Abstract
Purpose
To perform pulmonary function tests (PFT) in severe COVID-19 survivors one and five months after hospital discharge in order to assess the lung function, as well to identify clinical characteristics and PFT parameters associated with worse cardiopulmonary exercise testing (CPET).
Material and methods
A prospective study included 75 patients with severe form of COVID-19. PFT was conducted one and five months after hospital discharge, in addition to CPET in a second assessment. Patients with a previous history of chronic respiratory diseases were excluded from our study.
Results
One month after hospital discharge, all examined patients had diffusion lung capacity for carbon-monoxide(DLco%) below the 80% of predicted values (in mean 58%), with 40% of patients having a restrictive pattern (total lung capacity(TLC) < 80%). In a repeated assessment after five months, pathological DLco% persisted in 40% of patients, while all other PFT parameters were normal. CPET showed reduced maximum oxygen consumption during exercise testing (VO2peak%) values in 80% of patients (in mean 69%), and exercise ventilatory inefficiency in 60%. Patients with VO2peak < 60% had significantly lower values of examined PFT parameters, both one and five months after hospital discharge. Patients with VO2peak% ≥ 60% had a significantly higher increase after the second assessment for Forced expiratory volume in 1st second (FEV1%), Forced expiratory volume in 1st second and forced vital capacity ratio (FEV1/FVC), DLco% and Diffusion lung capacity for carbon monoxide corrected for alveolar volume (DLco/VA).
Conclusion
Significant functional abnormalities, according to PFT and CPET, was present both one and five months in severe COVID-19 survivors, thus emphasizing the importance of a comprehensive follow-up including both resting and dynamic functional assessment in these patients.
Keywords: COVID-19, Cardiopulmonary exercise testing, Long-term effect, Pulmonary function test
Introduction
Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in late December 2019 [1], [2]. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease it causes, COVID-19, is an emerging health threat [3]. Severe ill patients with COVID-19 are characterized by progressive respiratory failure due to lung infection of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [4]. Even though the pathogenesis and treatment of the acute SARSCoV-2 are to some extent elucidated, the intermediate and long-term outcomes are still unknown, particularly in survivors of severe disease course.
Concern that COVID-19 disease could cause serious sequelae such as progressive or residual lung fibrosis has been recently raised, especially while the impairment in lung function might last for months or even years. Until now, few studies have reported early prognosis in relation to the degree of lung injury in patients with COVID-19 [5]. The studies with SARS patients showed impaired diffusion lung capacity for carbon-monoxide (DLco) as the most common abnormality, ranging from 15.5% to 43.6% [6], [7], [8]. However, in COVID-19 patients further investigations are needed in this field.
In the clinical practice, part of rehabilitated patients with COVID-19 presented various levels of exertional dyspnea. Besides the impairment of static pulmonary function tests (PFT), a decreasing capability of oxygen uptake or utilization should also be noted. Therefore, conducting a dynamic functional assessment through a cardiopulmonary exercise testing (CPET) in COVID-19 patients could be of great importance. Up to date, insufficiently data regarding the CPET in severe ill COVID-19 survivors follow-up was reported.
Aims of our study were as follows: 1) to perform PFT in severe COVID-19 survivors one and five months after hospital discharge in order to assess the lung function; 2) to identify clinical characteristics and PFT parameters associated with worse CPET.
Materials and methods
Patient selection
A prospective study included 75 patients with severe form of COVID-19, according to World Health Organization classification who were admitted to the Intensive Care Unit (ICU) at Clinical Center Kragujevac between May and July 2020 and after stabilization of a respiratory condition, continued intrahospital treatment at the Clinic for Pulmonology [9]. The Institutional Ethical Committee of the Clinical Center Kragujevac approved this study (number 01/20/485 from 24/04/2020). All subjects were Caucasian origin. After 30-day follow-up from the hospital discharge, patients underwent PFT. After 5-month follow up from discharge we repeated PFT and performed CPET in all patients.
The study included all consecutive patients discharged in a period of recruitment, with no further randomization. Patients with previous history of chronic respiratory diseases and chronic cardiovascular conditions which could interfere with CPET results (only arterial hypertension was accepted), 2◦ and 3◦ obesity (BMI (body mass index) >35 kg/m2), as well as those who had a physical/psychological limitation for bicycle exercise testing, were not included in our study (10 patients).
Variables observed:
Socio-demographic characteristics of patients, used in further analysis, included age, gender and history of smoking, as well as medical history of obesity (BMI > 25 kg/m2, and < 35 kg/m2, considering exclusion criteria), diabetes mellitus, arterial hypertension and other comorbidities which are not met in exclusion criteria.
