Baseline Characteristics
A total of 361 confirmed COVID-19 patients were enrolled, but only 349 patients who had complete data were included in the study. Average age of the including patients was 61.73 ± 14.64 years. Among them 197(56.4%) patients were aged 60 years or older and 167(47.9%) patients were female. Among these patients, the most common original comorbidity was hypertension, 143(41.1%) patients had hypertension and 63(18.2%) patients took ACE inhibitors, while the other comorbidities were diabetes 66(19%), cardiovascular disease 41(11.7%), chronic obstructive pulmonary disease (COPD) 16(4.6%). The most common symptoms of early stage of onset was fever (87.1%), dry cough (67.3%), dyspnea (60.7%), fatigue (49.3%), expectoration (39.3%), anorexia (26.9%) and diarrhea (26.4%) successively (Table 1).
Table 1
Baseline characteristics of COVID-19 patients
| All patients(n = 349) | No extrapulmonary injury(n = 184) | Extrapulmonary injury (n = 165) | P value |
one injury(n = 43) | two injuries(n = 26) | three injuries(n = 36) | four injuries (n = 35) | five injuries (n = 25) |
Base line information | |
Age range, year | | | | | | | | 0.000 |
≤ 60 | 152(43.6) | 103(56.0) | 17(39.5) | 8(30.8) | 16(44.4) | 4(11.4) | 4(16.0) | |
> 60 | 197(56.4) | 81(44.0) | 26(60.5) | 18(69.2) | 20(55.6) | 31(88.6) | 21(84.0) | |
Gender | | | | | | | | 0.311 |
Male | 182(52.1) | 92(50.0) | 21(48.8) | 18(69.2) | 21(58.3) | 15(42.9) | 15(60.0) | |
Female | 167(47.9) | 92(50.0) | 21(51.2) | 8(30.8) | 15(41.7) | 20(57.1) | 10(40.0) | |
Original comorbidities | | | | | | | | |
Hypertension | 143(41.1) | 65(35.3) | 14(32.6) | 15(57.7) | 14(38.9) | 19(55.9) | 16(64.0) | 0.011 |
ACE inhibitors | 63(18.2) | 31(16.8) | 3(7.0) | 5(19.2) | 5(13.9) | 10(29.4) | 9(37.5) | 0.031 |
Diabetes | 66(19.0) | 28(15.2) | 10(23.3) | 8(32.0) | 5(13.9) | 9(25.7) | 6(24.0) | 0.220 |
Cardiovascular disease | 41(11.7) | 16(8.7) | 4(9.3) | 7(26.9) | 5(13.9) | 3(8.6) | 6(24.0) | 0.038 |
COPD | 16(4.6) | 4(2.2) | 3(7.0) | 1(3.8) | 4(11.1) | 3(8.6) | 1(4.0) | 0.165 |
Signs and symptoms | |
Fever | 304(87.1) | 160(87.0) | 40(93.0) | 22(84.6) | 30(83.3) | 30(85.7) | 22(88.0) | 0.846 |
Dry cough | 235(67.3) | 119(64.7) | 30(69.8) | 18(69.2) | 26(72.2) | 24(68.6) | 18(72.0) | 0.923 |
Fatigue | 172(49.3) | 88(47.8) | 22(51.2) | 13(50.0) | 17(47.2) | 17(48.6) | 15(60.0) | 0.920 |
Expectoration | 137(39.3) | 73(39.7) | 18(41.9) | 10(38.5) | 11(30.6) | 18(51.4) | 7(28.0) | 0.442 |
Diarrhea | 92(26.4) | 53(28.8) | 16(37.2) | 3(11.5) | 9(25.0) | 4(11.4) | 7(28.0) | 0.070 |
Anorexia | 94(26.9) | 47(25.5) | 14(32.6) | 9(34.6) | 5(13.9) | 10(28.6) | 9(36.0) | 0.320 |
