3  Results
The average age of the patients was 62.5 ± 12.6 years; 52% were male and 48% were female. 62% had morbidities such as diabetes, hypertension, cardiovascular disorders, hyperlipidemia, or kidney diseases. The onset symptoms of the patients were: fever (86%), cough (95%), fatigue (71%), shortness of breath (43%) and diarrhea (10%) (Table 1a ). The severities of the admitted patients were 62% of mild, 19% of severe, and 19% of critical, a classification according to Chinese Center for Disease Control (CDC) guidelines [1]. Patients received standard treatments based on the guidelines of Chinese CDC, including antiviral remedies (arbidol, lopinavir and ribonavir, interferon α inhalation), anti-inflammatory treatments (corticosteroid), and immune-modulator (thymalfasin, immunoglobulin) (Table 1a). Severe and critical cases were given high-flow oxygen, non-invasive or invasive ventilation, depending on their morbidities. Seventeen patients recovered and were discharged, while four patients did not survive.
Table 1a Clinical characteristics of COVID-19 patients.
No. (%)
Total (n = 21) Survival (n = 17) Non-survival (n = 4)
Age, mean (s.d.) 62.5 (12.6) 61.5 (9.5) 79.7 (14.3)⁎
Male 11 (52.3) 9 (53.9) 2 (50.0)
Comorbidities 13 (61.9) 9 (53.9) 4 (100)
 Type 2 diabetes 3 (14.3) 3 (17.6) 0 (0)
 Hypertension 10 (47.6) 8 (35.3) 2 (50.0)
 Cardiovascular disease 5 (23.8) 3 (17.6) 2 (50.0)
 Kidney diseases 1 (4.8) 1 (5.8) 0 (0)
Onset symptoms
 Fever 18 (85.7) 14 (82.3) 4 (100)
 Cough 20 (95.2) 16 (94.1) 4 (100)
 Fatigue 15 (71.4) 11 (64.7) 4 (100)
 Shortness of breath 9 (42.8) 5 (29.4) 4 (100)
 Diarrhea 2 (9.5) 2 (11.7) 0 (0)
Treatment
 Arbidol 15 (71.4) 12 (70.6) 3 (75.0)
 Lopinavir/ritonavir 7 (33.3) 4 (23.5) 3 (75.0)
 Interferon inhalation 7 (33.3) 4 (23.5) 3 (75.0)
 Corticosteroid 3 (14.3) 3 (17.6) 0 (0)
 Thymalfasin 6 (28.6) 6 (35.3) 0 (0)
 Oxygen 8 (38.1) 4 (23.5) 4 (100)
 Mechanical ventilation 4 (19.0) 0 (0) 4 (100)
⁎ p < 0.05, as compared to the patient group that survived.
In the stage of disease progression, there were significantly higher levels of C-reactive protein (CRP) (78 (28–134) versus 15 (7–36), in mg/L, p = 0.042) and interleukin-6 (IL-6) (195 (127–280) versus 12 (4–18), in pg/ml, p < 0.001), but lower levels of CD8+ subpopulation T cells (33 (23–135) versus 273 (122–377), cells/μl, p = 0.016) in non-surviving patients as compared with the patients survived (Table 1b ). Furthermore, in surviving patients, increases in levels of high-sensitivity CRP (hsCRP) were significantly associated with the disease severity (pre-infection: 1.2 (0.7–5.9); on admission: 11 (5.9–26), p < 0.02; progression: 9.8 (5.3–45); discharge: 2.2 (1.2–7.0), in mg/L) (Supplementary Table S1). The number of lymphocytes (LY) decreased significantly at the time of admission as compared with before infection; it did not show a full recovery at the time of discharge (pre-infection: 1.6 (1.4–2.2); on admission: 1.0 (0.8–1.5), p < 0.02; progression: 0.9 (0.5–1.4); discharge: 1.2 (0.8–1.9), in x109/L) (Supplementary Table S1). In patients did not survive, there was a continuous increase in hsCRP level or lymphopenia until death (Supplementary Table S1).
Table 1b Laboratory tests for COVID-19 patients during the stage of disease progression.