Considering the period of acute disease, presence of symptoms, length of hospital stay, both in ICU and in general, as well as modality of ventilation (MV/HFVO) were analyzed.
PFT included spirometry (Master Screen Pneumo Jaeger Germany), measuring forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and FEV1/FVC ratio [10], [11], [12]. Body plethysmography (Master Screen Body Jaeger, Germany) was performed to assess residual volume (RV), total lung capacity (TLC), as well as the RV/TLC ratio. Diffusion lung capacity for carbon-monoxide (DLco) and diffusion coefficient (DLco/VA) were measured according to current standards (MasterScreen Diffusion, ViaSys Healthcare, Germany) [13]. During PFT, the patients used disposable filters (Piston Ltd., Hungary) with 99.9999% bacterial and viral filtration efficiency [14]. In order to reduce the impact of age, gender and constitution, values were analyzed as a percentage of predicted values. Values below 80% of predicted were considered pathological. Considering the fact that all 75 patients had DLco below 80% of predicted values after one-month PFT follow-up, an additional 60% cut-off was used in further analysis.
The CPET was performed according to the ATS/ACCP Statement on an electronic ergometer (Jaeger, Germany) with Bruce treadmill protocol, and respiratory gas analysis was measured breath-by-breath with Oxycon Mobile (Mijnhardt/Jäger, Würzburg, German) [15]. Subjects were asked to avoid caffeine, alcohol, cigarettes, and strenuous exercise 24 h before scheduled testing. Oxygen uptake (VO2) at the peak was expressed in mL/kg/min. In order to reduce the impact of age, gender and weight, values were additionally analyzed as a percentage of predicted values. Values below 85% of predicted were considered pathological. However, considering the fact that 80% of patients had VO2peak below 85% of predicted (range 56–89%), and 60% cut-off was used in further analysis.
The ventilatory response during exercise was expressed as a linear regression function by plotting minute ventilation (VE) against carbon dioxide production (VCO2), excluding data above the ventilatory compensation point, and the slope (VE/VCO2 slope) was obtained from the regression line. Afterward, we considered subjects having a normal range of VE/VCO2 slope (exercise ventilatory efficiency-EVef) and subjects with VE/VCO2 slope over the upper limit (exercise ventilatory inefficiency - EVin) which present values over 31 [16].
Statistical analysis
Descriptive statistics were used to summarize the data; results are reported as medians and interquartile ranges or means and standard deviations, as appropriate. Categorical variables were compared by the χ2 or the Fisher exact test, while continuous variables were assessed by the independent and paired samples t-tests or the non-parametric Mann–Whitney and Wilcoxon signed rank tests. Pearson and Spearman correlations have been carried out between continuous variables. Categorical variables were summarized as counts and percentages. Missing variables in analysis were excluded pairwise. Statistical analysis was performed using Statistical Package for Social Science (SPSS) Version 25.0.
Results
A total of 75 patients with severe form of COVID-19 were included (mean age 51 years [range, 38–63 years]; 80% male). Symptoms began 8 ± 3 days before the admission. The most common symptom was shortness of breath, reported in all 75 patients, followed by cough in 63 patients (84%) and fever in 51 patients (68%), distribution of other symptoms are shown in Table 1 . The mean length of hospitalization was 27.6 ± 4.4 days, while the stay in the ICU was 8.8 ± 4.63 days on mean. Other baseline characteristics, comorbidities and admission laboratory values are shown in Table 1.
Table 1.
Baseline characteristics and admission laboratory values of 75 patients with COVID-19.
| Baseline respiratory symptoms | |
|---|---|
| No. (%) of patients | |
| Fever | 51 (68) |
| Cough | 63 (84) |
| Shortness of breath | 75 (100) |
| Sore throat | 24 (32) |
| other symptoms | |
| diarrhea | 12 (9) |
| Headache | 60 (80) |
| Loss of smell | 11 (15) |
| Loss of taste | 10 (13) |
| Chest pain | 15 (20) |
| Back pain | 56 (75) |
| Comorbidities | |
| Smoking history | 13 (17) |
| Obesity | 45 (60) |
| Diabetes mellitus type 2 | 24 (32) |
| Arterial hypertension | 48 (64) |
| Chronic kidney disease | 18 (24) |
| Total with ≥1 comorbidity | 60 (80) |
| Admission laboratory measures | |
| Mean(min-max) | |
| White blood cell count / μL | 6 100 (2 400–8300) |
| Absolute lymphocyte count / μL | 670 (500- 1000) |
| Lymphocyte count (%) | 11.05 (6.4- 28) |
| C reactive protein, mg/l | 191 (61–203) |
| Procalcitonin, ng/mL | 0.11 (0.05–0.33) |
| Alanine aminotransferase, IU/L | 75.5 (34–101) |
| D-dimer, mcg/ml | 7.80 (1.01–20) |
aPearson correlation test or logistic regression.
