DOI: 10.5061/dryad.k0p2ngf6b
title: Systemic corticosteroids and mortality in severe and critical COVID-19 patients in Wuhan, China

description: Background: Systemic corticosteroids are now recommended in many treatment
 guidelines, though supporting evidence is limited to one randomised
 controlled clinical trial (RECOVERY).  Objective: To identify
 whether corticosteroids were beneficial to COVID-19 patients. 
 Methods: 1514 severe and 249 critical hospitalized COVID-19 patients from
 two medical centers in Wuhan, China. Multivariable Cox models, Cox model
 with time-varying exposure and propensity score analysis
 (inverse-probability-of-treatment-weighting (IPTW) and propensity score
 matching (PSM)) to estimate the association of corticosteroid use with
 risk of in-hospital mortality in severe and critical cases. Results:
 Corticosteroids were administered in 531 (35.1%) severe and 159 (63.9%)
 critical patients. Compared to non-corticosteroid group, systemic
 corticosteroid use was not associated with beneficial effect in reducing
 in-hospital mortality in both severe cases (HR=1.77, 95% CI: 1.08-2.89,
 p=0.023), and critical cases (HR=2.07, 95% CI: 1.08-3.98, p=0.028).
 Findings were similar in time-varying Cox analysis. For severe COVID-19
 patients at admission, corticosteroid use was not associated with improved
 or harmful outcome in either PSM or IPTW analysis. For critical COVID-19
 patients at admission, results were consistent with multivariable Cox
 model analysis. Conclusion: Corticosteroid use was not associated with
 beneficial effect in reducing in-hospital mortality for severe or critical
 cases in Wuhan. Absence of the beneficial effect in our study in contrast
 to that was observed in the RECOVERY clinical trial may be due to biases
 in observational data, in particular prescription by indication bias,
 differences in clinical characteristics of patients, choice of
 corticosteroid used, timing of initiation of treatment and duration of
 treatment.    
description: Patients and methods Study
 Population Consecutive inpatients with laboratory
 confirmed or clinically diagnosed COVID-19 from Wuhan Hankou Hospital and
 No. Six Hospital of Wuhan between December 26th, 2019 and March 15th 2020
 were collected in this study. The final follow up date was March 19th,
 2020. Patients who met any of the following conditions were exclude from
 the study: 1. Non-severe or non-critical cases; 2. Not being diagnosed as
 severe cases within 24 hours since admission; 3. The time of being
 diagnosed of severe/critical cases were missing. Severe cases were defined
 as those who required oxygen therapy during hospital stay. Critical cases
 were defined based on the 7th trial version of Diagnosis and Treatment
 Scheme for Pneumonitis caused by COVID-19 Infection (16). Therefore, those
 who met any of the following conditions during the whole hospital stay
 were categorised as critical cases: 1. requiring mechanical ventilation;
 2. requiring treatment in intensive care unit (ICU); 3. shock occurred in
 hospital (16). Ethical considerations
 This study was approved by the ethics committees of Wuhan Hankou
 Hospital, No. Six Hospital of Wuhan and the First Affiliated Hospital of
 Sun Yat-sen University, and the informed consent was waived. The study
 followed the tenets of the Declaration of Helsinki and is reported as per
 the Strengthening the Reporting of Observational Studies in Epidemiology
 (STROBE) guideline. Data Collection and
 Definition We collected the patients’ clinical data,
 including demographic information, medical history, laboratory indexes,
 corticosteroid use and prognosis. The admission laboratory indexes were
 defined as the first records of laboratory indexes since admission.
 Corticosteroid use was defined as the use of intravenous systemic
 corticosteroids, including hydrocortisone, methylprednisolone, and
 dexamethasone. The dose of corticosteroids was converted to
 methylprednisolone-equivalent doses (1mg methylprednisolone = 0.1875mg
 dexamethasone = 5mg hydrocortisone) (20). At the time of the study limited
 guidance existed on when to use corticosteroids and therefore most
 decision were based on intuitiveness of the clinician following assessment
 of the clinical state and after excluding any contraindication for
 corticosteroid use. Exposure and Outcome
 We evaluated whether using corticosteroids could affect the
 in-hospital mortality of severe/critical cases. The time to death was
 defined as the time of being diagnosed of severe/critical cases to the
 date of death from any cause in hospital for the primary
 analysis. Statistical Analysis
 Data were expressed as mean and standard deviation (SD) if
 normally distributed, and median and interquartile range (IQR) with
 non-normal distribution, and frequency and percentages for categorical
 variables. We compared baseline characteristics and outcomes of patients
 who received corticosteroids and those who did not receive any
 corticosteroid using Students’ t test, Mann-Whitney test for continuous
 variables, and chi-square test or Fisher exact test for categorical
 variables. Survival with or without corticosteroid use was analysed using
 the Kaplan-Meier method and compared by log-rank test. The 28-day
 in-hospital mortality and its 95% confidence interval was reported for
 both corticosteroid use and non-corticosteroid use groups. We evaluated
 the associations between corticosteroid use and prognosis using two
 approaches. First, multivariable Cox regression models were applied to
 evaluate the association between corticosteroid use and mortality.
 Multivariable analysis was adjusted for age, gender, admission laboratory
 indexes (including lymphocyte, neutrophil granulocyte, platelet,
 haemoglobin, glucose, C-reaction protein (CRP), lactate dehydrogenase
 (LDH), creatinine, aspartate aminotransferase (AST), alanine
 aminotransferase (ALT), blood urea nitrogen (BUN), pulse oxygen saturation
 (SpO2), hypertension, diabetes, cancer, chronic obstructive pulmonary
 disease (COPD), chronic kidney disease (CKD) and smoking history. The
 proportion of missing values of baseline variables was 4.5%, ranging from
 0% to 10.6%. The missing data were imputed by multiple imputation for ten
 times in the multivariable analysis. Second, in Cox regression models,
 corticosteroid use was accounted as a time-varying exposure to mitigate
 immortal time bias. In time-varying analysis, data was reconstructed
 according to the time of corticosteroid use. Therefore, time from a
 diagnosis of severe/critical case to time of corticosteroid use was
 categorized as unexposed. The hazards ratios (HRs) and 95% confidence
 intervals (CIs) of Cox regression models were reported.
 We also performed propensity score driven analysis
 (inverse-probability-of-treatment-weighting (IPTW) and propensity score
 matching (PSM)) to account for confounding by indication bias in the
 time-dependant Cox regression analysis (21,22). Multivariable logistic
 regression was carried out with corticosteroid use as a binary outcome to
 obtain the predicted probability of corticosteroid use, which was taken as
 propensity score (PS). All baseline characteristics were used to construct
 PS for each three parts of patients. In IPTW, for the group with
 corticosteroids therapy, the weight was equal to 1/PS, while for the group
 without corticosteroids therapy, the weight was equal to 1/(1-PS). In PSM,
 calliper value was set as 20% of the standard deviation of propensity
 scores. We reported the effect sizes as hazard ratios in all four types of
 analysis 1) multivariable Cox regression; 2) Cox regression with
 time-varying exposure; 3) IPTW based analysis; and 4) PSM based analysis.
 Wilcoxon signed-rank test was used for pairwise comparison of mean blood
 glucose and lymphocytes before, during and after the use of
 corticosteroids, and method of Bonferroni was used for correction. We used
 Stata/MP 14.0 to conduct all data analyses, and statistical significance
 was set as p&lt;0.05 bilaterally.