Dyspnea | 212(60.7) | 98(53.3) | 25(58.1) | 14(53.8) | 27(75.0) | 28(80.0) | 20(80.0) | 0.004 |
Vital signs | |
Heart rate, bpm | 92.93 ± 16.83 | 91.17 ± 14.92 | 90.53 ± 15.37 | 93.58 ± 15.81 | 96.63 ± 23.21 | 96.80 ± 18.86 | 98.64 ± 0.55 | 0.360 |
Respiratory rate, rpm | 23.68 ± 6.98 | 22.45 ± 6.83 | 23.44 ± 6.30 | 23.54 ± 5.79 | 26.75 ± 8.05 | 25.31 ± 7.13 | 26.52 ± 6.51 | 0.000 |
Systolic pressure, mmHg | 132.2 ± 19.77 | 132.10 ± 18.20 | 132.49 ± 19.29 | 133.04 ± 18.75 | 133.0 ± 21.16 | 129.43 ± 23.18 | 134.36 ± 26.33 | 0.873 |
SpO2/FiO2 | 353.78 ± 128.65 | 316.53 ± 100.47 | 270.74 ± 134.40 | 170.47 ± 103.89 | 167.17 ± 101.84 | 151.13 ± 98.75 | 121.19 ± 74.29 | 0.000 |
ARDS | 148(42.4) | 20(10.9) | 15(34.9) | 19(73.1) | 34(94.4) | 35(100) | 25(100) | 0.000 |
Laboratory findings at admission | |
WBC, ×109/L | 7.65 ± 4.94 | 4.87 ± 2.56 | 7.35 ± 6.38 | 8.10 ± 6.17 | 10.50 ± 6.04 | 10.51 ± 5.22 | 12.92 ± 5.07 | 0.000 |
Neutrophils, ×109/L | 6.44 ± 6.52 | 4.25 ± 2.46 | 5.86 ± 5.82 | 10.43 ± 17.14 | 9.09 ± 5.64 | 9.37 ± 5.09 | 11.86 ± 4.95 | 0.000 |
lymphocytes, ×109/L | 1.55 ± 10.48 | 2.28 ± 14.38 | 0.94 ± 0.54 | 0.5 ± 0.23 | 0.81 ± 0.67 | 0.65 ± 0.35 | 0.56 ± 0.31 | 0.000 |
N/L | 11.08 ± 17.03 | 4.77 ± 4.47 | 7.32 ± 6.43 | 26.45 ± 41.75 | 15.62 ± 11.82 | 21.54 ± 20.11 | 27.89 ± 19.87 | 0.000 |
Platelets, ×109/L | 207.0 ± 95.9 | 240.8 ± 86.4 | 188.4 ± 99.51 | 185.56 ± 93.06 | 193.43 ± 98.24 | 142.06 ± 70.03 | 114.04 ± 61.77 | 0.000 |
RDW | 13.14 ± 5.88 | 12.56 ± 1.16 | 15.26 ± 16.11 | 13.30 ± 1.50 | 12.95 ± 1.35 | 12.95 ± 1.28 | 14.25 ± 3.86 | 0.001 |
HS-CRP, mg/L | 71.11 ± 69.56 | 42.35 ± 48.46 | 63.94 ± 56.51 | 93.77 ± 67.45 | 129.33 ± 77.28 | 90.74 ± 60.84 | 163.45 ± 81.25 | 0.000 |
PCT, ng/ml | 0.76 ± 4.75 | 0.32 ± 2.41 | 0.22 ± 0.47 | 0.67 ± 1.62 | 0.66 ± 1.03 | 0.61 ± 1.01 | 4.85 ± 15.34 | 0.000 |
IL-2R, U/ml | 952.04 ± 686.50 | 734.0 ± 387.31 | 839.14 ± 448.27 | 1443.14 ± 1357.08 | 1197.68 ± 677.09 | 1116.76 ± 439.55 | 1640.76 ± 1142.94 | 0.000 |
IL-6, pg/ml | 62.68 ± 141.44 | 19.54 ± 23.87 | 38.73 ± 48.97 | 76.78 ± 135.77 | 189.15 ± 346.97 | 98.21 ± 85.17 | 179.33 ± 203.38 | 0.000 |
IL-8, pg/ml | 42.42 ± 101.57 | 22.32 ± 39.85 | 57.46 ± 149.33 | 89.28 ± 275.33 | 37.11 ± 31.95 | 63.12 ± 58.83 | 87.17 ± 98.71 | 0.000 |
IL-10, pg/ml | 20.26 ± 19.57 | 6.51 ± 5.65 | 7.94 ± 7.11 | 10.56 ± 9.79 | 11.48 ± 6.88 | 14.43 ± 8.54 | 20.3 ± 19.57 | 0.000 |
TNF-α, pg/ml | 10.77 ± 7.96 | 8.34 ± 3.63 | 8.74 ± 2.52 | 11.24 ± 5.91 | 12.97 ± 7.13 | 16.05 ± 13.67 | 20.77 ± 14.71 | 0.000 |
PT, s | 15.32 ± 7.62 | 14.72 ± 10.02 | 14.53 ± 1.10 | 15.10 ± 1.87 | 15.16 ± 1.79 | 17.01 ± 3.94 | 18.78 ± 5.20 | 0.000 |