During hospitalization, mechanical ventilation (MV) was initiated in 30 patients and high-flow oxygen therapy (HFVO) in 45 patients. Acute respiratory distress syndrome (defined as PaO2/FiO2 < 300) was observed in 30 patients (40%).
Pulmonary function tests
We analyzed lung function one month after hospital discharge and noted that the most common abnormality was registered for DLco%, with all 75 patients having DLco% values below 80% and 45 patients (60%) having DLco values ≤ 60% of predicted values. DLco/VA was less than 80% in 30 cases (40%). Besides, the mean value of the DLco% corrected for alveolar volume (DLco/VA) was higher than DLco% (Table 2а ). The mean DLco%, one month after discharge, was 58% of predicted values and was the lowest compared to other pulmonary function parameters (Fig. 1 ). Furthermore, a significant decreasing (<80% of predicted value) was noted for FVC in 15 patients (20%), and TLC in 30 patients (40%) (Table 2а).
Table 2a.
Lung function 1 and 5 months after hospital discharge in severe COVID-19 patients.
| Lung function parameter | 1 month after the hospital discharge | 5 months after the hospital discharge | Lung function recovery after 5 months |
|---|---|---|---|
| Mean (± SD) | Mean (± SD) | Mean (± SD) | |
| FVC% | 96.67 (± 20.45) | 112.13 (± 18.82) | + 15.46 (± 3.91) |
| FEV1% | 96.17 (± 23.31) | 106.13 (± 26.46) | + 9.97 (± 9.85) |
| FEV1/FVC | 80.24 (± 5.29) | 76.04 (± 9.34) | - 4.19 (± 4.57) |
| DLco% | 58.83 (± 10.77) | 89.55 (± 19.85) | + 30.72 (± 12.51) |
| DLco/VA | 83.17 (± 11.01) | 107.85 (± 13.31) | + 24.68 (± 6.64) |
| TLC% | 84.33 (± 10.27) | 105.68 (± 12.31) | + 21.35 (± 5.94) |
| RV/TLC | 94.67 (± 19.29) | 94.43 (± 15.66) | - 0.23 (± 8.70) |
| No. (%) of patients | No. (%) of patients | No. (%) of patients | |
| FVC <80% | 15 (20%) | 0 | 15 (20%) |
| FEV1 < 80% | 15 (20%) | 0 | 15 (20%) |
| DLco < 80% | 75 (100%) | 30 (40%) | 45 (60%) |
| DLco ≤ 60% | 45 (60%) | 15 (20%) | 30 (40%) |
| DLco/VA < 80% | 30 (40%) | 0 | 30 (40%) |
| TLC%< 80% | 30 (40%) | 0 | 30 (40%) |
Fig. 1.
Lung function 1 and 5 months after hospital discharge in critical COVID-19 patients.
Considering the fact that all 75 patients had DLco values below 80% of predicted after one-month follow up, a 60% cut-off was used in the analysis. Female gender (60% of female vs. 0% of male respondents; χ2 test p = 0.041) and smoking history (100% of smokers vs. 25% of non-smokers; χ2 test p < 0.001) were found to had a significant influence of DLco values < 60% of predicted. Different modalities of ventilation (MV/HFVO) did not affect the patients value of Dlco ≤ 60% one month from hospital discharge (50% of patients treated both with MV and HFOV had values < 60% of predicted; χ2 test p = 1.000), as well as age, hospitalization length (both in ICU and in total), anamnestic data of obesity and evaluated comorbidities.
The affect of systemic corticosteroids and low-molecular-weight heparin (LMWH) on PFT parameters was not considered, since all patients were treated with this therapy during hospitalization.
Five months after hospital discharge 30 patients (40%) had DLco values below 80%, and 15 patients (20%) had values ≤ 60%, while no patients had DLco/VA values below 80% of predicted values. In addition, no patients had value below 80% of predicted values for other pulmonary function parameters after five month follow up (Table 2а; Fig. 1).
