Demographic and clinical characteristics of COVID-19 patients
A total of 78 patients with COVID-19 were enrolled in the study. The flow chart is displayed in Figure S1. They were all classified as non-severe patients on admission and received antiviral therapy after admission, such as Ribavirin, Arbidol, and/or IFN-α[7].
Of the 78 patients, 18 patients exacerbated even with treatment after admission and then rapidly developed to severe illness. The conditions of the remaining 60 patients were stable and gradually improved until discharge. Based on this, the 78 patients were divided into two groups, the exacerbated group (18 patients) and the stable group (60 patients).
Table 1 summarizes the patient demographics and clinical characteristics. The median age of the two groups was statistically different, at 57.5 years old for the exacerbated group and 35 years old for the stable group (p = 0.0001). The Body Mass Index (BMI) was also significantly different between the two groups, with 23.98 (IQR: 21.92–28.54) for the exacerbated patients and 22.77 (IQR: 21.09–24.46) for the stable patients (p = 0.0441). The percentage of patients with a smoking history was 22.2% and 3.3% for the exacerbated and stable groups, respectively (p = 0.0083).
Table 1
Clinical characteristics of 78 Patients with COVID-19
Characteristics Symptoms | All patients (n = 78) | Trend |
Exacerbation (n = 18) | Stable (n = 60) | P value |
Age, Median (range) - yrs | 36(31.5–57) | 57.5(44–63) | 35(31–48) | 0.0001 |
Age groups – No. % | - | - | - | |
20–39 yrs | 42/78(53.8) | 2/18(11.1) | 40/60(66.7) | < 0.0001 |
40–59 yrs | 24/78(30.8) | 9/18(50) | 15/60(25.0) | 0.0438 |
≥ 60 yrs | 12/78(15.4 | 7/18(38.9) | 5/60(8.3) | 0.0016 |
Sex – No.% | - | - | - | - |
Male | 28/78(35.9) | 8/18(44.4) | 20/60(33.3) | 0.3887 |
Body Mass Index, Median (range) | 22.86(21.36–25.39) | 23.98(21.92–28.54) | 22.77(21.09–24.46) | 0.0441 |
< 18.5 | 3/53(5.7) | 0/14 | 3/39(7.7) | 0.2583 |
18.5–23.9 | 30/53(56.6) | 7/14(50.0) | 23/39(59.0) | 0.5611 |
≥ 24 | 20/53(37.7) | 7/14(50.0) | 13/39(33.3) | 0.2698 |
Smoking history – No.% | | | | |
Current smokers | 6/78(7.7) | 4/18(22.2) | 2/60(3.3) | 0.0083 |
Symptoms – No.% | - | - | - | - |
Fever | 69/78(88.5) | 18/18(100) | 51/60(85) | 0.0806 |
Highest temperature (range) | 38.6(38–39) | 38.8(38.3-39.05) | 38.5(37.78-39) | 0.0516 |
Sore throat | 19/78(24.4) | 3/18(16.7) | 16/60(26.7) | 0.3860 |
Nasal congestion | 6/78(7.7) | 2/18(11.1) | 4/60(6.7) | 0.5348 |
Cough | 47/78(60.3) | 12/18(66.7) | 35/60(58.3) | 0.5263 |
Sputum production | 28/78(35.9) | 8/18(44.4) | 20/60(33.3) | 0.3887 |
Dyspnea | 30/78(38.5) | 6/18(33.3) | 24/60(40.0) | 0.6101 |
Chest pain | 6/78(7.7) | 2/18(11.1) | 4/60(6.7) | 0.5348 |
Fatigue | 45/78(57.7) | 10/18(55.6) | 35/60(58.3) | 0.8343 |
Myalgia | 23/78(29.5) | 4/18(22.2) | 19/60(31.7) | 0.4409 |
Anorexia | 24/78(30.8) | 9/18(50.0) | 15/60(25.0) | 0.0910 |
Headache | 23/78(29.5) | 6/18(33.3) | 17/60(28.3) | 0.6833 |
Diarrhea | 18/78(23.1) | 2/18(11.1) | 16/60(26.7) | 0.1601 |
Vomiting | 4/78(5.1) | 1/18(5.6) | 3/60(5.0) | 0.9253 |
Palpitation | 7/78(9.0) | 1/18(5.6) | 6/60(10.0) | 0.5628 |
Night Sweats | 2/78(2.6) | 0/18 | 2/60(3.3) | 0.4326 |
Coexisting disordersa – No. % | 17/78(23.1) | 6/18(33.3) | 11/60(18.3) | 0.1764 |
