3.1 Baseline characteristics
Baseline characteristics are shown in Table 1. The average age was 53 years, and 53 (51.6%) were male. Among these cases, fever on admission (263, 66.6%) was the most common symptom. Cough, shortness of breath, fatigue, and sputum production were present in 257 patients (65.1%), 118 patients (29.9%), 107 patients (27.2%), and 102 patients (25.9%), respectively. Headache (36, 9.1%), nausea or vomiting (36, 9.1%), myalgia or arthralgia (34, 8.6%), sore throat (22, 5.6%), and chill (7, 6.7%) were rare in our study. The most frequent comorbidities were hypertension (102, 25.8%) and diabetes (47, 11.3%). The proportion of coronary heart disease, hepatitis B infection, and chronic obstructive pulmonary disease was 6.4% (25/392), 2.3% (9/392), and 1.5% (6/392), respectively.
Table 1
Baseline characteristics of different degrees of CD4+ T cell in all patients.
Variables | All(N = 395) | CD4 + T: lower than the normal low limit (N = 195) | CD4 + T: higher than the normal low limit (N = 200) | P | Missing date |
Baseline |
Male/female(n) | 204/191 | 115/80 | 89/111 | 0.004 | |
Age(years) | 53.1 ± 15.7 | 55.0 ± 16.5 | 51.3 ± 14.8 | 0.033 | |
Temperature (℃) | 36.8 (36.5–37.3) | 36.9 (36.6–37.6) | 36.8 (36.5–37.1) | 0.036 | 31 (7.8%) |
Heart rate (min) | 85.0 (77.0–94.0) | 85.0 (78.0–96.0) | 84.5 (76.0–92.0) | 0.103 | 4 (1.0%) |
SBP (mmHg) | 126.0 (116.0-136.0) | 126.0 (115.0-136.5) | 126.0 (117.0-136.0) | 0.577 | 6 (1.5%) |
DBP (mmHg) | 78.0 (70.0–85.0) | 76.0 (70.0–85.0) | 78.0 (71.0–85.0) | 0.741 | 6 (1.5%) |
Symptoms and signs—No, % |
Fever on admission | 263 (66.6%) | 141 (72.3%) | 122 (61.0%) | 0.017 | |
Nasal congestion | 2 (0.5%) | 2 (1.0%) | 0 (0%) | 0.243 | |
Headache | 36 (9.1%) | 20 (10.3%) | 16 (8.0%) | 0.436 | |
Cough | 257 (65.1%) | 138 (70.8%) | 119 (59.5%) | 0.019 | |
Sore throat | 22 (5.6%) | 10 (5.1%) | 12 (6.0%) | 0.706 | |
Sputum production | 102 (25.9%) | 56 (28.9%) | 46 (23.0%) | 0.184 | 1 (0.3%) |
Fatigue | 107 (27.2%) | 59 (30.4%) | 48 (24.0%) | 0.153 | 1 (0.3%) |
Shortness of breath | 118 (29.9%) | 75 (38.5%) | 43 (21.5%) | < 0.001 | |
Nausea or vomiting | 36 (9.1%) | 23 (11.8%) | 13 (6.5%) | 0.068 | |
Myalgia or arthralgia | 34 (8.6%) | 20 (10.3%) | 14 (7.0%) | 0.249 | |
Chill | 12 (3.0%) | 8 (4.1%) | 4 (2.0%) | 0.223 | |
Throat congestion | 3 (0.8%) | 0 (0%) | 3 (1.5%) | 0.248 | |
Coexisting disorders—No, % |
Diabetes | 47 (11.9%) | 22 (11.3%) | 25 (12.5%) | 0.709 | |
Hypertension | 102 (25.8%) | 48 (24.6%) | 54 (27.0%) | 0.588 | |
Coronary heart disease | 25 (6.4%) | 15 (7.7%) | 10 (5.1%) | 0.277 | 3 (0.8%) |
Hepatitis B infection | 9 (2.3%) | 6 (3.1%) | 3 (1.5%) | 0.334 | 3 (0.8%) |
COPD | 6 (1.5%) | 5 (2.6%) | 1 (0.5%) | 0.119 | 3 (0.8%) |
Laboratory findings |
WBC (× 109/L) | 5.3 (4.2-7.0) | 5.0 (3.8-7.0) | 5.6 (4.5-7.0) | 0.008 | 2 (0.5%) |
Hb (g/L) | 131.0 (118.5–143.0) | 132.0 (117.0-143.0) | 129.0 (120.0-142.3) | 0.809 | 2 (0.5%) |
PLT (× 109/L) | 189.0 (145.5–252.0) | 160.0 (129.0-214.0) | 220.5 (170.0-364.0) | < 0.001 | 2 (0.5%) |
LYM (× 109/L) | 1.1 (0.8–1.5) | 0.8 (0.6-1.0) | 1.5 (1.2–1.8) | < 0.001 | 6 (1.5%) |
LYM < 1.1 × 109/L | 199 (51.2%) | 163 (84.5%) | 27 (13.8%) | < 0.001 | 6 (1.5%) |
ALT (U/L) | 23.0 (15.0–39.0) | 24.1 (15.4–38.8) | 22.0 (15.0–39.0) | 0.388 | 4 (1.0%) |