In a repeated PFT measurement five months after hospital discharge, HFVO was strongly associated with DLco values below 80% of predicted (50% of HFVO treated vs. 0% of MV treated patients; χ2 test p = 0.001), in addition to smoking history (100% of smokers vs. 0% of non-smokers had pathological DLco% values; χ2 test p = 0.001). When a 60% cut-off value was applied, only history of smoking retained a significant influence on a reduced DLco values (50% of smokers vs. 0% of non-smokers; χ2 test p = 0.002). Different modalities of ventilation (25% of HFVO vs. 0% of MV treated patients had DLco values < 60% of predicted; χ2 test p = 0.160) did not have a statistically significant influence on DLco below 60% of predicted values, nor did age, gender, hospitalization length, obesity and other comorbidities.
Also we recalculated PFT measurement according to GLI reference values and results are presented at Table 2b as lower limit of normal Z-score and Z-score (12,18).
Table 2b.
Lung function 1 and 5 months after hospital discharge in severe COVID-19 patients recalculated with GLI reference values.
| Lung function parameter | 1 month after the hospital discharge | 5 months after the hospital discharge | Lung function recovery after 5 months |
|---|---|---|---|
| Median (25th and 75th percentile) | Median (25th and 75th percentile) | p | |
| FEV1 (z- score) (a) | −0.9 (−1.5; −0.3) | 0.148 (−0.6; 0.7) | <0.01 |
| FVC(z- score) (a) | −1.3 (−1.8; −0.8) | −0.669 (−0.85; −0.12) | <0.01 |
| FEV1/FVC (z- score) (a) | 0.78 (0.3; 1.4) | 0.3 (−0.4; 0.8) | <0.001 |
| DLco (z- score) (b) | - 3.1 (−5.6; −1.3) | - 1.7 (−2.5; −0.3) | <0.02 |
| Kco(z- score) (b) | - 3.7 (−4.3; - 1.3) | 0.1 (−0.8; 1.6) | <0.01 |
| TLC(z- score) (b) | −2.8 (−3.3; −1.8) | −0.5 (−1.1; 0.4) | <0.001 |
| No. (%) of patients | No. (%) of patients | No. (%) of patients | |
| FVC < LLN(a) | 20 (26%) | 2 (2.6%) | 18 (23.4%) |
| FEV1 < LLN(a) | 15 (20%) | 0 | 15 (20%) |
| DLco < LLN(b) | 75 (100%) | 30 (40%) | 45 (60%) |
| Kco < LLN(b) | 30 (40%) | 0 | 30 (40%) |
| TLC%< LLN(b) | 30 (40%) | 0 | 30 (40%) |
GLI: The Global Lung Function Initiative, TLC: total lung capacity, TLCO: diffusing capacity for carbon monoxide, KCO: transfer coefficient for carbon monoxide, FEV1: forced expiratory volume in 1 s, FVC : forced vital capacity.
aGLI 2012 [12]: reference values for Caucasians, African Americans and North and South East Asians.
bGLI 2019 [17]: reference values for Caucasians.
A significant recovery in lung function, compared to the initial measurement, was observed 5 months after hospital discharge for the following parameters: FVC% (15.46 ± 3.91 (15.99%); p < 0.001), FEV1% (9.97 ± 9.85 (10.37%); p = 0.001), DLco/VA (12.40 ± 6.44 (16.9%); p < 0.001) and TLC% (21.35 ± 5.94 (25.32%); p < 0.001). We emphasize that the biggest increase was noted for DLco% (30.72 ± 12.51 (52.22%) compared to the initial measurement; p < 0.001) (Table 2a; Fig. 1). This was also noted and with GLI reference measurement (Table 2b).
After 5 months, in the group of patients without acute respiratory distress syndrome (ARDS) some patients had significant decreasing of FEV1% (<80% of predicted value), DLco%, while in the group of patients with ARDS, all patients had complete recovery of pulmonary function (Table 3 , Fig. 2 ).
Table 3.