Diabetes | 7/78(9) | 4/18(22.2) | 3/60(5.0) | 0.2606 |
Hypertension | 6/78(7.7) | 1/18(5.6) | 5/60(8.3) | 0.9370 |
Cancersb | 3/78(3.8) | 3/18(16.7) | 0/60(0) | 0.0013 |
Treatment – No. % | | | | |
Administration of antiviral medications | 78/78(100) | 18/18(100) | 60/60(100) | - |
Administration of intravenous antibiotics | 78/78(100) | 18/18(100) | 60/60(100) | - |
Administration of systemic corticosteroids | 3/78(3.8) | 3/18(16.7) | 0/60 | 0.0013 |
Use of intravenous immunoglobin | 16/78(20.5) | 5/18(27.8) | 11/60(19.3) | 0.3841 |
Oxygen therapy | 30/78(39.2) | 15/18(83.3) | 15/60(25.0) | < 0.0001 |
Onset of symptom to, median (range) | - | - | - | - |
First hospital visit | 4(2–7) | 6(2–8) | 3.5(2–7) | 0.3276 |
Hospital admission | 7(5–10) | 7(2–9) | 7(4.5–10) | 0.8501 |
Discharge | 20(16–24) | 23(20-36.3) | 19(16–23) | 0.0003 |
Exacerbation | - | 7.5(2-11.25) | - | - |
Hospitalization days, median (range) | 13(8–17) | 17(14.75–23.25) | 11.5(7–16) | 0.0006 |
Outcomes– No. % | | | | |
Discharge | 77/78(98.7) | 17/18(100) | 60/60(100) | 0.0661 |
Death | 1/78(1.3) | 1/18(5.6) | 0/60(0) | 0.0661 |
Data are presented as medians (interquartile ranges, IQR) and n/N (%). |
a Hypertension, diabetes, thyroid disease, asthma, arteriosclerosis, cancer. |
bAll cancer cases were stable disease. |
Continuous variables were compared by Student’s t-tests or Mann-Whitney tests, and categorical variables |
were compared by the chi-square tests. |
Time To Event Analysis In Covid-19 Patients
Of the 18 exacerbated patients, 17 cases eventually recovered and were discharged. The one patient that died (on day six after symptom onset) had been admitted with gastric cancer and was confirmed as COVID-19 positive after surgery. The median time from onset to exacerbation was 7.5 days (IQR:2–11.5) for the exacerbated patients (Fig. 1).
The disease course was defined from the day of symptom onset to discharge, and the data revealed the median disease course was longer for the exacerbated group compared with the stable group patients (23 vs. 19 days, p = 0.0015, Table 1 and Fig.S2). The average hospitalization days were 11.5 (IQR:7–16) days for stable patients and 17 (IQR:14.75–23.25) days for the exacerbated patients (p = 0.0006). Nevertheless, the two groups did not differ in the median duration from illness onset to a first hospital visit and hospital admission (Table 1), which indicated that the deterioration of patients after admission was not due to the pre-hospitalization delay.
Dynamic Changes In Febrile Patients
Of the 78 patients, a total of 88.5% of patients exhibited fever (temperature > 37.3 °C) during COVID-19 (Table.S1). After 12 days from the onset, the highest temperatures of all febrile patients subsequently improved, and the trend and magnitude were similar between the exacerbated and stable groups (Fig. 2A). The proportion of febrile patients also significantly declined on day 12 (Fig. 2B), but there were no differences in the proportion of febrile patients between the two groups within 12 days from onset. Interestingly, at 13–17 days from symptom onset, the proportion of febrile patients in the exacerbated group was significantly higher than in the stable group (33.3% vs. 5%, p = 0.001, Table S1, and Fig. 2B), indicating the longer duration of abnormal temperature in the exacerbated group.