Cr (umol/L) | 64.0 (53.0–78.0) | 66.5 (56.0–79.0) | 61.0 (50.0–77.0) | 0.005 | 5 (1.3%) |
D-dimer (mg/L) | 0.43 (0.24–0.99) | 0.50 (0.28–1.12) | 0.38 (0.22–0.84) | 0.023 | 14 (3.5%) |
K (mmol/L) | 4.0 (3.7–4.3) | 4.0 (3.6–4.3) | 4.1 (3.7–4.3) | 0.243 | 6 (1.5%) |
Hs-CRP (mg/L) | 5.0 (2.2–22.9) | 8.2 (5.0-48.5) | 4.9 (1.1-7.0) | < 0.001 | 45 (11.4%) |
PCT (ng/ml) | 0.05 (0.03–0.08) | 0.06 (0.04–0.11) | 0.04 (0.02–0.06) | < 0.001 | 21 (5.3%) |
CD4+T cells count | 410.0 (265.0-567.0) | 262.0 (188.0-325.0) | 564.0 (478.5–716.0) | < 0.001 | |
CD8+T cells count | 246.0 (154.0-348.0) | 168.0 (107.0-250.0) | 322.0 (244.3-443.5) | < 0.001 | |
CD4/CD8 ratio | 1.6 (1.2–2.2) | 1.4 (1.1–1.9) | 1.8 (1.4–2.3) | < 0.001 | |
Abnormalities on chest CT—No,% |
Ground-glass opacity | 170 (48.7%) | 78 (46.7%) | 92 (50.5%) | 0.473 | 46 (11.6%) |
Local patchy shadowing | 135 (38.7%) | 71 (42.5%) | 64 (35.2%) | 0.159 | 46 (11.6%) |
Treatment |
Oxygen inhalation | 328 (84.3%) | 174 (90.2%) | 154 (78.6%) | 0.002 | 6 (1.5%) |
Glucocorticoids | 94 (23.8%) | 64 (32.8%) | 30 (15.0%) | < 0.001 | |
Antiviral treatment | 388 (98.2%) | 191 (97.9%) | 197 (98.5%) | 0.721 | |
Intravenous immunoglobulin | 71 (18.2%) | 37 (19.2%) | 34 (17.3%) | 0.625 | 5 (1.3%) |
Antibiotic treatment | 179 (45.3%) | 112 (57.4%) | 67 (33.5%) | < 0.001 | |
Antifungal treatment | 4 (1.0%) | 2 (1.0%) | 2 (1.0%) | 1.000 | |
| Clinical outcome |
Death (No,%) | 27 (6.8%) | 25 (12.8%) | 2 (1.0%) | < 0.001 | |
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; COPD, Chronic obstructive pulmonary disease; WBC, white blood cell count; Hb, Hemoglobin; PLT, platelet count; LYM, lymphocyte; ALT, alanine aminotransferase; Cr, creatinine; Hs-CRP, hypersensitive C-reactive protein; PCT, procalcitonin. |
According to the low value of laboratory reference values of CD4+T count, the 395 patients were divided into two groups: lower CD4+T group and higher CD4+T group. Patients in the lower group were older (55.0 ± 16.5 vs 51.3 ± 14.8, P = 0.033), contained more males (115/195 [59.0%] vs 89/111 [44.5%], P = 0.004), and more likely to have shortness of breath (75/195 [38.5%] vs 43/200 [21.5%], P < 0.001) and fever on admission (141/195 [72.3%] vs 122/200 [61.0%], P = 0.017). And, there were no significant difference in the proportion of comorbidities, including hypertension, diabetes, coronary heart disease, hepatitis of B infection and chronic obstructive pulmonary disease, between the two groups. Analysis of moderate and severe patients alone, also showed the same trend (Supplementary table1, Supplementary table 2).
3.2 Laboratory And Radiographic Findings
Of these 395 patients, median (IQR) values of Hs-CRP (5.0 [2.2–22.9] mg/L) and PCT (0.05 [0.03–0.08] ng/ml) were elevated, while the median (IQR) values of lymphocyte count, CD4+T count, CD8+T count were within standard ranges (Table 1). In moderate patients, only the median (IQR) value of Hs-CRP was elevated. (Supplementary table1.). In severe patients, median (IQR) values of Hs-CRP, PCT and D-dimer were elevated, while the median (IQR) values of lymphocyte count, CD4+T count, CD8+T count were decreased. (Supplementary table2). According to lung CT (computed tomography, CT) findings, in all patients, the proportion of ground-glass opacity and local patchy shadowing was 48.7% (170/349) and 38.7% (135/349), respectively.
