A total of 1147 patients with COVID-19 were screened for the study. 40 patients were excluded for participating in any double-blind clinical trial (n = 15), death or discharge from the hospital on the first day of admission (n = 21), underwent long-term corticosteroid therapy (n = 3), or no valid medical history provided (n = 1). From 1107 patients remained, 382 patients were identified as ARDS (eFigure 1, Additional file 1). Among these patients, 84 have been described previously by Wu et al[5]. In addition, 91 patients with ARDS participated in the open-label trial of lopinavir - ritonavir.[18]
Baseline characteristics of the ARDS patients at hospital admission by receiving systemic corticosteroid treatment are shown in Table 1. In the entire cohort, the mean age was 60.7 ± 14.1 years, and 234 (61.3%) patients were male. 147 (38.5%) were treated with NIMV, 94 (24.6%) with IMV, and 11 (2.9%) with ECMO.
Table 1
Characteristics of patients with acute respiratory distress syndrome associated with coronavirus disease 2019
Characteristics
|
All
|
Corticosteroids
|
No corticosteroids
|
P-value
|
N
|
382 (100.0)
|
226 (59.2)
|
156 (40.8)
|
…
|
Age, year
|
60.7 ± 14.1
|
59.1 ± 14.0
|
63.0 ± 14.0
|
0.0077
|
Male sex
|
234 (61.3)
|
150 (66.4)
|
84 (53.8)
|
0.0135
|
Smoking history
|
35 (9.2)
|
24 (10.6)
|
11 (7.1)
|
0.2347
|
Days from onset at admission
|
11.0 (8.0–15.0)
|
10.0 (7.0–14.0)
|
12.0 (9.0–16.5)
|
0.0029
|
Medical history
|
|
|
|
|
Chronic pulmonary disease
|
20 (5.2)
|
12 (5.3)
|
8 (5.1)
|
0.9376
|
Hypertension
|
136 (35.6)
|
79 (35.0)
|
57 (36.5)
|
0.7508
|
Diabetes
|
67 (17.5)
|
36 (15.9)
|
31 (19.9)
|
0.3193
|
Chronic liver disease
|
15 (3.9)
|
11 (4.9)
|
4 (2.6)
|
0.2546
|
Chronic renal disease
|
6 (1.6)
|
2 (0.9)
|
4 (2.6)
|
0.1945
|
Cardiovascular disease
|
28 (7.3)
|
12 (5.3)
|
16 (10.3)
|
0.0682
|
Malignant tumor
|
12 (3.1)
|
7 (3.1)
|
5 (3.2)
|
0.9527
|
Hematological malignant tumor
|
2 (0.6)
|
1 (0.5)
|
1 (0.7)
|
0.8339
|
Immunosuppressive conditions
|
14 (3.7)
|
9 (4.0)
|
5 (3.2)
|
0.6911
|
SOFA score at admission
|
2.0 (2.0–3.0)
|
2.0 (2.0–3.0)
|
2.0 (2.0–3.0)
|
0.1383
|
Corticosteroid therapy before admission
|
40 (10.5)
|
28 (12.4)
|
12 (7.7)
|
0.1405
|
Temperature on admission, ℃
|
36.8 ± 0.7
|
36.9 ± 0.8
|
36.7 ± 0.5
|
0.0069
|
Heart rate, min− 1
|
90.9 ± 15.3
|
92.9 ± 16.3
|
88.0 ± 13.1
|
0.0018
|
Respiratory rate, min− 1
|
24.0 ± 6.3
|
24.5 ± 7.1
|
23.3 ± 5.0
|
0.0609
|
Laboratory findings at admission
|
Blood leukocyte count, × 109/L
|
8.1 (5.2–11.3)
|
8.4 (5.1–11.7)
|
7.5 (5.4–10.0)
|
0.2593
|
Lymphocyte count, × 109/L
|
0.7 (0.5–1.0)
|
0.6 (0.5–0.8)
|
0.8 (0.6–1.1)
|
< .0001
|
Neutrophil count, × 109/L
|
6.9 (4.0–10.2)
|
7.4 (4.2–10.7)
|
5.7 (4.0–8.7)
|
0.0508
|
SpO2/FiO2
|
229.3 (175.5–352.4)
|
218.6 (170.0–366.7)
|
241.5 (184.0–332.8)
|
0.2133
|
CRP, mg/L
|
89.0 (38.0–159.9)