Laboratory tests Reference value No. (%)
Total (n = 21) Survival (n = 17) Non-survival(n = 4) p
IL-6 (pg/ml) 0.1–2.9 15 (8–79, 19) 12 (4–18, 15) 195 (127–280, 4) <0.001
CRP (mg/L) <4 20 (7–45, 21) 15 (7–36, 17) 78 (28–134, 4) 0.042
CD3+ (cells/μl) 805 to 4459 562 (203–939, 19) 680 (303–945, 15) 232 (129–340, 4) 0.062
CD4+ (cells/μl) 345 to 2350 297 (135–557, 19) 416 (172–557, 15) 168 (108–250, 4) 0.121
CD8+ (cells/μl) 345 to 2350 166 (50–336, 19) 273 (122–377, 15) 33 (23–135, 4) 0.016
CD4+/CD8+ ratio 0.96–2.05 1.7 (1.2–3.1, 19) 1.6 (1.3–2.4, 15) 5.0 (2.0–6.2, 4) 0.079
CD19+ (cells/μl) 240 to 1317 104 (49–174, 19) 104 (49–236, 15) 84 (34–134, 4) 0.650
CD16+/CD56+ (cells/μl) 210 to 1514 164 (49–252, 19) 168 (106–252, 15) 33 (10–223, 4) 0.124
P value is compared the group that survived with the group that did not survive by a Mann-Whitney U test. Data is presented as median (IQR, n).
We next analyzed the serum lipid levels (in mmol/L) of the patients before they were infected by SARS-CoV-2 and during their entire courses of the disease. The average timeline of disease course was shown in Fig. 1 . The low-density lipoprotein (LDL) levels in all patients showed significant decreases at the time on admission as compared to the levels prior to infection (pre-infection: 3.5 (3.0–4.4); admission: 2.8 (2.3–3.1), p < 0.01); the LDL levels remained relatively low during the treatment (2.5 (2.3–3.0)) and returned to the levels prior to infection in patients that survived by the time of discharge (3.6 (2.7–4.1)) (Fig. 1, Supplementary Table S1). The high-density lipoprotein (HDL) levels also showed significant decreases at the time on admission as compared to levels prior to infection (pre-infection: 1.4 (1.0–1.8); admission: 1.1 (0.8–1.4), p = 0.03). Unlike LDL, HDL levels remained relatively low during the treatment stage and after recovery (progression: 1.2 (1.0–1.4); discharge: 1.0 (1.0–1.4)) (Fig. 1, Supplementary Table S1). Total cholesterol (TC) levels showed a pattern similar to LDL during the disease course (pre-infection: 5.2 (4.6–6.5); admission: 3.5 (3.3–4.1), p < 0.01; progression: 4.5 (4.0–4.8); discharge: 5.2 (4.4–6.1); Fig. 1, Supplementary Table S1).
Fig. 1 Ratio changes for LDL (A), HDL (B) and TC (C) in COVID-19 patients during the course of disease. For each data point, the ratio is normalized to the levels of LDL, HDL and TC prior to infection for the same patient. The days listed are the duration (median (IQR)) for each period during the disease course. The date on admission is set as “day 0”. Data is presented as “mean ± 95% confidence interval”. # indicates p < 0.05 as compared to the levels of pre-infection stage, and * indicates p < 0.05 as compared to the levels on admission, by a Mann-Whitney U test. The sample actual values at each stage are listed in Supplementary Table S1. The ratios of hsCRP at each time point are normalized to the levels prior to infection in the same patients. Pearson correlation coefficient analysis show the ratios of hsCRP significantly inversely correlated with the ratios of LDL (D), HDL (E) and TC (F) during the disease course; n = 33 data pairs for each analysis.
The LDL, HDL and TC levels in the patients that did not survive (n = 4) decreased continuously until death (Fig. 1, Supplementary Table S1). Particularly, LDL levels showed an irreversible decrease by the most percentage (~60%) until death (1.1 (0.9–1.2), p = 0.02 versus the levels on admission) (Fig. 1, Supplementary Table S1). Supplementary table S2 showed a timeline of disease course for a non-surviving patient, from hospital admission to death, with continuous and irreversible decreases in LDL, HDL, and TC levels. LDL, HDL and TC levels in normal subjects and non-COVID-19 patients (COPD) control groups did not show significant difference as compared with the levels in COVID-19 patients before their viral infections (Supplementary Table S3). Logistic regression analysis showed increasing odds of lowered LDL levels associated with disease progression (Chi-Square = 7.49; p = 0.006; odds ratio: 4.48, 95% IC: 1.55–12.92, p = 0.006) and in-hospital mortality (Chi-Square = 10.87; p = 0.001; odds ratio: 21.72, 95% IC: 1.40–337.54, p = 0.028). The ratio changes of LDL, HDL and TC inversely correlated with the ratio changes of hsCRP during the disease course (Fig. 1).