Demographics and Clinical Characteristics
The study cohort included 115 hospitalized patients with confirmed severe [73 (63.5%)] and critically ill [42 (36.5%)] COVID-19 diseases. The median duration from symptoms onset to hospital admission was 14 (IQR, 10-20) days. The median duration of hospitalization was 21 (IQR, 14-38) days. As given in Table 1, for the study population, the median age was 63 years (IQR, 55-70; range 26-97, years), 70 (60.9%) were more than 60 years, and 57 (49.6%) were men. The most common symptoms at illness onset were fever [84 (73%)], dry cough [89 (77.4%)], dyspnea [67 (58.3%)], expectoration [39 (33.9%)] and myalgia/fatigue [32 (27.8%)]. Most patients [68 (59.1%)] had one or more comorbidities, among which hypertension [54 (47%)] and diabetes [29 (25.2%)] were the most common coexisting conditions. Most patients took antibacterial [97 (84.3%)], antiviral [102 (88.7%)] and glucocorticoid therapy [61 (53%)]. 73 (63.5%) patients accepted high flow oxygen inhalation through nasal cannula, noninvasive and invasive mechanical ventilation were performed in 27 (23.5%) and 15 (13%) cases. There were 93 (80.9%) survivors and 22 (19.1%) non-survivors.
Compared with severe patients (given in Table 1), the median age of more than 60 years [31 (73.8%) VS 39 (53.4%), P=0.031], dry cough [39 (92.9%) VS 50 (68.5%), P=0.003] and dyspnea [33 (78.6%) VS 34 (46.6%), P=0.001] were more commonly seen in the critically ill patients. The proportion of critically ill patients receiving glucocorticoid therapy [31 (73.8%) VS 30 (41.1%), P=0.001] and mechanical ventilation [16 (21.9%) VS 26 (61.9%), P=0.000] were higher than that of the severe patients. 22 (52.4%) critically ill patients were died, and 20 (47.6%) were survived. All the severe patients [73 (100%)] were survivors.
Compared with survivors (given in Table 1), the median duration from symptoms onset to hospital admission [10 (IQR, 8-14) VS 14 (IQR, 10-23) days, P=0.015], the median duration of hospitalization [7 (IQR, 3-15) VS 26 (IQR, 17-44)days, P=0.000] and survival time [7 (IQR, 3-15) VS 62 (IQR, 46-62) days, P=0.000] were significantly shorter for non-survivors.
Laboratory Parameters on Admission
Compared with severe patients [given in Table 2 (continuous variables) and Supplementary Table S1 (categorical variables)], critically ill patients were more prone to express as significantly higher leukocytes, neutrophils, neutrophil percentage, NLR, CRP, procalcitonin, D-dimer, AST, ALT, lactate dehydrogenase, urea, troponin. The critically ill group had a significantly lower lymphocytes, lymphocyte percentage, eosinophils, eosinophil percentage, platelet count and albumin than the severe group.
Compared with survivors [given in Table 2 (continuous variables) and Supplementary Table S1 (categorical variables)], non-survivors were more prone to express as significantly higher leukocytes, neutrophils, neutrophil percentage, NLR, CRP, procalcitonin, D-dimer, PT, AST, lactate dehydrogenase, creatine kinase, urea, total bilirubin, troponin, as well as lower lymphocytes, lymphocyte percentage, eosinophils, eosinophil percentage, monocytes, monocyte percentage, platelet count, albumin.
CT Imaging Features on Admission
On admission, chest CT scan was performed to evaluate pulmonary involvement (Table 3). Compared with severe patients, the lesions in critically ill patients were more extensive, showing higher incidences of diffuse distribution and higher lung involvement score. Crazy paving was more commonly observed in the lesions of critically ill patients. These findings were similar between the survivors and non-survivors except for crazy paving.
Independent Risk Factors Associated with Disease Severity
Twenty-five variables were included in the LASSO Regression Model, the results showed that, a total of 11 variables with the smallest partial likelihood deviance were included in the Multivariate Logistic Regression Analysis, as given in Supplementary Figure S1 and Table 4. Multivariate Logistic Regression Analysis (Table 4) showed that D-dimer, eosinophil percentage, total bilirubin and lung involvement score were the independent risk factors associated with disease severity, with P < 0.05. The Odds Ratio (OR) values were 6.33 (95% confidence interval [CI], 1.27-45.57), 8.02 (95%CI, 1.82-45.04), 12.38 (95%CI, 1.24-223.65) and 1.22 (95%CI, 1.08-1.40) respectively. Among them, lung involvement score was treated as a continuous variable, and for each additional point scored, the risk of critically ill illness increased by 1.22 times.
Independent Risk Factors Associated with Patients’ Prognosis and A Survival Nomogram Building
Twenty-seven variables were included in the LASSO regression, a total of 8 variables with the smallest partial likelihood deviance were then included in the Cox Proportional Hazard Model, as given in Figure 1 A-B and Table 4. Cox Proportional Hazard Model (Table 4) showed that troponin and total bilirubin were the independent risk factors associated with patient’s prognosis. The Hazard Ratio (HR) values were 9.02 (95%CI, 3.02, 26.97), 3.16 (95%CI, 1.13, 8.85) respectively. Patients with troponin≥26.2 ng/L were 9.02 times more likely to die than those with troponin <26.2 ng/L, and patients with total bilirubin>20 μmol/L were 3.16 times more likely to die than those with total bilirubin ≤ 20 μmol/L.
A nomogram was then built based on troponin and total bilirubin to predict the 7-day, 14-day and 1-month survival probability, as given in Figure 1 C and Table 5. The nomogram had a C-index of 0.92 (95%CI, 0.87, 0.98) for predicting patient survival probability. The calibration curve (Figure 1 D) showed that the predicted rates were consistent with the actual results. Kaplan-Meier survival plots according to troponin and total bilirubin were shown in Figure 2.
Validation of the Survival Nomogram in the Critically Ill Population
In the current study, considering that all the dead patients were critically ill patients, we further validated the survival nomogram in the cohort of critically ill patients. The detailed information of basic demographics and clinical characteristics, laboratory parameters and CT imaging features of survivors and non-survivors in the critically ill cohort was given in Supplementary Table S2, S3, S4. Troponin and total bilirubin selected by LASSO COX in the total study population were used to build a nomogram (Figure 3) for predicting prognosis of critically ill patients. The 7-day, 14-day and 1-month survival probability were given in Table 5. The nomogram had a C-index of 0.83 (95%CI: 0.75, 0.94).
Stratified analysis by Gender in the Subgroup of Critically Ill Patients
In order to find out the potential causes of higher female mortality in critically ill patients, this study further performed the subgroup analysis with respect to gender in this cohort, as shown in Supplementary Table S5. There was no significant difference between men and women in gender, age and coexisted comorbidities and medication. Only Oxygen support methods were different between female and male patients. The use of mechanical ventilation in female group was significantly higher than that in male group. There was no significant difference in total lung involvement score between the two groups.