Of 1141 consecutive hospitalized patients with COVID-19 registered by June 30, 2020, 49 patients were excluded from this study based on these criteria: (1) diagnosis after May 2020 (25 patients); (2) duplicate registrations from 2 facilities (11 patients); (3) no clinical status information for Day 1 due to transfer from another hospital (9 patients); (4) no need to be hospitalized (2 patients), (5) PCR testing only performed on spinal fluid (1 patient), and (6) negative results on PCR, but clinical diagnosis (1 patient). Thus, 1092 patients were included in the final analysis (Figure 1).
Clinical characteristics and prognosis of the 1092 patients analyzed are shown in Supplemental Table 1 and 2. The mortality was 2.1% on Day 14, and 3.8% on Day 28. Of the 235 patients who received corticosteroids for COVID-19, 163 (69.4%) received early corticosteroids within 3 days after admission. The remaining 72 patients (30.6%) who started corticosteroid >4 days after admission had a greater decline in SpO2/FiO2 from admission to just before corticosteroid initiation and a significantly worse score on the 7-point ordinal scale on Day 15 compared with the 163 early-treatment patients (Supplemental Table 3 and 4). In evaluating the efficacy of corticosteroids for the primary endpoint (improvement in clinical status on Day 15), the research team considered it inappropriate to include patients with delayed corticosteroid administration and worsening respiratory status; moreover, early corticosteroids have been reported to be effective against COVID-19.20 Therefore, the 163 patients who received early corticosteroids within 3 days after admission were designated as the unmatched corticosteroid group, and the 857 patients who did not receive corticosteroids for COVID-19 were categorized as the unmatched non-corticosteroid group. After propensity score matching, 118 patients were assigned to either the corticosteroid and non-corticosteroid groups.
Baseline characteristics before/after propensity score matching
The distribution of the patients’ baseline characteristics according to corticosteroid exposure is shown in Table 1, both in the unmatched and matched samples. The unmatched samples included a significantly higher number of male patients and those who were older age, had a higher weight and body mass index, and had more comorbidities (hypertension and diabetes) in the corticosteroid versus non-corticosteroid group. In addition, clinical and laboratory data for the corticosteroid versus non-corticosteroid group showed significantly poorer clinical status in a 7-point ordinal scale on Day 1, lower SpO2/FiO2, higher rates of fever and dyspnea, higher CRP concentrations, and lower lymphocyte counts.
Standardized mean differences for each covariate before and after propensity score matching are shown in Figure 2. The differences between corticosteroid and pretreatment variables were attenuated in the matched versus unmatched samples for propensity score. In fact, baseline characteristics were well balanced between the corticosteroid and non-corticosteroid groups after propensity score matching (Table 1). Regarding the baseline score on the 7-point ordinal scale in the matched samples, 4 was the most common score for both the corticosteroid and non-corticosteroid groups (44.9% vs. 50.8%), followed by a score of 5 (40.7% vs. 39.0%).
Regarding the specific COVID-19 treatment administered both in the propensity score–unmatched and matched corticosteroid groups, nearly 90% of the corticosteroids administered for COVID-19 were methylprednisolone, with a median starting dose of 80 mg/day and a mean administration period of 11.0 days (Table2).
The odds of improvement in a 7-point ordinal scale on Day 15 were significantly lower in the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% CI, 0.388–0.962; p = 0.034). (Table 3). In critically ill patients with a baseline 7-point ordinal score of 2 or 3, the clinical status on Day 15 was similar in both groups (OR, 0.953; 95% CI, 0.215–4.224; p=0.950). In contrast, for patients with mild to severe disease with a baseline score of 4 or 5, the odds of improvement were lower in the corticosteroid group than in the non-corticosteroid group.
Key secondary outcomes
The key secondary outcomes are shown in Table 4. No significant differences were observed between the two groups with respect to time to PCR negativity or duration of hospitalization. The duration of fever was significantly longer in the corticosteroid group (HR, 0.746; 95% CI, 0.560–0.994; p = 0.045). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (HR, 1.758; 95% CI, 1.323–2.337; p<0.001), regardless of baseline score of 7-point ordinal scale (Figure 3). The number of patients requiring invasive mechanical ventilation was higher in the corticosteroid versus non-corticosteroid group (33.9% vs. 17.8%; p = 0.0072), with median time from admission to tracheal intubation of 2 days for both groups (Supplemental Figure 1). The duration of invasive mechanical ventilation was shorter in the corticosteroid versus non-corticosteroid group (HR, 1.466; 95% CI, 0.841–2.554; p = 0.177) (Figure 4A). Mortality on Day 28 tended to be higher in the corticosteroid versus non-corticosteroid group (10.2% vs. 4.2%; p = 0.1289), and the HR was 2.417 (95% CI, 0.868–6.733; p = 0.091) (Supplemental Figure 2A).
Subgroup analysis based on initial dose, administration period and timing of corticosteroids
Subgroup analysis was performed based on initial dose, administration period, and timing of corticosteroids (Table 5). Of the 106 patients who received methylprednisolone, the duration of invasive mechanical ventilation was significantly shorter in the pulse/semi-pulse group (initial dose ≥250 mg/day) than in the standard dose group (initial dose <250 mg/day) (median, 8 days vs. 15 days; HR, 2.831; 95% CI, 1.347–5.950; p = 0.006) (Figure 4B). In the patients receiving corticosteroids for ≤10 days, the time to PCR negativity of the swab solution tended to be shorter (HR, 1.437; 95% CI, 0.968–2.132; p = 0.072) compared with the patients receiving corticosteroids for >11 days.
Safety outcomes for both the corticosteroid and non-corticosteroid groups were also analyzed. Results showed no significant difference in the frequency of thromboembolism between the corticosteroid and non-corticosteroid groups (2.5% vs. 3.4%).