|
96.7 (45.9–160.0)
|
68.7 (28.6–138.5)
|
0.0026
|
D-dimer, mg/L
|
1.5 (0.7–8.0)
|
1.5 (0.6–9.5)
|
1.5 (0.7–7.1)
|
0.9913
|
Lactate dehydrogenase, U/L
|
409.0 (304.0–545.0)
|
429.0 (320.0–569.0)
|
386.5 (277.0–509.5)
|
0.0124
|
Bilateral involvement
|
358 (93.7)
|
214 (94.7)
|
144 (92.3)
|
0.3455
|
Antivirus drugs
|
|
|
|
|
Lopinavir
|
91 (24.0)
|
72 (31.9)
|
19 (12.4)
|
< .0001
|
Ganciclovir
|
32 (8.4)
|
19 (8.4)
|
13 (8.5)
|
0.9754
|
Interferon
|
103 (27.2)
|
65 (28.8)
|
38 (24.8)
|
0.3994
|
Oseltamivir
|
64 (16.9)
|
52 (23.0)
|
12 (7.8)
|
0.0001
|
Respiratory support
|
|
|
|
|
High-frequency oscillation ventilation
|
146 (38.8)
|
100 (45.2)
|
46 (29.7)
|
0.0023
|
NIMV
|
147 (38.5)
|
104 (46.0)
|
43 (27.6)
|
0.0003
|
IMV
|
94 (24.6)
|
59 (26.1)
|
35 (22.4)
|
0.4130
|
ECMO
|
11 (2.9)
|
8 (3.5)
|
3 (1.9)
|
0.3530
|
Hyperglycemia
|
32 (8.4)
|
20 (8.8)
|
12 (7.7)
|
0.6882
|
In-hospital 60-day mortality
|
203 (53.1)
|
135 (59.7)
|
68 (43.6)
|
0.0019
|
In-hospital days for all patients
|
12.0 (7.0–18.0)
|
14.0 (9.0–21.0)
|
10.0 (6.0–13.0)
|
< .0001
|
In-hospital days for survivors
|
13.0 (10.0–19.0)
|
16.0 (11.0–24.0)
|
11.0 (8.5–15.0)
|
< .0001
|
Median survival time, days
|
18.0 (15.0–20.0)
|
19.0 (15.0–21.0)
|
15.0(12.0–23.0)
|
0.0239
|
Duration of viral shedding from symptom onset, days
|
18.0 (14.0–23.0)
|
19.0 (14.0–23.0)
|
18.0 (14.0–24.0)
|
0.7217
|
Note: Data are n (%), mean (SD), or median (IQR). For continuous variables, t-test or Mann-Whitney U test was used to calculate the P value unless otherwise noted. For categorical variables, chi-square test was used to calculate the P value unless otherwise noted.
Abbreviations: ARDS, acute respiratory distress syndrome; SOFA, sequential Organ Failure Assessment; CRP, c-reactive protein; MV, mechanical ventilation; NIMV, non-invasive mechanical ventilation; IMV, invasive mechanical ventilation; ECMO, extracorporeal membrane oxygenation; SpO2, pulse oxygen saturation; FIO2, fraction of inspired oxygen. ARDS was defined according to World Health Organization interim guidance.
A total of 226 (59.2%) ARDS patients had a prescription of systemic corticosteroids. Corticosteroids were more likely prescribed to the younger (p = 0.0077) and males (p = 0.0135). Corticosteroids group had lower lymphocyte count and higher levels of CRP and lactate dehydrogenase at admission than non-corticosteroids group, indicating a propensity in prescribing corticosteroids to patients with more severe immune dysfunction and inflammatory response (Table 1). The 60-day hospital death in patients who ever used corticosteroids were higher than the patients who did not use corticosteroids (135 [59.7%] vs. 68 [43.6%], p = 0.0019). However, the median survival duration were significantly longer in corticosteroid group ( 19.0 [IQR 15.0–21.0] vs. 15.0 [IQR 12.0–23.0], p = 0.0239).
