General clinical characteristics
In the 206 full cohort, all patients were residents of Wuhan with a median age of 62.5 years (ranged from 27 to 92 years). 89 (43.2%) were younger than 60 years and most patients are retirees (68.9%) and female (55.8%). Hypertension (27.2%), diabetes (10.2%) and cardiovascular disease (12.7%) were the most common comorbidity in COVID-19 patients. There were 48 patients of Digestive only (23.3%), 89 patients of Respiratory only (43.2%) and 69 cases of Digestive + Respiratory (33.5%), respectively. A series of respiratory symptoms were including cough/expectoration (25.7%), chest tightness (23.8%), shortness of breath (14.6%), and pharyngodynia (6.4%). Of digestive symptom patients, 67 patients (57.3%) were presented with diarrhea. Patients who reported diarrhea were more likely to have a fever in Digestive only group (13/23, 56.5% vs. 6/25, 24.0%, P = 0.021); and were younger (49.5y vs. 61.4y, P = 0.001) in Digestive + Respiratory group (Table 1).
Table 1
Clinical characteristics based on the classification of digestive symptoms with or without diarrhea of Digestive only and Digestive + Respiratory patients on admission.
Items | Total(including Respiratory only) | | Digestive only | Digestive + Respiratory |
| | With Diarrhea (N = 67) | Without Diarrhea (N = 139) | P | With Diarrhea (N = 23) | Without Diarrhea (N = 25) | P | With Diarrhea (N = 44) | Without Diarrhea (N = 25) | P |
Age (years) | 51.6(27–84) | 62.0(27–92) | 0.128 | 55.5(32–84) | 67.6(32–92) | 0.424 | 49.5(27–81) | 61.4(36–84) | 0.001 |
Gender (Male/Female) | 23/44 | 68/71 | 0.048 | 6/17 | 7/18 | 0.882 | 17/27 | 13/12 | 0.282 |
Fever | 48(71.6%) | 90(64.7%) | 0.324 | 13(56.5%) | 6(24.0%) | 0.021 | 35(79.5%) | 19(76.0%) | 0.731 |
Highest temperature, °C | 39.8 | 39.8 | - | 39 | 39.8 | - | 39.8 | 39.5 | - |
Organ function injury | | | | | | | | | |
TBil (≤ 19.0 µmol/L) | 7(10.4%) | 10(7.2%) | 0.436 | 2(8.7%) | 2(8.0%) | 1 | 5(11.4%) | 2(8.0%) | 1 |
DBil (≤ 6.8 µmol/L) | 6(9.1%) | 15(10.9%) | 0.696 | 3(13.0%) | 0(0.0%) | 0.205 | 3(7.0%) | 2(8.0%) | 1 |
ALT (≤ 35U/L) | 17(25.4%) | 54(39.1%) | 0.052 | 7(30.4%) | 8(32.0%) | 0.907 | 10(22.7%) | 9(36.0%) | 0.235 |
AST (≤ 40U/L ) | 6(9.0%) | 25(18.1%) | 0.086 | 2(8.7%) | 5(20.0%) | 0.484 | 4(9.1%) | 6(24.0%) | 0.182 |
ALP (< 150U/L) | 0(0.0%) | 5(3.6%) | 0.274 | 0(0.0%) | 2(8.0%) | 0.508 | 0(0.0%) | 0(0.0%) | - |
GGT (< 50U/L ) | 16(23.9%) | 29(21.0%) | 0.642 | 4(17.4%) | 6(24.0%) | 0.836 | 12(27.3%) | 3(12.0%) | 0.139 |
LDH (< 245U/L ) | 23(34.3%) | 46(34.1%) | 0.971 | 9(39.1%) | 10(40.0%) | 0.951 | 14(31.8%) | 8(32.0%) | 0.988 |
hsTNI (< 26.2 ng/L) | 0(0.0%) | 4(3.5%) | 0.463 | 0(0.0%) | 1(4.8%) | 1 | 0(0.0%) | 0(0.0%) | - |
D-Dimer (< 0.5 ng/L) | 25(45.5%) | 57(52.3%) | 0.408 | 7(36.8%) | 12(75.0%) | 0.041 | 18(50.0%) | 11(50.0%) | 1 |
Immune inflammation | | | | | | | | | |
WBC (3.5-9.5G/L) | 7(10.4%) | 29(21.2%) | 0.059 | 2(8.7%) | 4(16.7%) | 0.666 | 5(11.4%) | 6(24.0%) | 0.3 |
Neutrophil (1.8-6.3G/L) | 7(10.4%) | 28(20.4%) | 0.075 | 3(13.0%) | 5(20.8%) | 0.701 | 4(9.1%) | 6(24.0%) | 0.182 |
Lymphocyte(1.1-3.2G/L) | 18(26.9%) | 52(38.0%) | 0.117 | 6(26.1%) | 10(41.7%) | 0.260 | 12(27.3%) | 7(28.0%) | 0.948 |
