Corticosteroid therapy in critically ill patients with COVID-19: a multicenter, retrospective study

We retrospectively studied all critically ill patients with COVID-19 admitted to 10 Intensive Care Units (ICUs) in Hubei province between December 30, 2019 and February 19, 2020. The data was censored on April 9, 2020. All patients were consecutive. Those receiving chronic corticosteroid therapy before the onset of critical illness were excluded. COVID-19 was diagnosed according to World Health Organization interim guidance. Critically ill patients were defined as those admitted to the ICU who required mechanical ventilation or had a fraction of inspired oxygen of at least 60%. This study was approved by the institutional ethics board of the participating medical centers (NO. 2020045).

Data was extracted from the medical records of patients, reviewed and verified by the research team from the Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University. Extracted data included epidemic data, demographic data, comorbidities, complications, treatments and time course of illness. Laboratory findings and respiratory mechanic variables on day 1 of ICU admission were also collected. Severity of illness was assessed using the Acute Physiology and Chronic Health Evaluation (APACHE) II score and organ dysfunction was assessed using the Sequential Organ Failure Assessment (SOFA) score, both of which were recorded on day 1 of ICU admission. The primary outcome was determined as 90-day mortality after ICU admission and secondary outcome as duration of SARS-CoV-2 RNA clearance.

ARDS was diagnosed according to the Berlin Definition and acute kidney injury (AKI) was diagnosed according to the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines [9, 10]. Acute cardiac injury was defined as blood levels of hypersensitive troponin I above the upper reference limit (> 26.2 pg/ml). Duration of SARS-CoV-2 RNA clearance was defined as the time from ICU admission until the occurrence of two negative Nucleic-acid Amplification tests (NAAT) without a positive test afterward. Corticosteroid therapy was defined as the use of systemic corticosteroids when dosage equivalent to at least 60 mg of hydrocortisone per day [11]. The type, daily dose, and duration of corticosteroid administration were collected. All preparations were converted to hydrocortisone-equivalent doses (methylprednisolone 1:5, dexamethasone 1:25, prednisolone 1:4).

All statistical analyses were performed using R Project. A p value less than 0.05 was considered statistically significant. We calculated the a priori sample size using online software (A-priori Sample Size Calculator for Multiple Regression: https://​www.​danielsoper.​com/​statcalc/​calculator.​aspx?​id=​1). Totally, 14 variables were selected in our study. We assumed that anticipated effect size was 15%, desired statistical power was 80%, alpha level (type I error) was 0.05 [12‐14]. The calculated sample size was 135. In current study, 294 patients were included (survivor: 148, non-survivor: 146). We tested the associations of corticosteroid therapy and 90-day mortality or SARS-CoV-2 RNA clearance using three approaches: logistic regression, Cox and MSM.

Cox was used to adjust for baseline differences and immortal time bias. To examine outcomes as a time to event (i.e., death), we performed a Cox adjusting for the same above-mentioned baseline covariates with corticosteroid therapy as a time-varying covariate.

MSM was used to adjust for baseline differences and time varying confounders (indication bias and immortal time bias). Time-varying variables were determined as PaO₂/FiO₂, ventilation status and SOFA scores on the day of corticosteroid therapy initiation. Refining marginal structural models involves the calculation of two weights for each observation: treatment selection weight and censoring weight. The treatment selection weight at time k is a ratio of two weights. The numerator is the product of probabilities that a patient receives his observed treatment at time k, given the baseline variable. The denominator is calculated similarly by incorporating the time-varying variable (SOFA on the day, SOFA on the previous day, mode of ventilation on the day and mode of ventilation on the previous day). The weights are recalibrated until the first day of corticosteroid therapy and kept constant afterward. Since SOFA scores were recorded on Days 1, 3, 7, 14, and 28, we imputed missing values for the remaining days using the following rules: (a) If ICU length of stay (LOS) ≥ 28, we used linear interpolation for each of the intervals 4–6 days, 8–13 days and 15–27 days. (b) If 14 ≤ ICU LOS ≤ 27, we used linear interpolation for 4–6 days and 8–13 days and the Last-Observation-Carried-Forward method from day 15 onwards. (c) Missing values are managed similarly for ICU LOS less than 14 days. Ventilation status was recorded also on Days 1, 3, 7, 14, and 28. We imputed the mode of ventilation between these days using the Last-Observation-Carried-Forward method.