Among patients prescribed corticosteroids, methylprednisolone was the most frequently administered corticosteroids (213, 94.2%) (Table 2). Corticosteroid treatment lasted for 7.0 (IQR 4.0–12.0) days in total. The maximum dose in methylprednisolone equivalent was 80.0 (IQR 40.0–80.0) mg per day and duration of maximum dose was 3.0 (IQR 2.0–5.0) days. Corticosteroids were initiated 13.0 (IQR 10.0–16.0) days after symptom onset. 82.3% (186/226) of the patients received corticosteroids started the therapy within 2 days after ARDS diagnosis. Survivors had shorter duration from symptom onset to corticosteroids (11.0 [9.0–14.0] vs. 14.00 [IQR 11.0–18.0], p = 0.0031) and had earlier initiation of corticosteroids with regard to the date of ARDS onset (0.0 [IQR − 1.0–1.0] vs. 1.00 [IQR 0.0–2.0], p = 0.0102) when compared with non-survivors. Clinical characteristics of survivors and non-survivors received corticosteroid were summarized in eTable 1 (Additional file 1).
Table 2
Administration of corticosteroids, stratified by outcome
|
All
(n = 226)
|
Non-survivors
(n = 135)
|
Survivors
(n = 91)
|
P-value
|
Corticosteroid prescribed
|
|
|
|
|
Methylprednisolone
|
213 (94.2)
|
132 (62.0)
|
83(38.0)
|
0.0004
|
Prednisolone
|
41 (18.1)
|
11 (73.2)
|
30 (26.8)
|
0.0007
|
Dexamethasone
|
5 (2.2)
|
4 (80.0)
|
1 (20.0)
|
0.4470
|
Maximum dose (methylprednisolone equivalent, mg)
|
80.0 (40.0–80.0)
|
80.0 (40.0–80.0)
|
80.0 (40.0–80.0)
|
0.0821
|
Days of corticosteroid treatment
|
7.0 (4.0–12.0)
|
6.0 (3.0–11.0)
|
9.0 (5.0–12.0)
|
0.0069
|
Days of maximum dose
|
3.0 (2.0–5.0)
|
3.0 (1.0–5.0)
|
4.0 (2.0–5.0)
|
0.0287
|
Days from symptom onset to corticosteroid treatment
|
13.0 (10.0–16.0)
|
14.0 (11.0–18.0)
|
11.0 (9.0–14.0)
|
0.0031
|
Days from admission to corticosteroid treatment
|
1.0 (0.0–3.0)
|
1.0 (0.0–4.0)
|
1.0 (0.0–2.0)
|
0.1892
|
Days from ARDS to corticosteroid treatment
|
0.0 (0.0–2.0)
|
1.0 (0.0–2.0)
|
0.0 (-1.0–1.0)
|
0.0102
|
Days from ventilation to corticosteroid treatment
|
-1.0 (-3.0–0.0)
|
-1.0 (-3.0–0.0)
|
-2.0 (-4.0–1.0)
|
0.7576
|
Note: Data are n (%) or medium (IQR). For continuous variables, t-test or Mann-Whitney U test was used to calculate the P value unless otherwise noted. For categorical variables, chi-square test was used to calculate the P value unless otherwise noted.
In the logistic regression model generating propensity score, the pre-selected variables most closely correlated with prescription of systemic corticosteroids included age, blood lymphocyte count, heart rate and CRP. (eTable 2, Additional file 1) The multivariable regression model of propensity for corticosteroid treatment had area under the receiver operating characteristic curve (ROC) of 0.71, indicating good discrimination.