CRP (༜8 mg/L) | 21(38.9%) | 66(54.5%) | 0.056 | 7(36.8%) | 9(37.5%) | 0.965 | 14(40.0%) | 9(45.0%) | 0.718 |
ESR (༜15 mm/h) | 40(71.4%) | 103(84.4%) | 0.043 | 14(77.8%) | 20(90.9%) | 0.381 | 26(68.4%) | 19(86.4%) | 0.122 |
IL-2(0.1–4.1 pg/ml) | 3(4.8%) | 1(0.8%) | 0.214 | 3(13.0%) | 1(4.2%) | 0.348 | 0(0.0%) | 0(0.0%) | - |
IL-4(0.1–3.2 pg/ml) | 4(6.3%) | 11(8.8%) | 0.558 | 2(8.7%) | 5(20.8%) | 0.416 | 2(5.0%) | 1(5.0%) | 1 |
IL-6(0.1–2.9 pg/ml) | 59(93.7%) | 119(95.2%) | 0.918 | 20(87.0%) | 23(95.8%) | 0.348 | 39(97.5%) | 18(90.0%) | 0.255 |
IL-10(0.1-5.0 pg/ml) | 6(9.5%) | 20(16.0%) | 0.225 | 3(13.0%) | 8(33.3%) | 0.101 | 3(7.5%) | 2(10.0%) | 1 |
TNF-a (0.1–23 pg/ml) | 0(0.0%) | 6(4.8%) | 0.184 | 0(0.0%) | 0(0.0%) | - | 0(0.0%) | 0(0.0%) | - |
IgG (7.51–15.6 g/L) | 3(13.0%) | 3(6.0%) | 0.576 | 2(15.4%) | 1(6.7%) | 0.583 | 1(10.0%) | 1(25.0%) | 0.505 |
IgM (0.46–3.04 g/L) | 1(4.3%) | 4(8.0%) | 0.940 | 0(0.0%) | 0(0.0%) | - | 1(10.0%) | 0(0.0%) | 1 |
C3(0.79–1.52 g/L) | 3(13.0%) | 14(28.0%) | 0.160 | 2(15.4%) | 4(26.7%) | 0.655 | 1(10.0%) | 1(25.0%) | 0.505 |
C4(0.16–0.38 g/L) | 3(13.0%) | 13(26.0%) | 0.214 | 0(0.0%) | 4(26.7%) | 0.102 | 3(30.0%) | 2(50.0%) | 0.580 |
CD3 + Tlymphocytes | 19(30.6%) | 30(22.4%) | 0.214 | 7(31.8%) | 8(33.3%) | 0.913 | 12(30.0%) | 7(29.2%) | 0.944 |
CD4 + T lymphocytes | 21(33.9%) | 43(32.1%) | 0.805 | 8(36.4%) | 9(37.5%) | 0.936 | 13(32.5%) | 7(29.2%) | 0.781 |
CD8 + T lymphocytes | 12(19.4%) | 26(19.4%) | 0.994 | 3(13.6%) | 5(20.8%) | 0.702 | 9(22.5%) | 6(25.0%) | 0.819 |
Indicators of organ function injury and immune inflammation were expressed in terms of the number and percentage of abnormalities; Digestive Only: gastrointestinal symptoms cases; Respiratory Only: respiratory symptoms cases; Digestive + Respiratory: both digestive and respiratory symptoms. Because not all patients have the same test, the denominators of each indicator may be inconsistent in their calculations. A significance level of P ≤ 0.05 was used. |
Mild liver damage and activation of the immunoinflammatory system are the most common manifestations in mild patients on admission
Mild liver injury was the most common observed in mild patients on admission. In the increased ALT (30.6%) and AST (15.0%) level, the mean value was 36.4 U/L and 31.9 U/L, respectively. Most (17.5%) of the abnormal ALT and AST are 40 ~ 80U/L, and those ≥ 80U/L are less than 5%. Abnormal LDH was also common accounted for 32.0%. It seems that the proportion of abnormal liver function in the Respiratory only group was slightly higher than that of the other two groups but not statistically significant (Table 2, p = 0.186). The function of bile secretion was also slightly declined with increased levels of TBil and DBil, and increased activities of ALP and GGT. The levels of TP and albumin were slightly decrease which implied hepatic synthetic function was acceptable. Other abnormal creatinine, electrolyte disturbance, troponin, platelets, coagulation indexes and D-dimer were not common. Overall, hepatobiliary system is more vulnerable to damage while renal and cardiac disfunctions were rare in mild patients.