Lung function 1 and 5 months after the hospital discharge in COVID-19 patients with or without ARDS.
| Presence of ARDS | Lung function parameter | 1 month after the hospital discharge | 5 months after the hospital discharge | Lung function recovery after 5 months |
|---|---|---|---|---|
| Yes, n = 30 (40%) | No. (%) of patients | No. (%) of patients | No. (%) of patients | |
| FVC <80% | 0 (0%) | 0 (0%) | 0 (0%) | |
| FEV1 < 80% | 0 (0%) | 0 (0%) | 0 (0%) | |
| DLco < 80% | 30 (100%) | 0 (0%) | 30 (100%) | |
| DLco ≤ 60% | 15 (50%) | 0 (0%) | 15 (50%) | |
| DLco/VA < 80% | 15 (50%) | 0 (0%) | 15 (50%) | |
| TLC%< 80% | 15 (50%) | 0 (0%) | 15 (50%) | |
| No, n = 45 (60%) | FVC <80% | 15 (33%) | 0 (0%) | 15 (33%) |
| FEV1 < 80% | 15 (33%) | 15 (33%) | 0 (0%) | |
| DLco < 80% | 45 (100%) | 30 (67%) | 15 (33%) | |
| DLco ≤ 60% | 30 (67%) | 15 (33%) | 15 (33%) | |
| DLco/VA < 80% | 15 (33%) | 0 (0%) | 15 (33%) | |
| TLC%< 80% | 15 (33%) | 0 (0%) | 15 (33%) |
Fig. 2.
Lung function 1 and 5 months after hospital discharge in patients with and without ARDS.
In addition, patients with ARDS also had a significantly higher increase for the following pulmonary function parameters after 5 months: DLco% (ARDS : +45.25% (± 2.90); without ARDS +23.45% (± 8.26) (p < 0.001); DLco/VA (ARDS: + 31.35% (± 4.90); without ARDS + 21.35% (± 4.56) (p < 0.001); TLC% (ARDS: + 25.45% (± 5.85); without ARDS+ 19.30% (± 4.94) (p = 0.026) (Fig. 2).
Cardiopulmonary exercise testing
In addition to standard PFT, five months after hospital discharge, CPET was performed. The mean VO2peak percentage was 69% (SD 12.62; range 56–89) of the predicted values. We found that 60 patients (80%) had VO2peak values below 85%, with 30 patients (40%) having values below 60%. The mean value of the VE/VCO2 slope was 34.24 (SD 7.99; range 26.96 – 48.30), with 45 patients (60%) having pathological values.
In further analysis, all patients were classified according to VO2peak% values. Although values of VO2 peak < 85% of predicted values are considered to be pathological, we have chosen a value of 60% to be set as a cut-off value, because 80% of the examined patients had VO2peak values below 85%, with a range of 56–89%. We found that patients with VO2peak values <60% of predicted values, compared to group with VO2peak ≥ 60%, measured one month after hospital discharge, had significantly lower following lung function parameters: FVC% (p = 0.005), FEV1% (p < 0.001), FEV1/FVC (p < 0.001), DLco% (p < 0.001), DLco/VA (p = 0 0.005), TLC% (p = 0.005) (Table 4 ).
Table 4.
Lung function 1 and 5 months after hospital discharge in COVID-19 patients, presented by VO2peak% categories.
| VO2peak% values | Lung function parameter | 1 month after the hospital discharge | 5 months after the hospital discharge | Lung function recovery after 5 months |
|---|---|---|---|---|
| Mean (± SD) | Mean (± SD) | Mean (± SD) | ||
| VO2peak < 60% | FVC% | 84.50 (± 15.28) | 98.60 (± 10.54) | + 14.1 (± 4.74) |
| FEV1% | 76.50 (± 15.28) | 77.65 (± 6.90) | + 1.15 (± 8.38) | |
| FEV1/FVC | 73.28 (± 0.75) | 64.19 (± 1.88) | - 9.05 (± 2.63) | |
| DLco% | 46.00 (± 1.05) | 62.75 (± 4.90) | + 16.75 (± 3.85) | |
| DLco/VA | 77.50 (± 5.79) | 94.70 (± 3.48) | + 17.20 (± 2.32) | |
| TLC% | 79.00 (± 6.32) | 99.35 (± 2.79) | + 30.35 (± 3.53) | |
| RV/TLC | 112.00 (± 24.24) | 110.80 (± 18.39) | - 1.2 (± 6.11) | |
| VO2peak ≥ 60% | FVC% | 111.00 (± 16.30) | 126.33 (± 15.15) | + 15.33 (± 3.52) |
| FEV1% | 115.33 (± 13.69) | 128.23 (± 16.91) | + 12.90 (± 7.94) | |
| FEV1/FVC | 84.43 (± 1.89) | 82.13 (± 5.29) | - 2.30 (± 3.43) | |
| DLco% | 62.00 (± 4.23) | 103.93 (± 5.21) | + 41.93 (± 5.38) | |
| DLco/VA | 89.67 (± 11.72) | 119.23 (± 8.63) | + 29.57 (± 6.4.72) | |