In terms of laboratory findings, compared with patients in higher CD4+T group, patients in the lower CD4+T group showed lower median lymphocyte count (0.8 (0.6-1.0) vs 1.5 (1.2–1.8), P < 0.001, cells × 109/L), CD8+T count (168.0 [107.0-250.0] vs 322.0 [244.3-443.5], P < 0.001, cells/ul), CD4/CD8 (1.4 [1.1–1.9] vs 1.8 [1.4–2.3], P < 0.001), but a higher median hypersensitive C-reactive protein (Hs-CRP) (8.2 [5.0-48.5] vs 4.9 [1.1-7.0], P < 0.001, mg/L) and procalcitonin (PCT) (0.06 [0.04–0.11 vs 0.04 [0.02–0.06], P < 0.001, ng/ml) (Table 1). Analysis of moderate and severe patients alone showed that lymphocyte count and CD8+T were more commonly reduced in severe patients. There was no significant change in the proportion of CD4+T lower than the lower limit of normal in moderate and severe patients, but the proportion of CD4+T lower than the lower limit of normal in moderate and severe patients accounted for 48.2% (95/197) and 50.5% (100/198), respectively. (Fig. 2A). The analysis also found that it is the CD8+T count that reflects the severity of the patient’s condition, not the CD4+T count. (Fig. 2B).
In terms of computed tomography findings, in moderate patients, compared with patients in the higher group, patients in the lower group more often represented as local patchy shadowing (45 [47.4%] vs 33 [32.4%], P = 0.031). Ground-glass opacity and local patchy shadowing did not differ between the two groups in the entire patient population. (Table 1).
3.3 Treatment And Clinical Outcome
In all cases, the proportion of use of oxygen inhalation, and mechanical ventilation were 84.3% (328/389), and 7.7% (30/388), respectively. The most common therapy is treatment with antiviral treatment (388/395, 98.2%), followed by antibiotic treatment (179/395, 45.3%), glucocorticoids treatment (94/395, 23.8%), intravenous immunoglobulin treatment (71/395, 18.2%), and only four patients (4/395, 1.0%) were treated with antifungal drugs. During follow-up, 27 patients died (27/395, 6.8%), and the rest were discharged (368/395, 93.2%).
Compared with patients in the higher CD4+T group, patients in the lower group needed more oxygen inhalation (174/193 ,90.2% vs 154/196, 78.6%, P = 0.002), mechanical ventilation (26/193, 13.5% vs 4/195, 2.1%, P < 0.001), antibiotic treatment (112/195, 57.4% vs 67/200, 33.5%, P < 0.001) and glucocorticoids treatment (64/195, 32.8% vs 30/200, 15.0%, P < 0.001). Other treatments were similar between the two groups, such as antiviral treatment, intravenous immunoglobulin treatment, and antifungal treatment. The case in-hospital death rate was significant higher in patients with lower CD4+T level than in those with higher CD4+T level (25/195, 12.8% vs 2/200, 1.0%, P < 0.001). The detailed treatment of moderate and severe patients were shown in supplementary table1 and supplementary table2.
3.4 Survival Curves Of In-hospital Death
Kaplan-Meier survival curves of the COVID-19 patients grouped by CD4+T count are shown in Fig. 3. The low CD4+T group had a higher in-hospital death rate than the high CD4+T group during the follow-up period (log rank < 0.001). The same trend was also found in severe patients (log rank < 0.001). Kaplan-Meier survival analysis was not performed on moderate patients because no patients died during follow-up.
3.5 Results of Cox proportional hazards analyses of in-hospital death
Cox proportional hazard regression analysis was performed to test the associations between the lower CD4+T group and in-hospital death for COVID-19 patients. Results of univariate analyses indicated that patients with lower CD4 + T count exhibited a 13.659-fold increase in in-hospital death compared to patients with higher CD4+T count (hazard ratio (HR) :13.659; 95% confidence intervals (CI):3.235–57.671). Meanwhile, age, history of hypertension, history of COPD, white blood cell count, lymphocyte count, CD8+T lower group, required mechanical ventilation or glucocorticoids or intravenous immunoglobulin treatment or antibiotic treatment or antifungal treatment were correlated with the risk of in-hospital death in patients with severe COVID-19 (Supplementary Table 3).