Table 2
Multiorgan function change characteristics based on the classification of main symptoms in COVID-19 patients on admission.
Items | Total (N = 206) | Digestive Only(N = 48) | Respiratory Only(N = 89) | Digestive + Respiratory (N = 69) | P |
Blood Biochemistry | | | | | |
TBil (µmol/L) | 12.9 (2.15–35.7) | 12.1 (6.7–22.9) | 13.1 (2.15–35.7) | 13.2 (4.1–26.3) | 0.391 |
≤19.0 µmol/L | 189 (91.7%) | 44 (91.7%) | 83 (93.3%) | 62 (89.9%) | 0.743 |
>19.0 µmol/L | 17 (8.3%) | 4(8.3%) | 6 (6.7%) | 7 (10.1%) | |
DBil (µmol/L) | 4.6 (1.7–16.6) | 4.2(2.3–9.6) | 5.1 (2.0-16.6) | 4.2 (1.7–9.7) | 0.008 |
≤ 6.8 µmol/L | 185 (89.8%) | 45 (93.8%) | 76 (85.4%) | 64 (92.8%) | 0.186 |
> 6.8 µmol/L | 21 (10.2%) | 3 (6.2%) | 13 (14.6%) | 5 (7.2%) | |
TP (g/L) | 63.5 (52.7–81.8) | 63.9(54.2–74.5) | 62.9 (58.8–81.8) | 64.0 (52.7–76.4) | 0.525 |
<64 g/L | 107 (51.9%) | 24 (50.0%) | 47 (52.8%) | 36 (52.2%) | 0.951 |
≥64 g/L | 99 (48.1%) | 24 (50.0%) | 42 (47.2%) | 33 (47.8%) | |
Albumin (g/L) | 36.5 (23.9–68.0) | 36.3 (27.8–43.8) | 36.3 (24.6–68.0) | 36.9 (23.9–47.8) | 0.723 |
<35 g/L | 76 (36.9%) | 13 (27.1%) | 37 (41.6%) | 26 (37.7%) | 0.242 |
≥35 g/L | 130 (63.1%) | 35 (72.9%) | 52 (58.4%) | 43 (62.3%) | |
ALT (U/L) | 36.4 (7-498) | 32.4 (7-176) | 40.8 (7-498) | 33.7 (7-152) | 0.229 |
≤35U/L | 143 (69.4%) | 35 (72.9%) | 60 (67.4%) | 48 (69.6%) | 0.800 |
>35U/L | 63 (30.6%) | 13 (27.1%) | 29 (32.6%) | 21 (30.4%) | |
AST (U/L) | 31.9 (10–346) | 29.9 (11–81) | 35.4 (12–346) | 28.9 (10–135) | 0.167 |
≤40U/L | 175 (85.0%) | 41 (85.4%) | 75 (84.3%) | 59 (85.5%) | 0.972 |
>40U/L | 31 (15.0%) | 7 (14.6%) | 14 (15.7%) | 10 (14.5%) | |
ALP (U/L) | 72.5 (19–250) | 76.4 (27–214) | 75.1 (19–250) | 66.3 (33–141) | 0.100 |
<150U/L | 203 (97.6%) | 46 (95.8%) | 86 (96.6%) | 69 (100.0%) | 0.123 |
>150U/L | 5 (2.4%) | 2 (4.2%) | 3 (3.4%) | 0 (0.0%) | |
GGT (U/L) | 38.6 (7-291) | 39.6 (8-196) | 39.9 (7-291) | 36.1 (11–162) | 0.786 |
<50U/L | 157 (76.2%) | 39 (81.2%) | 65 (73.0%) | 53 (76.8%) | 0.554 |
>50U/L | 49 (23.8%) | 9 (18.8%) | 24 (27.0%) | 16 (23.2%) | |
LDH (U/L) | 230.7 (15–649) | 241.2 (88–649) | 230.4 (15–527) | 223.7 (114–497) | 0.549 |
