Dear Editor:

Corticosteroids are widely used in the treatment of critically ill patients for active anti-inflammatory and immunosuppressive effects. However, the therapeutic effects of corticosteroid treatment are still disputable.Some studies have shown that corticosteroids can delay coronavirus RNA clearance[1], increase mortality[2]and cause adverse events[3]. Conversely, other studies have confirmed the clinical value of corticosteroids in shortening hospital stays and decreasing the need for mechanical ventilation[4]. Similarly, the use of corticosteroids in COVID-19 patients is controversial.Expert consensus in China has indicated that corticosteroids can be used as appropriate in critical patients[5]. However, World Health Organization interim guidance opposes the routine use of corticosteroids in treatment[6]. Therefore, we herein discussed the therapeutic effects of corticosteroids in COVID-19 patients based on the experience of frontline physicians and a meta-analysis.

We analyzed the data of 67 difficult and complicated cases from 28 hospitals in 13 regions of Jiangsu Province, including 1 mild, 13 typical, 45 severe, and 8 critical patients. The severity of illness was defined by the expert consensus in China[5]. All patients were divided into two groups according to whether they used corticosteroids or not. The clinical characteristics, laboratory findings, and treatments are shown inTable 1. Data are presented as numbers (%)or median (IQR).Pvalues were calculated by chisquare test, Fisher"s exact test, or Mann-WhitneyUtest. Multidisciplinary experts guided the therapy by remote consultation through tracking vital signs and examination results and observing the dynamic changes in the patients" conditions. The results showed that the conditions of 18 corticosteroid users were improved or stable and that no patients died. We further analyzed the oxygen and blood indexes of 12 patients with complete data (≥4 consultations, followup time ≥10 days). The average course of corticosteroid treatment was 8 days. It was determined that short-term treatment with corticosteroids improved oxygen saturation (SaO2) and the ratio of arterial oxygen tension (PaO2) to inspiratory oxygen fraction(FiO2), and promoted the absorption of pulmonary lesions (Table 2). All statistical analyses were conducted by SPSS software (version 13.0). The results indicated that corticosteroids played a positive role in improving the short-term oxygenation of COVID-19 patients. To include more cases to test the hypothesis, we decided to carry out a meta-analysis.

We carried out a systematic literature search on the PubMed, EMBASE, and Web of Science databases for relevant studies on COVID-19. We used the following keywords in our search: "2019-nCoV","COVID-19", and "SARS-CoV-2". To avoid literature omission, we did not use "corticosteroids" or other keywords related to treatment. Articles dated up to March 15, 2020 were searched without language limit.Inclusion criteria were as follows: (1) the definite diagnosis of COVID-19; (2) two groups of corticosteroid use and non-corticosteroid use; (3) the clinical data available to extract. Exclusion criteria were as follows: (1) repeated publication; (2) failure to get the full text or detailed abstract; (3) the articles of editorials, reviews, or expert consensus; (4) difficulty in extracting the necessary data. Two researchers independently selected articles and extracted the data by reading the titles, abstracts, and full texts of the articles. The binary data analysis was conducted by Stata software (version 14.1).

A total of 2431 articles were preliminarily retrieved.After deduplication and assessment of titles, abstracts,and full texts, six articles were chosen for study[7–12](Fig. 1). We used the Newcastle-Ottawa scale to evaluate the quality of the study[13](Table 3). We also included our research data, in which 38 patients used corticosteroids including 32 patients with severe conditions. The conditions of 18 users were improved or stable, while 16 of the non-users achieved the same result. The conditions of the remaining patients were aggravated or even deteriorated. Characteristics of studies included are shown inTable 3.

Table 1 The clinical characteristics, laboratory findings, and treatment of COVID-19 patients

Finally, a total of 1625 subjects, including 441 corticosteroid users and 1184 non-users, were included from these 7 articles. The forest plot of critical and non-critical patients (Fig. 2A) showed critical patients are more likely to use corticosteroids(OR, 4.82; 95% CI, 3.55–6.54). The result of corticosteroid use (Fig. 2BandC) showed the improvement rate of the corticosteroid group was lower than that ofthe noncorticosteroid group (OR, 0.54; 95% CI,0.33–0.88), but corticosteroid use was not associated with mortality of COVID-19 patients (OR, 2.64; 95%CI, 0.86–2.08). Due to the small number of articles,we did not conduct heterogeneity analysis.

Table 2 The effect of corticosteroid therapy on severe and critical patients of COVID-19 patients

Fig. 1 Flowchart for study selection.

Some related meta-analyses of corticosteroid therapy for lung diseases used mortality, need for intensive care unit (ICU) admission or mechanical ventilation as prognostic indicators. In this metaanalysis, we selected only mortality. Because we thought the need for ICU or mechanical ventilation was the evaluation criteria for critical patients who need to use corticosteroids according to the experts consensus. It could not be used as a prognostic indicator simply. However, although the composite endpoints included admission to the ICU, mechanical ventilation, or death, a study by Weijie Get al[11]was included after discussion due to the large number of subjects and extra subgroups of non-severe and severe patients.

Limitations of this research and next steps

Currently, evidence for the use of corticosteroid therapy for COVID-19 patients is mostly empirical.This meta-analysis provided the first preliminary systematic review showing the prognosis and shortterm efficacy of corticosteroid use for COVID-19.Obviously, our analysis has some limitations. First,the effect of mechanical ventilation on patients"oxygenation status was not considered. Moreover, due to the limited data, the changes of indicators in the noncorticosteroid group were not discussed. Second,the studies included in the meta-analysis were mostly retrospective studies rather than high-quality randomized controlled trial (RCT) studies. Third, due to the small number of included articles, we included two that used discharge as an evaluation of improvement/stabilization, which was not consistent with other included studies. Fourth, the included studies were all Chinese studies. More studies from other different countries and regions need to be considered to carry out RCT studies and subgroup analysis.

We believed, based on the front-line COVID-19 treatment experience, that the use of corticosteroids might have a positive effect on improving the shortterm oxygenation of critically ill patients. However,there is no evidence-based support for this claim.Some researchers have indicated that corticosteroids should be applied when the body"s inflammatory response is over activated (i.e.inflammatory cytokine storm). It is necessary to make a comprehensive evaluation based on the patient"s vital signs,oxygenation status, and dynamic changes in inflammatory indicators and imaging examinations. We hope that through our first-line experience and preliminary meta-analysis, new thoughts could be inspired for future researchers. Strictly following the indications of corticosteroid use, avoiding the occurrence of adverse events, and applying a more standardized and reasonable regimen of corticosteroids need not only to be proved by scientific evidence but also to be tested by the practical experience of front-line experts of multiple disciplines.

?

Fig. 2 Forest plot of corticosteroid therapy on COVID-19 patients. A: The use of corticosteroids in critical and non-critical patients. B:Effect of corticosteroids on improvement/stabilization. C: Effect of corticosteroids on mortality. OR: odds ratios; CI: confidence interval.

Acknowledgments

This work was supported by the Jiangsu Provincial Key Research and Development Program(BE2020616), and the National Natural Science Foundation of China (No. 81770031 and No.81700028).