APTT, s | 43.24 ± 13.79 | 41.6 ± 11.17 | 43.66 ± 13.43 | 45.56 ± 16.68 | 40.58 ± 14.64 | 45.73 ± 18.21 | 52.03 ± 16.75 | 0.175 |
D-Dimer, µg/ml | 5.37 ± 8.48 | 1.96 ± 3.95 | 4.61 ± 10.95 | 7.02 ± 10.32 | 10.61 ± 9.01 | 11.01 ± 9.74 | 14.46 ± 9.31 | 0.000 |
Fibrinogen, g/L | 4.85 ± 1.70 | 5.00 ± 1.29 | 4.64 ± 1.31 | 5.19 ± 1.70 | 5.67 ± 1.83 | 3.98 ± 2.35 | 3.98 ± 2.48 | 0.000 |
High-sensitivity cardiac troponin I, pg/ml | 739.22 ± 3470.45 | 43.50 ± 234.79 | 12.50 ± 14.70 | 83.87 ± 175.67 | 637.00 ± 1973.86 | 2581.52 ± 8213.76 | 3861.09 ± 5633.70 | 0.000 |
CK-MB, ng/ml | 6.38 ± 23.815 | 5.46 ± 23.41 | 1.73 ± 2.29 | 2.49 ± 2.35 | 6.38 ± 10.29 | 16.01 ± 48.75 | 9.60 ± 9.89 | 0.000 |
ALT, U/L | 46.57 ± 157.70 | 29.92 ± 29.31 | 35.15 ± 43.84 | 35.40 ± 29.29 | 37.03 ± 23.34 | 29.06 ± 17.51 | 235.92 ± 550.67 | 0.000 |
AST, U/L | 57.33 ± 199.81 | 32.29 ± 21.97 | 40.74 ± 34.90 | 46.76 ± 35.05 | 48.79 ± 28.41 | 46.74 ± 26.18 | 306.76 ± 703.085 | 0.000 |
TBIL, µmol/L | 13.67 ± 28.29 | 9.27 ± 4.30 | 10.57 ± 4.60 | 13.36 ± 5.36 | 12.69 ± 8.02 | 17.11 ± 16.38 | 48.34 ± 96.96 | 0.000 |
Albumin, g/L | 33.78 ± 6.30 | 35.81 ± 5.13 | 34.63 ± 7.01 | 33.06 ± 7.78 | 29.72 ± 6.45 | 29.5 ± 4.89 | 29.7 ± 5.51 | 0.000 |
Creatinine, µmol/L | 92.70 ± 95.60 | 80.08 ± 84.84 | 73.24 ± 27.97 | 108.72 ± 107.63 | 115.94 ± 175.19 | 104.32 ± 58.97 | 152.96 ± 84.20 | 0.000 |
e-GFR, ml/min/1.73 m2 | 82.95 ± 27.34 | 91.01 ± 22.95 | 89.66 ± 20.88 | 75.00 ± 31.37 | 75.61 ± 29.37 | 68.43 ± 24.93 | 50.90 ± 27.98 | 0.000 |
LDH, U/L | 420.40 ± 295.79 | 295.80 ± 135.91 | 351.79 ± 150.49 | 428.88 ± 168.20 | 559.94 ± 250.14 | 613.06 ± 334.78 | 981.92 ± 514.34 | 0.000 |
Glu, mmol/L | 8.36 ± 4.49 | 7.08 ± 3.20 | 8.42 ± 3.12 | 10.51 ± 5.95 | 8.49 ± 3.20 | 11.66 ± 7.22 | 11.01 ± 5.80 | 0.000 |
Treatments | | | | | | | | |
Antiviral | 287(82.2) | 163(88.6) | 39(90.7) | 19(73.1) | 30(83.3) | 25(71.4) | 11(44.0) | 0.000 |
Antibiotic | 270(77.4) | 122(66.3) | 33(76.7) | 23(88.5) | 34(94.4) | 33(94.3) | 25(100) | 0.000 |
Corticosteroid | 226(64.8) | 90(48.9) | 29(67.4) | 22(84.6) | 32(88.9) | 32(91.4) | 21(84.0) | 0.000 |
Immunoglobulin | 159(45.6) | 56(30.4) | 20(46.5) | 15(57.7) | 24(66.7) | 27(77.1) | 17(68.0) | 0.000 |
Oxygen support | | | | | | | | |
HFNC | 40(11.5) | 3(1.6) | 7(16.3) | 6(23.1) | 10(27.8) | 10(28.6) | 4(16.0) | 0.000 |
NIV | 86(24.6) | 12(6.5) | 11(25.6) | 14(53.8) | 21(58.3) | 15(42.9) | 13(52.0) | 0.000 |
IV | 101(28.9) | 1(0.5) | 8(18.6) | 12(46.2) | 30(83.3) | 31(88.6) | 19(76.0) | 0.000 |
Prognosis | | | | | | | | |
death | 140(40.1) | 17(9.2) | 11(25.6) | 20(76.9) | 34(94.4) | 33(94.3) | 25(100) | 0.000 |