<245U/L | 140 (68.0%) | 29 (60.4%) | 63 (67.4%) | 48 (69.6%) | 0.539 |
>245U/L | 66 (32.0%) | 19 (39.6%) | 29 (32.6%) | 21 (30.4%) | |
CREA (44–133 µmol/L) | 73.3 (39.6–430) | 67.8 (44.4–121) | 79.2 (41.6–430) | 69.5 (39.6–121) | 0.128 |
Glu (3.9–6.1 mmol/L) | 6.1 (1.79–20.06) | 5.62 (3.95–13.49) | 6.4 (1.79–15.04) | 6.1 (3.94–20.06) | 0.700 |
K (3.5–5.2 mmol/L) | 4.0 (2.8–5.79) | 4.1 (3.27–5.79) | 4.0(2.8–5.79) | 4.0 (2.8–5.1) | 0.276 |
Ca (2.03–2.54 mmol/L) | 2.2 (0.2–4.51) | 2.2 (1.92–3.21) | 2.2(1.78–4.51) | 2.2 (0.2–2.54) | 0.642 |
hsTNI (< 26.2 ng/L) | 4.6 (0.4–38.0) | 4.9 (0.5–34.7) | 5.1(0.4–38.0) | 3.5 (0.7–19.2) | 0.285 |
Blood routine and coagulation function | | | | | |
HGB (130–175 g/L) | 122.3 (80–159) | 119.6 (94–151) | 122.5 (80–161) | 123.9 (93–159) | 0.390 |
PLT (125-350G/L) | 241.9 (24–537) | 239.9 (91–479) | 242.9 (24–463) | 241.8 (102–537) | 0.982 |
APTT (28-43.5 s) | 37.1 (13.7–56.3) | 37.3 (28.1–55.8) | 37.7 (26.2–56.3) | 36.3 (13.7–49.9) | 0.329 |
PT (11–16 s) | 13.3 (11.4–16.6) | 13.4 (11.4–15.4) | 13.4 (11.9–16.6) | 13.2 (11.7–15.0) | 0.237 |
D-Dimer (< 0.5 ng/L) | 1.0 (0.2–20) | 1.0 (0.2–20) | 1.0 (0.2-13.01) | 0.9 (0.2–8.78) | 0.383 |
With regard to inflammatory cytokines (Table 3), 20 (9.7%) and 69 (33.5%) patients had neutropenia and lymphopenia, respectively. Procalcitonin was normal in all cases. The Respiratory only group exhibited more enhanced levels of CRP (59.7% vs.37.2%) and TNF-a (7.4 pg/ml vs. 4.19 pg/ml) than those of the Digestive only group (all P < 0.05). Minority of mild patients presented dysregulation of cytokines such as IL-2 (4, 2.1%), IL-4 (15, 8.0%), IL-10 (26, 13.8%) and TNF-α (6, 3.2%) while almost everyone showed an increase in IL-6 (178, 94.7%). More importantly, the levels of IL-2 (2.92 pg/ml vs. 2.62 pg/ml, P = 0.003), IL-4 (2.57 pg/ml vs. 2.15 pg/ml, P = 0.009) and IL-10 (4.42 pg/ml vs. 3.75 pg/ml,P = 0.08) were higher in Digestive only group compared to those of the cases with Respiratory Only. Among groups, no significant differences in immune system parameters were found(P༞0.05).
Table 3
Inflammation and immune characteristics based on the classification of main symptoms in COVID-19 patients.