Multivariate survival analysis was performed with Cox’s proportional hazard regression model to identify the independent factors correlated with prognosis. After adjusting for age, sex and temperature (Mode 1), the HR of the lower CD4+T group for in-hospital death was 14.182 (95%CI: 1.884-106.786, P = 0.010). After adjusting for history of hypertension, history of diabetes and shortness of breath (Mode 2), the HR of the lower CD4+T group for in-hospital death was 13.631 (95%CI: 3.190-58.243, P < 0.001). After adjusting for white blood cells, platelet and creatinine (Mode 3), the HR of the lower CD4+T group for in-hospital death was 8.170 (95%CI: 1.877–35.566, P = 0.005). After adjusting for hypersensitive C-reactive protein, procalcitonin and D-dimer (Mode4), the HR of the lower CD4 + T group for in-hospital death was 10.644 (95%CI: 2.439–46.458, P = 0.002). After adjusting for CD8+T lower group and lymphocyte count lower group (Mode 5), the HR of the lower CD4+T group for in-hospital death was 13.650 (95%CI: 1.976–94.279, P = 0.008). After adjusting for age, history of hypertension, shortness of breath, white blood cell count platelet count, D-dimer and CD4/CD8 (Mode 6), the HR of the low CD4+T cells count group for in-hospital death was 7.656 (95%CI: 1.610-36.396, P = 0.010). Multivariate analysis demonstrated that presenting with lower CD4+T count was an independent risk factor for in-hospital death. Variables like age, white blood cell count and shortness of breath also showed significance for independently predicting in-hospital death in this study (Table 2, Fig. 4). Similarly, Cox proportional hazards analyses was also performed on severe patients, and the results also suggested that lower CD4+T count was an independent risk factor for in-hospital death (Supplementary table4, Supplementary table5, Supplementary Fig. 1).
Table 2
Results of multivariate Cox proportional-hazards regression analyzing the effect of baseline variables on in-hospital death in all patients.
Mode | HR (95%CI) | P |
Not Adjusted CD4+T, low vs. high | 13.659 (3.235–57.671) | < 0.001 |
Mode 1 |
CD4+T, low vs. high | 14.182 (1.884-106.786) | 0.010 |
Sex, male vs. female | 1.383 (0.561–3.406) | 0.481 |
Age, per 1 year | 1.093 (1.052–1.135) | < 0.001 |
Temperature, per 1℃ | 0.777 (0.445–1.354) | 0.372 |
Mode 2 |
CD4+T, low vs. high | 13.631 (3.190-58.243) | < 0.001 |
Hypertension, yes vs. no | 5.823 (2.595–13.070) | < 0.001 |
Diabetes, yes vs. no | 0.824 (0.322–2.113) | 0.688 |
Shortness of breath, yes vs. no | 7.848 (2.942–20.934) | < 0.001 |
Mode 3 | | |
CD4+T, low vs. high | 8.170 (1.877–35.566) | 0.005 |
WBC, per 1 × 109/L | 1.294 (1.193–1.404) | < 0.001 |
PLT, per 1 × 109/L | 0.992 (0.987–0.997) | 0.003 |
Cr, per 1 umol/L | 1.002 (0.995–1.009) | 0.576 |
Mode 4 |
CD4+T, low vs. high | 10.644 (2.439–46.458) | 0.002 |
Hs-CRP, per 1 mg/L | 0.989 (0.974–1.005) | 0.193 |
PCT, per 1 ng/ml | 1.017 (0.925–1.118) | 0.724 |
D-dimer, per 1 mg/L | 1.028 (1.018–1.038) | < 0.001 |
Mode 5 | | |
CD4+T, low vs. high | 13.650 (1.976–94.279) | 0.008 |
CD8+T, low vs. high | 3.159 (0.853–11.707) | 0.085 |
CD4/CD8 ratio, per 1 unit | 1.422 (1.105–1.830) | 0.006 |
LYM count, low vs. high | 0.996 (0.306–3.243) | 0.994 |
Mode 6 | | |
CD4+T, low vs. high | 7.656 (1.610-36.396) | 0.010 |
Age, per 1 year | 1.074 (1.034–1.115) | < 0.001 |
Hypertension, yes vs. no | 2.031 (0.766–5.386) | 0.154 |
Shortness of breath, yes vs. no | 3.435 (1.167–10.114) | 0.025 |
WBC, per 1 × 109/L | 1.224 (1.097–1.366) | < 0.001 |
PLT, per 1 × 109/L | 0.996 (0.991–1.001) | 0.149 |
D-dimer, per 1 mg/L | 0.997 (0.992–1.002) | 0.207 |
CD4/CD8 ratio, per 1 unit | 1.106 (0.793–1.542) | 0.552 |
Abbreviations: WBC, white blood cell count; PLT, platelet count; Cr, creatinine; Hs-CRP, hypersensitive C-reactive protein; PCT, procalcitonin; LYM, lymphocyte. |