Abbreviations: COPD: chronic obstructive pulmonary disease; ARDS: acute respiratory distress syndrome; WBC: White blood count cell; N/L: neutrophil-to-lymphocyte ratio; RDW: RBC Distribution Width; HS-CRP: high-sensitivity C-reactive protein; PCT: procalcitonin; e-GFR: glomerular filtration rate; HFNC: high-flow nasal cannula; NIV: non-invasive ventilation; IV: invasive ventilation. |
Associated risk factors in patients with different number of extrapulmonary organ function impairment
In the study, we compared the clinical features and laboratory findings according to whether patients had extrapulmonary injury and stratified by the number of injured organs. All the patients were separated to six groups (no extrapulmonary injury, one to five extrapulmonary organ injury).
Overall, 165 patients developed extrapulmonary organ injury. We found that aged patients, especially aged over 60 years old, were more likely to suffer from extrapulmonary injury (P < 0.001). The proportion of male patients was higher in patients with extrapulmonary injury than that of female patients but no significant difference was observed. (P = 0.311). Patients with hypertension (P = 0.011) (including taken ACE inhibitors, P = 0.031) and cardiovascular disease (P = 0.038) were prone to extrapulmonary organ damage. We also found that with the increasing number of injured extrapulmonary organs, the respiratory rate increased significantly (P < 0.001) and the S/F ratio decreased notably (P < 0.001). Of 148 patients with ARDS, 128 cases developed extrapulmonary injury. The proportion of ARDS was much higher in patients with extrapulmonary injury than in those without extrapulmonary injury(P < 0.001), and more than 90% patients with three and more extrapulmonary organs dysfunction developed ARDS.
By comparing the results of laboratory tests on admission, we discovered that the count of neutrophils, lymphocytes, platelets, and neutrophils/lymphocytes ratio (N/L) were different in different groups (P < 0.001). Furthermore, the more extrapulmonary organs were injured, the higher neutrophils count, N/L ratio, and the lower lymphocytes count were observed. There were also significant differences in inflammation indicators (including hs-CRP, PCT, IL-2R, IL-6, IL-8, IL-10 and TNF-α) in different groups (P < 0.001). The level of serum IL-2R and IL-6 rose with the increasing number of injured extrapulmonary organs. The similar phenomenon was found in the D-dimer, fibrinogen, high-sensitivity cardiac troponin I, CK-MB, LDH and liver and kidney function indicators. However, there was no significant difference in APTT among different groups (P = 0.175) (Table 1).