In survival analysis, univariable time-dependent Cox regression model showed the prescription of corticosteroids was associated with a lower risk of death (HR: 0.48; CI: 0.25, 0.93; p = 0.0285) (Table 3). When adjusted for propensity score, the estimated HR was 0.49 (CI: 0.25, 0.93; p = 0.0298). In full model adjusted for age, sex, SOFA score, propensity score, and comorbidities, the association remained significantly (HR: 0.51; CI: 0.27, 0.99 ; p = 0.0471) (Fig. 1). The association was found among patients treated within 1 day after ARDS onset (HR: 0.50; CI: 0.26, 0.98; p = 0.0439). The patients received corticosteroids 2 days after ARDS onset all survived, thus the estimated HR of this subgroups were not calculated. In patients treated within 14 days after symptom onset, corticosteroids group showed a trend of lower risk of death (HR: 0.47; CI: 0.22, 0.98; p = 0.0446).
Table 3
Estimated effects of corticosteroid treatment on sixty-day mortality in patients with ARDS associated with COVID-19
|
No.
|
Hazard Ratio
|
95% CI
|
P- Value
|
All ARDS patients
|
|
|
|
|
Univariate model
|
382
|
0.48
|
0.25, 0.93
|
0.0285
|
Propensity scorea adjusted model
|
361
|
0.49
|
0.25, 0.93
|
0.0298
|
Full multivariate modelb
|
325
|
0.51
|
0.27, 0.99
|
0.0471
|
Subgroup analysisb
|
|
|
|
|
Initiated ≤ 1 days after ARDS onset vs. no corticosteroids (reference)
|
290
|
0.50
|
0.26, 0.98
|
0.0439
|
Initiated ≤ 14 days after symptom onset vs. no corticosteroids (reference)
|
243
|
0.47
|
0.22, 0.98
|
0.0446
|
Initiated > 14 days after symptom onset vs. no corticosteroids (reference)
|
220
|
0.54
|
0.13, 2.26
|
0.4007
|
Note: All of the models assessed the effects of corticosteroids as a time-varying covariate. All patients in the subgroup with corticosteroid treatment initiated > 1 days after ARDS onset were survived. So the HR of this subgroup was not reported.
Abbreviations: ARDS, acute respiratory distress syndrome; FIO2, fraction of inspired oxygen; SOFA, sequential Organ Failure Assessment; SpO2, pulse oxygen saturation.
a Propensity score was calculated by a non-parsimonious logistic regression model that included: age; sex; SOFA score at admission; temperature, respiratory rate, SpO2/FiO2 ratio, blood lymphocyte count, blood neutrophil count, and level of c-reactive protein at admission. bAdjusted for age, sex, SOFA score at admission, propensity score of corticosteroid treatment, and comorbidities : diabetes, hypertension, chronic pulmonary disease, chronic renal or liver disease, solid malignant tumor, hematologic malignancy, and immunosuppressive status.
In sensitivity analysis, narrowing to patients meet the Berlin definition of ARDS did not alter the association between corticosteroids and lower risk of death. The HR of corticosteroids on mortality were negative albeit insignificant when excluding patients treated with lopinavir or vital signs, laboratory findings and SOFA score on the ARDS onset date were used in time-dependent Cox regression analysis adjusting for the same confounders. (eTable 3, Additional file 1)
Viral shedding was observed in 9.2% (188/382) of the whole population, including 69.3% (124/179) of survivors and 31.5% (64/203) of the non-survivors. We found no difference in duration of viral shedding from symptom onset between corticosteroids treated group and the corresponding group (19.0 [IQR 14.0–23.0] vs. 18.0 [IQR 14.0–24.0], p = 0.7217) (Table 1) and between survivors and non-survivors (18.0 [IQR 14.0–23.0] vs. 18.0 [IQR 14.0–23.25], p = 0.9704) (eTable 1, Additional file 1).
CRP level decreased among corticosteroids group on the first 4 days after ARDS onset (Fig. 2), while an increase was found in non-corticosteroids group. CRP levels were significantly lower in corticosteroids treated group after 2 days of ARDS onset, indicating a suppression of inflammatory response due to corticosteroid treatment. The IL-6 level was comparable between the two groups(eFigure 2, Additional file 1).