2/Heart rate was decreased in the altered exercise capacity group (66.03 ± 9.58% vs. 96.62 ± 14.69%, p < 0.0001).
As expected, the univariate analysis showed correlation between VO
2peak and the predicted values of FEV1, FVC, TLC, DL
CO but not with K
CO (Table
3, see Additional file
1). Notably, VO
2peak was also correlated with skeletal muscle mass and grip test. In addition, VO
2peak was correlated with left ventricle mass index, GLS, E/E’ ratio, RVEDs, TRV and PacT (Table
3, see Additional file
1). Interestingly, in multivariable analysis, age, sex, predicted TLC, ASMMI, GLS and E/E’ ratio, showed an independent correlation with VO2peak (Table
3).
Table 3
Multivariable analysis to identify the factors associated with VO2peak
Age, years | 0.18 | 0.004 (0.000;0.008) | 0.070 | 0.01 (0.003–0.012) | 0.001 |
Body mass index, kg/m2 | 0.33 | 0.016 (0.007;0.025) | 0.0006 | (–) | |
Pulmonary function | | | | | |
FVC, % predicted | 0.52 | 0.007 (0.005;0.009) | < 0.0001 | (–) | |
FEV1, % predicted | 0.51 | 0.007 (0.005;0.009) | < 0.0001 | (–) | |
TLC, % predicted | 0.52 | 0.009 (0.006;0.012) | < 0.0001 | 0.01 (0.003–0.01) | 0.0004 |
DLCO, % predicted | 0.38 | 0.005 (0.003;0.007) | < 0.0001 | (–) | |
Skeletal muscle mass and function | | | | | |
ASMMI, kg/m2 | 0.34 | 0.072 (0.032;0.113) | 0.0006 | 0.09 (0.05–0.12) | < 0.0001 |
Grip test, kg | 0.25 | 0.006 (0.001;0.011) | 0.027 | (–) | |
Transthoracic echocardiography | | | | | |
LVMi, g/m2 | − 0.29 | − 0.003 (− 0.005; − 0.001) | 0.009 | (–) | |
PAcT, ms | 0.35 | 0.003 (0.001;0.005) | 0.017 | (–) | |
Finally, we identified a slight but statistically significant increase in circulatory inflammatory biomarkers (CRP, IL6, TNFα) in patients with reduced VO
2peak compared to normal exercise capacity group (Table
4). There was a negative correlation between VO2peak and IL6 (r = − 0.24, p = 0.013), TNFa (r = − 0.34, p = 0.0003) and CRP (r = − 0.29, p = 0.003).
Table 4
Comparison of circulatory inflammatory biomarkers between patients with normal and reduced exercise capacity
CRP, mg/L (< 5 mg/l) | 3.61 ± 6.00 | 2.46 ± 4.26 | 5.79 ± 7.99 | 0.012 |
Interleukin-6, pg/ml (< 7 pg/l) | 5.80 ± 7.58 | 5.17 ± 7.21 | 6.96 ± 8.18 | 0.013 |
Interleukin-8, pg/ml (6.7–16.2 pg/ml) | 116.03 ± 249.6 | 131.24 ± 299.17 | 88.06 ± 110.27 | 0.835 |
TNFα pg/ml (4.05–8.34 pg/ml) | 19.36 ± 8.87 | 17.3 ± 7.82 | 23.14 ± 9.51 | < 0.0001 |
Discussion
Three months after hospitalization for a severe COVID-19 pulmonary infection, we show that 35% of survivors of COVulnerability cohort have a clinically occult impaired exercise capacity, which was unmasked by CPET whereas clinical symptoms and 6-MWT were not contributive. Beyond alteration of pulmonary function, exercise limitation was associated to sarcopenia and reduced skeletal muscle function but no significant cardiac dysfunction.
Our results highlight the importance to perform a global and systematic evaluation of severe patients during follow up, including CPET to detect exercise limitation beyond the existence of lung sequelae. Indeed, the initial disease severity during the acute hospitalization was not related to the exercise capacity at 3 months, highlighting the complexity to predict which patient will develop an exercise limitation. Furthermore, CPET is able to unmask an exercise limitation that cannot be identified by dyspnea measure or 6-MWT [
19]. In line with this observation, we showed that these two latter criteria were similar between normal and impaired exercise capacity groups and were not contributive for the diagnosis of exercise limitation. Thus, our study adds a piece of evidence for the high rate of exercise limitation in COVID-19 survivors as previously reported in coronavirus outbreak [
4,
20,
21] and more recently identified in COVID-19 patients [
10,
11,
22].