Data was collected from critically ill COVID-19 patients who admitted to ten participating hospitals between December 30, 2019 and February 19, 2020. Within the study period, two patients were excluded due to long-term treatment with glucocorticoids prior to contraction of COVID-19, and seven cases were excluded due to missing outcome variables. In total, 294 patients with COVID-19 were included in this study. 183 of 294 patients (62.2%) received corticosteroid therapy (Table 1). Immunosuppression was more common in non-corticosteroid group than in corticosteroid group. Troponin I (TnI), bilirubin and SOFA scores of corticosteroid group were higher than those of non-corticosteroid group. Lymphopenia was more obvious in corticosteroid group than in non-corticosteroid group. Respiratory failure in patients receiving corticosteroid treatment was more severe than that in patients not receiving corticosteroid treatment, resulting in a lower PaO₂/FiO₂ value, higher percentage of mechanical ventilation, longer ventilation duration, and higher frequency of ARDS. Secondary infections are more likely to occur in the corticosteroid group during ICU stay. However, there was no significant difference in crude 90-day mortality between patients treated with corticosteroid and those not treated with corticosteroid (97 of 183 [53%] vs 49 of 111 [44%]; p = 0.18). 90-day survivors in the corticosteroid-treated group took longer to clear RNA than those in the non-corticosteroid group (10 [5, 17.5] vs 7 [1, 15]; p = 0.049).

The distribution of patients with or without steroid therapy in 10 medical centers was shown in Fig. 1. The most widely-used steroid was methylprednisolone (Table 2), with 175 of 183 patients (96%) receiving methylprednisolone therapy and 11(6%) patients receiving hydrocortisone therapy. The median of Hydrocortisone equivalent per ICU day was 200 mg (IQR, 100–320.9) and the median duration of steroids treatment was 9 days (IQR, 5–14). The median of PaO₂/FiO₂ was 119 mmHg (IQR, 82–200) and SOFA score was 4 (IQR, 3–6) at corticosteroid initiation. 127 of 183 (69.4%) patients received corticosteroid treatment prior to ICU admission (Fig. 2). The time of corticosteroid initiation before ICU admission is shown in Additional file 1: Figure S1.

Univariate analysis indicates that adverse outcomes are positively correlated with clinical condition at the time of ICU admission, including positive end-expiratory pressure (PEEP), PaO₂/FiO₂, APACHE II score and laboratory testing (creatinine, TnI, bilirubin and platelet count) (Additional file 2: Table S1). Non-survivors had more complications, including shock, ARDS and AKI. Variables were included in the multivariate analysis if p value ≤ 0.2. In our logistic regression, adjusted variables included age, hypertension, cardiovascular disease, PEEP, plateau pressure, mean arterial pressure, creatinine, TnI, lymphocyte percentage, bilirubin, platelet count, secondary infection and APACHE II score. After accounting for these adjustments, there was no association between corticosteroid therapy and 90-day mortality (OR, 0.15; 95% CI 0.00, 2.59; p = 0.22) (Table 3). There was also no significant association between corticosteroid treatment and 90-day mortality when analyzed using Cox (HR, 1.37; 95% CI 0.54, 3.47; p = 0.51) and MSM (OR, 1.37; 95% CI 0.93, 2.02; p = 0.11).

Sensitivity analysis was performed by comparing patients who were treated with different dosages of corticosteroids. MSM with inverse probability weighting analysis showed that both high and low dosage of corticosteroid therapy were not associated with mortality (corticosteroids > 300 mg/day vs no corticosteroids OR, 1.01; 95% CI 0.62, 1.64; p = 0.98; corticosteroids ≤ 300 mg/day vs no corticosteroids OR, 1.42; 95% CI 0.93, 2.17; p = 0.1). However, the initiation of corticosteroid in three days after ICU admission were associated with higher mortality in logistic regression model (OR, 4.49, 95% CI 1.17, 17.25, p = 0.025), Cox (HR, 3.89; 95% CI 1.94, 7.82; p < 0.001) and MSM (OR, 2.32, 95% CI 1.16, 4.65; p = 0.017). The association between corticosteroid therapy and higher 90-day mortality remained unchanged after the adjustment for clustering by site (data not shown).

Unadjusted analyses showed significant differences in the time of RNA clearance between patients receiving corticosteroid treatment and those who had not received corticosteroid treatment (10 days [IQR, 5–17.5] vs 7 days [1, 15], p = 0.049) (Table 1). Cox accounting for time-varying exposure showed no significant association between initiation of corticosteroid therapy and time to SARS-CoV-2 RNA clearance (HR, 1.10; 95% CI 0.36, 3.37; p = 0.86) (Table 3). Similarly, MSM analysis did not show significant association between corticosteroid therapy and SARS-CoV-2 RNA clearance (OR, 0.85; 95% CI 0.63, 1.17; p = 0.33). Sensitivity analysis also revealed that different doses of corticosteroid were not associated with SARS-CoV-2 RNA clearance. Although initiation of corticosteroids in 3 days after ICU admission promoted RNA clearance in Cox (HR, 0.26; 95% CI 0.13, 0.54; p < 0.001), this effect was no longer present after adjustment of time variables. In general, our analyses did not determine significant associations between corticosteroid treatment and SARS-CoV-2 RNA clearance.