| TLC% | 90.33 (± 10.70) | 115.30 (± 8.34) | + 24.67 (± 4.74) | |
| RV/TLC | 82.00 (± 1.47) | 87.67 (± 10.01) | + 5.67 (± 2.48) | |
| No. (%) of patients | No. (%) of patients | No. (%) of patients | ||
| VO2peak < 60% | FVC <80% | 15 (50%) | 0 (0%) | 15 (50%) |
| FEV1 < 80% | 15 (50%) | 15 (50%) | 0 (0%) | |
| DLco < 80% | 30 (100%) | 30 (100%) | 0 (0%) | |
| DLco ≤60% | 30 (100%) | 15 (50%) | 15 (50%) | |
| DLco/VA < 80% | 15 (50%) | 0 (0%) | 15 (50%) | |
| TLC%< 80% | 15 (50%) | 0 (0%) | 15 (50%) | |
| VO2peak ≥ 60% | FVC <80% | 0 (0%) | 0 (0%) | 0 (0%) |
| FEV1 < 80% | 0 (0%) | 0 (0%) | 0 (0%) | |
| DLco < 80% | 45 (100%) | 0 (0%) | 45 (100%) | |
| DLco ≤ 60% | 15 (33%) | 0 (0%) | 15 (33%) | |
| DLco/VA < 80% | 15 (33%) | 0 (0%) | 15 (33%) | |
| TLC%< 80% | 15 (33%) | 0 (0%) | 15 (33%) | |
The same trend maintained when lung function parameters measured 5 months after hospital discharge were observed: FVC% (p < 0.001), FEV1% (p < 0.001), FEV1/FVC (p < 0.001), DLco% (p < 0.001), DLco/VA (p < 0.001), TLC% (p < 0.001) (Table 4). We note that 5 months after hospital discharge, no patients with VO2peak ≥ 60% had pathological values of measured lung function parameters, which was not observed in a group of patients with VO2peak% values < 60% of predicted values for FEV1% and DLco% (Table 4, Fig. 3 ). Also, cardiopulmonary exercise testing five months after hospital discharge are presented at Table 5 with mean value of CPET parameters.
Fig. 3.
Lung function 1 and 5 months after hospital discharge, by VO2peak% categories.
Table 5.
Cardiopulmonary exercise testing five months after hospital discharge.
| CPET parameter | Mean (SD) |
|---|---|
| VO2 peak% | 69 (12.44) |
| O2 pulse% | 84.2 (19.54) |
| VE | 42.6 (13.5) |
| VE/VCO2 | 32.24 (7.88) |
| PET CO2 | 30.2 (2.33) |
| ΔPET CO2 | 4.0 (1.68) |
| Max RR | 25.8 (4.56) |
| BORG scale | 2.6 (1.2) |
CPET - cardiopulmonary exercise testing; VO2 peak% - percentage of predicted maximum oxygen consumption during exercise testing; O2 pulse% - percentage of predicted oxygen pulse; VE - ventilatoty efficiency; VE/VCO2 (slope) - ventilatory equivalents for Carbon dioxide; PET CO2 - end-Tidal carbon dioxide tension; ΔPET CO2 - change in end-Tidal carbon dioxide tension during to the anaerobic treshold; Max RR - maximal respiratory rate.
Interestingly, pathological values of VO2peak < 80% were more present in patients treated with HFVO compared to MV (100% of HFVO, and 50% MV treated patients; χ2 test p = 0.005). Age, gender, hospitalization length (both in ICU and in total), as well as anamnestic data of smoking, obesity and evaluated comorbidities did not significantly affect the presence of pathological VO2peak values.
Even with a new cut-off introduced, HFVO had a significant affect on reduced VO2peak values < 60% of predicted (67% of patients treated with HFVO, and no patients treated with MV; χ2 test p = 0.001). In addition, a smoking history had a strong negative affect on VO2peak values (all patients with smoking history had VO2peak values < 60% of predicted, compared to non smokers; χ2 test p = 0.001). Age, gender, hospitalization length, obesity and evaluated comorbidities continued to have no significant impact on VO2peak values.
Considering the recovery of lung function, we observed that patients with VO2peak < 60% of predicted values had a significant increase in the following parameters after 5 months of discharge: FVC% (p = 0.004), DLco% (p = 0.004), DLco/VA (p = 0.004) and TLC% (p = 0.004). A similar trend was present in the group of patients with VO2peak% values ≥ 60%, where a significant increase was observed for the following parameters: FVC% (p = 0.001), FEV1% (p = 0.001), DLco% (p = 0.001), DLco/VA (p = 0.001), TLC% (p = 0.00) (Fig. 3).