Items | Total | GIS | RPS | GRS | P |
WBC (G/L) | 5.54 (1.73–11.64) | 5.65 (2.66–11.64) | 5.44 (1.73–10.24) | 5.58 (2.42–10.48) | 0.789 |
<9.5G/L | 196 (95.1%) | 46 (95.8%) | 84 (94.4%) | 66 (95.7%) | 0.906 |
>9.5G/L | 10 (4.9%) | 2(4.2%) | 5 (5.6%) | 3 (4.3%) | |
Neutrophil (G/L) | 3.58 (0.93–8.67) | 3.61 (1.36–8.1) | 3.51 (0.93–8.56) | 3.65 (1.13–8.67) | 0.854 |
<6.3G/L | 191 (92.7%) | 45 (93.7%) | 82 (92.1%) | 64(92.8%) | 0.941 |
>6.3G/L | 15 (7.3%) | 3(6.3%) | 7 (7.9%) | 5 (7.2%) | |
Lymphocyte (G/L) | 1.35 (0.28–3.4) | 1.41 (0.42–2.18) | 1.28 (0.28–3.4) | 1.39 (0.39–2.76) | 0.302 |
<1.1G/L | 69 (33.5%) | 16 (33.3%) | 34 (38.2%) | 19 (27.5%) | 0.371 |
≥1.1G/L | 137 (66.5%) | 32 (66.7%) | 55 (61.8%) | 50 (72.5%) | |
Procalcitonin(ug/L) | 0.14 (0.03–2.99) | 0.13 (0.03–2.99) | 0.14 (0.03–2.99) | 0.14 (0.03–2.99) | 0.139 |
༜0.5ug/L | 183(88.8%) | 42(87.5%) | 80(89.9%) | 61(88.4%) | 0.906 |
≥ 0.5ug/L | 23(11.2%) | 6(12.5%) | 9(10.1%) | 8(11.6%) | |
C-reactive protein(mg/L) | 20.5(0.3–173) | 19.3(0.6–173) | 26.2(0.3–136) | 21.8(0.6–168) | 0.569 |
༜8 mg/L | 90(51.4%) | 27(62.8%) | 31(40.3%) | 32(58.2%) | 0.029 |
≥ 8 mg/L | 85(48.6%) | 16(37.2%) | 46(59.7%) | 23(41.8%) | |
ESR (mm/h) | 42.1(2-140) | 38.2 (7–99) | 46.8 (2-140) | 38.5 (2-112) | 0.357 |
༜15 mm/h | 35(19.7%) | 6(15.0%) | 14(17.9%) | 15(25.0%) | 0.411 |
≥ 15 mg/L | 143(80.3%) | 34(85.0%) | 64(82.1%) | 45(75.0%) | |
Inflammatory cytokines | | | | | |
IL-2(0.1–4.1 pg/ml) | 2.66 (2.07–4.93) | 2.92 (2.07–4.93) | 2.62 (1.85–4.08) | 2.59 (1.82–3.98) | < 0.001 |
IL-4(0.1–3.2 pg/ml) | 2.32 (0.98–8.23) | 2.57 (1.04–8.23) | 2.15 (1.00-4.18) | 2.00 (0.98–4.80) | 0.002 |
IL-6(0.1–2.9 pg/ml) | 40.09 (1.96-437.81) | 45.53 (1.96-437.81) | 43.18 (2.27-424.93) | 31.64 (2.05-383.95) | 0.559 |
༜2.9 pg/ml | 10(5.3%) | 4(8.5%) | 3(3.7%) | 3(5.0%) | 0.610 |
2.9–90 pg/ml | 159(84.6%) | 37(78.7%) | 69(85.2%) | 53(88.3%) | |
≥ 90 pg/ml | 19(10.1%) | 6(12.8%) | 9(11.1%) | 4(6.7%) | |
IL-10(0.1-5.0 pg/ml) | 3.84 (1.75–15.98) | 4.42 (2.15–15.98) | 3.75 (1.92–9.34) | 3.46 (1.75–6.30) | 0.021 |
TNF-a (0.1–23 pg/ml) | 5.76 (0.90-67.26) | 4.19 (1.01–21.26) | 7.40 (0.90-67.26) | 4.78 (1.27–20.73) | 0.014 |
Immune system indexes | | | | | |
IgG (7.51–15.6 g/L) | 11.53 (7.3–16.8) | 11.39 (7.30–16.80) | 11.67(8.15–16.60) | 11.56 (6.83–19.30) | 0.912 |
IgM (0.46–3.04 g/L) | 1.32 (23.8%) | 1.06 (0.50–2.31) | 1.68 (0.39–12.03) | 1.03 (0.46–1.96) | 0.200 |
C3(0.79–1.52 g/L) | 0.91 (14.6%) | 0.94 (0.64–1.24) | 0.90 (0.53–1.24) | 0.91 (0.71–1.10) | 0.684 |
C4(0.16–0.38 g/L) | 0.23(6.4%) | 0.23 (0.14–0.41) | 0.24 (0.08–0.41) | 0.19 (0.03–0.29) | 0.055 |
CD3+Tlymphocytes (58.17–84.22%) | 73.07(26.12–93.02) | 73.67(45.44–93.02) | 72.12(49.40-85.88) | 73.10(26.12–92.20) | 0.996 |
CD4+ T lymphocytes (25.34–54.37%) | 46.69(10.70-75.73) | 48.87(24.19–75.73) | 47.62(35.22–64.48) | 44.67(10.70-70.46) | 0.186 |