Once raising awareness of exercise limitation in the follow-up of COVID-19 patients, we aimed to decipher the underlying mechanisms by performing a comprehensive multi-organ evaluation to identify factors associated with a reduced exercise capacity. Whilst most of studies are focusing on lung alterations [
11,
22], our study is the first to identify sarcopenia as a main contributor. Indeed, a reduced exercise capacity was associated with a decrease in muscle mass and function assessed by ASMMI and grip test. The reduction of VO2/kg leg muscle mass in the group with a reduced exercise capacity suggest strongly that the muscle is dysfunctional. The reduction of anaerobic threshold is also an argument for an alteration of muscle function responsible of the exercise limitation. Moreover, sarcopenia was very common among patients with low exercise capacity, thus clarifying the suspicion of muscular deconditioning reported by previous studies [
11]. Such a link between exercise limitation and sarcopenia has been reported in chronic cardiac and lung diseases [
23,
24]. However, in our cohort, COVID-19 survivors with an exercise limitation had a higher rate of sarcopenia (almost 40%) compared with these diseases (15–34%) [
25‐
27] highlighting the important chronic impact of COVID-19 on muscle mass. Based on these results, prevention and treatment of sarcopenia must be considered during follow up of COVID-19 survivors.
If obesity and high BMI are clearly associated with higher frequency of severe COVID-19 infections and worse prognosis in the acute phase [
28,
29], we showed that patients with low BMI may be more vulnerable in the follow-up phase with a lower exercise capacity.
We also found that an impaired exercise capacity was associated with a lower lung function and particularly with a decrease in lung volume that characterized COVID-19 survivors [
8,
9,
22,
30,
31]. A reduction of gas transfer measured by DL
CO was also present, but this difference disappeared when this value was related with alveolar ventilation (K
CO), confirming the restrictive pulmonary pattern in patients presenting a decreased effort capacity. However, the breathing reserve at VO
2peak was higher in the reduced exercise group suggesting that this restrictive profile is not responsible of the exercise limitation.
Echocardiography at rest suggest that the role of cardiac dysfunction can be ruled out regarding the lack of systolic and diastolic function abnormalities and the weak correlation between systolic and diastolic parameters with VO2peak. However, we cannot exclude a cardiac dysfunction during exercise based on VO2/heart rate in patients with impaired exercise capacity. Another explanation to the VO2/heart reduction could be the reduction of peripheral extraction associated with muscle dysfunction. Further explorations such effort cardiac echography would be interested to determine the impact of cardiac dysfunction, but it was not in the scope of this study.
We also observed that inflammatory circulating biomarkers are higher in patients with low exercise capacity. That could be an important component of the phenotype of patients with low exercise capacity associated with altered lung function and muscle alteration. Lower muscle mass may be related to persistent systemic inflammation from acute COVID-19 infection [
32,
33] to chronic sequelae [
30]. Indeed, a high level of circulating inflammatory biomarkers, related to a chronic inflammation, is known to be associated with lower skeletal muscle strength and muscle mass [
34,
35] and can participate to the deconditioning process observed in our patients. The higher level of IL-6 and TNFα in the reduced exercise capacity group at 3 months of the acute disease highlight a persistent inflammatory signature. These results are consistent with the IL-6 and TNFα serum levels that are described to be independent and significant predictors of COVID-19 disease severity [
36]. Decrease in hemoglobin level in the reduced exercise capacity group can be linked to this persistent inflammation.
One limitation of our study includes the absence of preexisting evaluation of these patients before the acute phase of the disease and organ alteration that may precede the hospitalization. For example, sarcopenia could be induced by diabetes prior to COVID-19 infection. BMI values before COVID-19 infection showed a difference between groups, it can limit the interpretation and allow to hypothesize that other parameters, like a preexisting muscle mass and function alteration, was already present between groups.
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