Patients with VO2peak% values ≥ 60% had a significantly higher increase after the second assessment, compared to group with VO2peak < 60%, for the following parameters: FEV1% (p = 0.005), FEV1/FVC (p = 0.005), DLco% (p < 0.001), DLco/VA (p < 0.001). In contrast, patients with VO2peak < 60% had a significantly higher increase in TLC% (p = 0.005) (Table 4).
Univariate Relationship between VO2peak (% Predicted Value) and CPET Parameters five months after hospital discharge did not show any statistically significant relationship (p>0.05) (Table 6 ).
Table 6.
Univariate Relationship between VO2peak (% Predicted Value) and CPET Parametersa five months after hospital discharge.
| CPET parameters | VO2peak% |
|
|---|---|---|
| Rho | P | |
| O2 pulse% | 0.279 | 0.651 |
| VE | 0.874 | 0.135 |
| VE/VCO2 (slope) | −0.385 | 0.552 |
| PET CO2 | −0.654 | 0.225 |
| ΔPET CO2 | −0,246 | 0.085 |
Some subjects may have had COVID-19 infection and were not tested.
Discussion
Our study, involving severe COVID-19 survivors, had the following main findings: 1) all patients had a significant alteration in diffusion capacity (DLco<80%) 1 month after hospital discharge; 2) 40% of patients had a restrictive ventilatory impairment (TLC<80%) 1 month after hospitalization; 3) in 40% of patients DLco stayed below 80% of predicted values, 5 months after hospital discharge; 4) a significant recovery in lung function after 5 months from hospital discharge, compared to the initial measurement, was observed for FVC%, FEV1%, DLco%, DLco/VA and TLC%; 4) VO2peak was bellow 85% of predicted values in 80% of patients and mean VO2peak was 69%, after 5 months from hospital discharge; 5) ventilatory inefficiency (VE/VCO2 slope over 31) was found in 60% of patients, 5 months after hospital discharge; 6) patients with VO2peak% values ≥ 60% had a significantly higher increase after the second assessment, compared to group with VO2peak < 60%, for the following parameters FEV1%, FEV1/FVC, DLco%, DLco/VA.
Published data suggest that impaired lung function caused by COVID-19 pneumonia could even last for years, with DLco reduction being the most common pathological finding (up to 43.6%), followed by TLC reduction [6,18,19]. Our study showed that in early recovery, most of the patients with severe or critical COVID-19 developed significant pulmonary function impairment, the most common and significant of which was impaired DLco. Because the mean value of DLco/VA was higher than Dlco, the decreasing diffusion could be partially explained by the volume affect (so-called “small lung”). Pathological changes in the lungs can explain the impaired DLco to a certain extent. The initial abnormalities in COVID-19 are similar to SARS affects and includes injury of microvasculature with thickening of the interstitium, followed by the development of alveolar abnormalities with subsequent loss of the alveolar spaces [20]. An autopsy on patients who died from COVID-19 showed different degrees of destruction in alveolar structure and pulmonary interstitial fibrosis [21,22].
In our study we found a restrictive ventilatory defects (TLC<80% of predicted values) after one month of hospital discharge in 40% severe COVID-19 survivors. Possible pathophysiological mechanisms responsible for the formation of a restrictive pattern might involve hyaline membrane formation, capillary damage and bleeding, alveolar septal fibrous proliferation, and lung parenchyma consolidation [23]. One meta-analysis which included six studies in patients with COVID-19 pneumonia, showed a 15% prevalence of the restrictive pattern in these patients [19]. Moreover, patients included in Swiss COVID19-lung study, after 4-month follow-up, generally had lower lung volumes, although still within the normal range, with FVC and TLC values being significantly lower in patients with severe/critical COVID-19 pneumonia compared to those with mild/moderate disease [24].
We have observed a significant recovery five months after hospital discharge, compared to the initial measurement, for the following parameters: FVC%, FEV1%, TLC%, DLco/VA, but the most significant increase was noted for DLco%. These findings could be partially explained by the fact that DLco% was initially lower compared to the other parameters. Before the COVID-19 pandemic, data from populations ranging from those with mild H1N1 influenza to acute respiratory distress syndrome commonly describe diffusion impairments in the months to years after acute illness [25]. Therefore, these impairments in the early post-acute illness period, do not appear to be unique for COVID-19, although patients' long-term trajectory remains to be seen.