Dynamic Profiling Of Laboratory Findings
To elucidate the dynamic changes in laboratory indicators throughout the disease course, blood routine and lymphocyte subsets (Fig. 3), biochemical and coagulation indicators (Fig. 4), plasma cytokines, and inflammatory biomarkers (Fig. 5) were collected during hospitalization at 3-day or 4-day intervals.
At days 0–3 from symptom onset, the exacerbated cases exhibited higher WBC (8.1 vs. 4.8 × 109/L, Fig. 3A) and neutrophil counts (6.5 vs. 3.1 × 109/L, Fig. 3B), and higher levels of lactate dehydrogenase (LDH; 337.2 vs.216.5 U/L, Fig. 4D), D-dimer (4.1 vs. 0.6 mg/L, Fig. 5C), and lower levels of albumin (33 vs. 38.6 g/L, Fig. 4C), compared with stable patients (all p < 0.05).
At days 4–7 from symptom onset, we observed a clear distinction of the neutrophil-lymphocyte-ratio(NLR) between the exacerbated and stable cases (6.4 vs.2.5, p = 0.0015, Fig. 3C).
At days 8–12 from the onset, the WBC(Fig. 3A) and neutrophil counts (Fig. 3B), and the levels of NLR (Fig. 3C), albumin (Fig. 4C) and LDH (Fig. 4D) decreased slightly in the exacerbated group, but still with significant statistical differences between the two groups. Notably, higher levels of alanine aminotransferase (ALT; 68.3 vs.22.1 U/L, p = 0.0007; Fig. 4A), aspartate aminotransferase (AST; 48 vs. 24.2 U/L, p = 0.0019; Fig. 4B), C-reactive protein (CRP; 50.8 vs.18.4 mg/L, p = 0.0003; Fig. 5G), ESR; 38.2 vs.23 mm/h, p = 0.0368; Fig. 5H) and interleukin-6 (IL-6; 22.9 vs. 5.4 pg/mL, p = 0.0002; Fig. 5C) were observed in the exacerbated patients when compared with the stable patients at this point. The lymphocyte counts of exacerbated patients were significantly lower than in stable patients (1.0 vs.1.3 × 109/L, p = 0.0023; Fig. 3E). The level of D-dimer between the two groups showed the same trend as before. (Fig. 4I).
At days 13–17 from symptom onset, an obvious distinction of lymphocyte counts remained between the two groups (1.1 vs. 1.3 × 109/L, p = 0.02; Fig. 3E). More specifically, the lowest proportions of CD3+T cells and CD8+T cells were observed in exacerbated patients at this time point, which significantly differed from the stable patients (54.4% vs. 78.3%, p = 0.0012, Fig. 3F; 17.6% vs. 28.9%, p = 0.0289, Fig. 3H; respectively). However, the differences in CD4+T cells between the two groups did not reach a statistical significance at any time point (Fig. 3G). There was a noticeable rise in the platelet count (PLT) at this time in the exacerbated patients, which was significantly higher than in the stable patients (Fig. 3D). Additionally, the WBC (Fig. 3A), neutrophil counts (Fig. 3B), and the NLR (Fig. 3C), LDH (Fig. 4D), and IL-6 (Fig. 5C) levels were greatly decreased at this duration, all of which showed the same tendency between the two groups.
At days 18–22 from the onset, only AST (Fig. 4B), albumin (Fig. 4C), PLT (Fig. 3D), and ESR (Fig. 5H) exhibited significant differences between the two groups.
At days 23–27 from the onset, except for PLT(Fig. 3D), there were no discernible differences in any of the laboratory indicators between the exacerbated and stable patients (Fig. 3–5).
High-risk Factors Associated With Progression
To explore the early warning indicators of progression, we assessed the risk factors of progression of COVID-19 patients (Fig. S3). The results showed that age ≥ 60 years, smoking history, WBC ≥ 4 × 109/L, neutrophil count ≥ 6.3 × 109/L, lymphocyte ≤ 1.0 × 109/L, NLR ≥ 2.5, LDH > 245 U/L, Album < 35 g/L and D-dimer ≥ 0.5 mg/L were high-risk factors associated with progression of the illness (Fig. S3).