Because there was some certain collinearity between laboratory findings, partial collinear indicators were filtered out after correlation testing. Only 7 indicators screened out and other significant factors tested by single-factor analysis were included in the ordered logistic regression model. Indicator assignments were shown in Table 2. Using likelihood ratio test to determine the parallelism of the 5 regression equations, the results showed that the ordered logistic regression model could be used to analysis (2 = 77.280, P = 0.955). Likelihood ratio test showed that the model was statistically significant (2 = 328.009, P = 0.000). In the final logistic model, variables such as age 60 or older (OR 1.826, 95% CI 1.060–3.142), ARDS (OR 2.748, 95% CI 1.051–7.185), lymphocytes count lower than 1.1 × 109/L (OR 0.478, 95% CI 0.240–0.949), IL-6 greater than 7 pg/ml (OR 1.664, 95% CI 1.005–2.751) and D-Dimer greater than 0.5 µg/ml (OR 2.190, 95% CI 1.176–4.084) were significantly associated with the extrapulmonary injury (Table 3).
Table 2
Value assignment of ordinal logistic regression model variables
Variable | Value assignment |
Age range, year | ≤ 60 = 0, > 60 = 1 |
Hypertension | No = 0, Yes = 1 |
ACE inhibitors | No = 0, Yes = 1 |
Cardiovascular disease | No = 0, Yes = 1 |
Respiratory rate, rpm | < 24 = 0, ≥ 24 = 1 |
SpO2/FiO2 | ≤ 150 = 1, 150–235 = 2, 235–315 = 3, > 315 = 4 |
ARDS | No = 0, Yes = 1 |
Neutrophils, ×109/L | ≤ 1.8 = 1, 18 − 6.3 = 2, > 6.3 = 3 |
lymphocytes, ×109/L | < 1.1 = 0, ≥ 1.1 = 1 |
RDW | < 14.9 = 0, ≥ 14.9 = 1 |
HS-CRP, mg/L | ≤ 1 = 0, > 1 = 1 |
PCT, ng/ml | < 0.5 = 0, ≥ 0.5 = 1 |
IL-6, pg/ml | < 7 = 0, > 7 = 1 |
D-Dimer, µg/ml | < 0.5 = 0, ≥ 0.5 = 1 |
LDH, U/L | ≤ 225 = 0, > 225 = 1 |
Dependent Variable: Extrapulmonary injury | No extrapulmonary injury = 0, One extrapulmonary injury = 1, Two extrapulmonary injuries = 2, Three extrapulmonary injuries = 3, Four extrapulmonary injuries = 4, Five extrapulmonary injuries = 5 |
Abbreviations: ARDS: acute respiratory distress syndrome; RDW: RBC Distribution Width; HS-CRP: high-sensitivity C-reactive protein; PCT: procalcitonin. |
Table 3
Ordinal logistic regression model of extrapulmonary injury
Variable | Estimate | Std. Error | Wald value | P | OR | 95% Confidence Interval |
Lower Bound | Upper Bound |
Age range | 0.602 | 0.277 | 4.711 | 0.030 | 1.826 | 1.060 | 3.142 |
Hypertension | 0.136 | 0.299 | 0.206 | 0.650 | 1.146 | 0.637 | 2.059 |
ACE inhibitors | 0.202 | 0.383 | 0.279 | 0.598 | 1.224 | 0.578 | 2.591 |
Cardiovascular disease | -0.390 | 0.392 | 0.989 | 0.320 | 0.677 | 0.314 | 1.459 |
Respiratory rate | 0.042 | 0.271 | 0.024 | 0.878 | 1.043 | 0.613 | 1.774 |
ARDS | 1.011 | 0.490 | 4.250 | 0.039 | 2.748 | 1.051 | 7.185 |
lymphocytes | -0.739 | 0.351 | 4.444 | 0.035 | 0.478 | 0.240 | 0.949 |
RDW | -0.181 | 0.380 | 0.226 | 0.634 | 0.834 | 0.396 | 1.758 |