In our study, five months after hospital discharge, 40% of patients had DLco values below 80%, and 20% had values below 60% of predicted values. A prospective observational Swiss COVID-19 lung study found that DLco%-predicted at four months after hospital discharge was the most important, independent correlate of a more severe initial disease.22 Furthermore, results from the study with the most extended follow-up duration (the median follow-up was 186 days) showed that the pulmonary diffusion abnormality during follow-up was higher in patients with more severe acute disease [26]. In this study DLco <80% has been found in 29% of patients with severe and 56% with critical COVID-19.
In our study in the group of patients without ARDS some patients had significant decreasing of FEV1% and DLco% after 5 months of follow-up, while in the group of patients with ARDS all patients had complete recovery of pulmonary function. A complete pulmonary function recovery was found in 54 examined patients 6 months after H1N1-related ARDS, as well [27]. In a study by Orme and colleagues, the 80% prevalence of reduced diffusion capacity in ARDS survivors not caused by Influenza A H1N1 was reported, while 20% of patients had a restrictive pattern after 12/month follow up [28].
It has been known for many years that most critically ill patients face long-lasting functional impairment after discharge [29]. There is an emerging body of evidence suggesting that morbidity following a critical illness is multifactorial and may be viewed as a sum of physical disability and cognitive and/or psychological deficits [30]. Exercise testing, while analyzing the integrated influence of multiple factors, e.g. pulmonary mechanics, pulmonary circulation, cardiac, peripheral muscle and psychosocial factors that determine an individual patient's functional level, may be a more suitable assessment tool for functional outcome than the resting PFT in these patients.
To our knowledge, this is the first study that assessed the clinical status and exercise capacity of severe COVID-19 patients performing complete CPET evaluation after five months from hospital discharge. We have found that an mean VO2peak was 69% of predicted values. Besides, 80% of patients had VO2peak below 85%, with 40% having values below 60%. During 3/month CPET follow/up in non-severe COVID-19 survivors, Clavario and colleagues, have found a median VO2peak of 90.9%, with 34.5% of patients having VO2peak below 85% of predicted values [31]. In a comparison with SARS, Ong and colleagues, reported reduced VO2%peak in 41% of SARS survivors after a 3/month follow/up, in a study which included 22.7% of patients who required invasive ventilation [32]. It is important to note that ventilatory efficiency for carbon dioxide (VE/VCO2) provides a complementary information about ventilatory limitation and prognosis as well as abnormal VE/VCO2 slope define Evin [33]. The mean values of VE/VCO2 slope in our study was 34.24, with 60% of patients having pathological values above 31. The RESPIDOVID2 study investigators, who have analyzed CPET more than five months after COVID-19 pneumonia of different severity, found a 29% of prevalence of Evin [34].
In our study patients with VO2peak < 60% had significantly lower values of a lung function parameters (FVC%, FEV1%, FEV1/FVC, DLco%, DLco/VA, TLC%) measured one month after hospital discharge. On the contrary, in a study conducted by Dorelli et al., measured exercises capacities have had discordance with resting pulmonary functions in a significant number of cases [35].
Also it should be mentioned that in our country there is not any specific rehabilitation program for severe COVID-19 patients after hospitalization which can have positive effect on respiratory function recovery according to available research data. At the discharged patients received information how they can perform several exercise at home condition, but this is on patients and it is not possible to monitor this.
Our study had several limitations. Firstly, the baseline data of pulmonary function are unavailable and the observed impaired pulmonary function cannot be directly attributed to COVID-19. Secondly, this study included a relatively small number of patients and it is monocentric. Thirdly, the functional capacity evaluation was conducted five months after hospital discharge, and no data available about the baseline condition before COVID-19.
In our study all patients with severe COVID-19 had impaired pulmonary diffusion capacity and notable number of them had restrictive pattern of ventilation one month after discharge. Significant recovery in lung function was observed for DLco%, FVC%, FEV1%, but DLco% was only parameter which has been impaired in more than half of patients, 5 months after hospital discharge. The exercise capacity and ventilatory inefficiency were significantly lower in majority of examined patients after five months. In accordance with our and similars studies it is clear that early respiratory rehabilitation of patients can effect on better recovery of lung function [36]
Our results emphasize the importance of a comprehensive follow-up including both resting and dynamic functional assessment in severe or critical COVID-19 survivors.
Declarations of Competing Interest
None.
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