CD8+ T lymphocytes (14.23–38.95%) | 22.47(5.09–58.88) | 21.40(7.57–38.74) | 21.33(7.27–34.99) | 23.78(5.09–58.88) | 0.282 |
Dynamic Longitudinal Changes Of Immune Systems In Mild Patients
We then analyzed the dynamic changes of white blood cells (WBCs), neutrophils, lymphocytes and different lymphocyte subsets in the peripheral blood of these mild patients. No obvious differences of WBC and neutrophil counts between three groups was found during the course of disease (Fig. 1A and B). The lymphocyte counts in Digestive only groups were higher than Respiratory only group at 4–6 days but without a statistical significance (1.46 vs. 1.10, p = 0.153) and became close during the following period of disease progression (Fig. 1C). As for lymphocyte subsets, CD3 + and CD8 + T cell counts of patients with digestive symptoms was higher at 7–9 days (CD3+, 77.32 vs. 61.48 vs. 84.33, p = 0.123, CD8+, 32.87 vs. 18.37 vs. 40.64, p = 0.375). At 31–33 days, a peak value of CD3 + and CD4 + T lymphocytes appeared in Digestive only and Digestive + Respiratory groups compared to Respiratory only group. (CD3+, 82.75 vs. 64.41, p = 0.016, 81.27 vs. 64.41, p = 0.0002, CD4+, 59.40 vs.39.63, p = 0.01, 47.06 vs. 39.63, p = 0.141, Fig. 1D-F). No significant differences in B cell and NK cell counts were observed during the whole course (Fig. 1G and H). The dynamic profile of immunoglobulin and complement levels were also analyzed among the three groups but no significant differences were found (Fig. 2).
Dynamic Longitudinal Changes Of Inflammatory Cytokines In Mild Patients
We further analyzed the dynamic changes of peripheral IL-2, IL-4, IL-6, IL-10 and TNF-α levels. As is shown in Fig. 3, IL-6 presented a fluctuation during day 19 to 39, especially in patients with only respiratory symptoms. It was shown a peak at 31–33 days (Fig. 3A). However, compared with the moderate trend of IL-2, IL-4, IL-10 and TNF-α in Respiratory only group, a significant increase of IL-2 and IL-4 in Digestive only group at 34–36 days (IL-2, 4.51 vs. 3.08, p = 0.049, IL-4, 4.63 vs. 2.67, p = 0.041, Fig. 3B-E).
Significant linear correlation between inflammatory factors in Digestive only patients
Finally, we used Pearson correlation analysis to compared the correlation of inflammatory indicators among the three group patients. As shown in Fig. 4, the level of LDH and ESR in the group only/accompanied with respiratory symptoms showed stronger linear correlation(Respiratory Only group: R2 = 0.211, R = 0.459, P < 0.001; Digestive + Respiratory group: R2 = 0.212, R = 0.46, P < 0.001)than the patients with Digestive Only(R2 = 0.052, R = 0.227; P = 0.171). However, compared with Respiratory Only group, Digestive only cases showed stronger correlation and linearity in IL-2 and TNF-a (R2 = 0.003, R=-0.057; P = 0.615 vs. R2 = 0.443, R = 0.666; P < 0.001, respectively).