HS-CRP | 0.194 | 0.562 | 0.119 | 0.730 | 1.214 | 0.403 | 3.655 |
PCT | 0.628 | 0.357 | 3.087 | 0.079 | 1.874 | 0.930 | 3.773 |
IL6 | 0.509 | 0.257 | 3.916 | 0.048 | 1.664 | 1.005 | 2.751 |
D-Dimer | 0.784 | 0.318 | 6.099 | 0.014 | 2.190 | 1.176 | 4.084 |
LDH | 0.232 | 0.400 | 0.337 | 0.562 | 1.261 | 0.576 | 2.765 |
[SpO2/FiO2 = 1] | 0.238 | 0.479 | 0.246 | 0.620 | 1.269 | 0.496 | 3.245 |
[SpO2/FiO2 = 2] | 0.079 | 0.452 | 0.031 | 0.861 | 1.082 | 0.446 | 2.627 |
[SpO2/FiO2 = 3] | -0.360 | 0.378 | 0.906 | 0.341 | 0.698 | 0.332 | 1.465 |
[SpO2/FiO2 = 4] | - | - | - | - | - | - | - |
[Neutrophils = 1] | 0.000 | 0.553 | 0.000 | 1.000 | 1.000 | 0.338 | 2.959 |
[Neutrophils = 2] | -0.142 | 0.318 | 0.198 | 0.656 | 0.868 | 0.466 | 1.618 |
[Neutrophils = 3] | - | - | - | - | - | - | - |
Abbreviations: ARDS: acute respiratory distress syndrome; RDW: RBC Distribution Width; HS-CRP: high-sensitivity C-reactive protein; PCT: procalcitonin. |
Effect of extrapulmonary organ injury on COVID-19 patients’ prognosis.
Of 140 patients in death, 123 patients had extrapulmonary organ injury. With the increasing number of injured extrapulmonary organs, higher fatality rate was observed (P < 0.001). Moreover, of 25 cases with 5 extrapulmonary organs injury, all the patients died.
To identify the impact of extrapulmonary organs injury on the patients’ prognosis, we used Kaplan-Meier curve and log-rank test to analysis the relationship between the extrapulmonary organs injury and surviving. We found that there were significant differences in survival rate when the five extrapulmonary organs injury we focused on occurred. The survival rate of patients with myocardial damage was lower than the patients without (2 = 268.884, P = 0.000). The similar trends were found in liver injury, kidney injury, blood system injury and circulatory system injury patients separately (2 = 51.684, 2 = 141.527, 2 = 85.940, 2 = 242.322; P = 0.000). The results were showed in the Fig. 1–5. However, when all the extrapulmonary organs injury were included in the multivariate COX proportional hazards model, the result showed that only myocardial injury (P = 0.000, HR: 5.068, 95% CI: 2.728–9.417) and circulatory system injury (P = 0.000, HR: 4.076, 95% CI: 2.216–7.498) were the independent factors associated with COVID-19 patients’ prognosis (Table 4).
Table 4
COX proportional hazards model
Variable | Estimate | Std. Error | Wald value | P | HR | 95% Confidence Interval |
Lower Bound | Upper Bound |
myocardial injury | 1.623 | 0.316 | 26.370 | 0.000 | 5.068 | 2.728 | 9.417 |
liver injury | 0.175 | 0.197 | 0.797 | 0.372 | 1.192 | 0.811 | 1.752 |
kidney injury | -0.297 | 0.220 | 1.824 | 0.177 | 0.743 | 0.483 | 1.143 |
blood system injury | 0.255 | 0.188 | 1.838 | 0.175 | 1.291 | 0.893 | 1.866 |
circulatory system injury | 1.405 | 0.311 | 20.418 | 0.000 | 4.076 | 2.216 | 7.498 |