Efficacy and safety of glucocorticoids use in patients with COVID-19: a systematic review and network meta‑analysis

Background Currently, some meta-analyses on COVID-19 have suggested that glucocorticoids use can reduce the mortality rate of COVID-19 patients, utilization rate of invasive ventilation, and improve the prognosis of patients. However, optimal regimen and dosages of glucocorticoid remain unclear. Therefore, the purpose of this network meta-analysis is to analyze the efficacy and safety of glucocorticoids in treating COVID-19 at regimens. Methods This meta-analysis retrieved randomized controlled trials from the earliest records to December 30, 2022, published in PubMed, Embase, Cochrane Library, CNKI Database and Wanfang Database, which compared glucocorticoids with placebos for their efficacy and safety in the treatment of COVID-19, Effects of different treatment regimens, types and dosages (high-dose methylprednisolone, very high-dose methylprednisolone, Pulse therapy methylprednisolone, medium-dose hydrocortisone, high-dose hydrocortisone, high-dose dexamethasone, very high-dose dexamethasone and placebo) on 28-day all-caused hospitalization mortality, hospitalization duration, mechanical ventilation requirement, ICU admission and safety outcome were compared. Results In this network meta-analysis, a total of 10,544 patients from 19 randomized controlled trials were finally included, involving a total of 9 glucocorticoid treatment regimens of different types and dosages. According to the analysis results, the 28-day all-cause mortality rate was the lowest in the treatment with pulse therapy methylprednisolone (OR 0.08, 95% CI 0.02, 0.42), but the use of high-dose methylprednisolone (OR 0.85, 95% CI 0.59, 1.22), very high-dose dexamethasone (OR 0.95, 95% CI 0.67, 1.35), high-dose hydrocortisone (OR 0.64, 95% CI 0.34, 1.22), medium-dose hydrocortisone (OR 0.80, 95% CI 0.49, 1.31) showed no benefit in prolonging the 28-day survival of patient. Compared with placebo, the treatment with very high-dose methylprednisolone (MD = -3.09;95%CI: -4.10, -2.08) had the shortest length of hospital stay, while high-dose dexamethasone (MD = -1.55;95%CI: -3.13,0.03) and very high-dose dexamethasone (MD = -1.06;95%CI: -2.78,0.67) did not benefit patients in terms of length of stay. Conclusions Considering the available evidence, this network meta‑analysis suggests that the prognostic impact of glucocorticoids in patients with COVID-19 may depend on the regimens of glucocorticoids. It is suggested that pulse therapy methylprednisolone is associated with lower 28-day all-cause mortality, very high-dose methylprednisolone had the shortest length of hospital stay in patients with COVID-19. Trial registration PROSPERO CRD42022350407 (22/08/2022). Supplementary Information The online version contains supplementary material available at 10.1186/s12879-023-08874-w.


Introduction
SARS-Cov-2 was first discovered in Wuhan, China in 2019 [1].COVID-19, caused by SARS-Cov-2 [2], has been declared as a global pandemic by world health organization (WHO) in March 2020.The main clinical manifestations of COVID-19 are fever, dry cough and fatigue, with a small number of patients accompanied by nasal congestion, runny nose, sore throat and diarrhea [3], patients with severe novel coronavirus pneumonia are characterized by a severe cytokine storm, in which the overproduction of pro-inflammatory cytokines leads to increased vascular permeability and multiple organ failure [4], poses severe challenges to not only to human health, but also global health care system [5,6].
As effective anti-inflammatory drugs, glucocorticoids are often used as adjuvant treatment of viral pneumonias and ARDS treatments [7], such as severe acute respiratory syndrome (SARS) [8], middle east respiratory syndrome (MERS) [9], etc.National Institutes of Health in the United States have included glucocorticoids as a treatment for COVID-19 patient [10].Glucocorticoid bind to the glucocorticoid receptors, thus affects many physiological pathways, including metabolism, cell apoptosis, and benefits COVID-19 patients through its immunosuppressive action [11].Some recent studies suggest that the use of glucocorticoids can effectively reduce the mortality, increase ventilator-free days and improve the prognosis of COVID-19 patients [12,13].However, the glucocorticoid regimen and dosage used in those studies are different, so the optimal glucocorticoid regimen for COVID-19 patients remains unknown.Moreover, side effects of glucocorticoids, including hyperglycemia, electrolyte disorders, and water and sodium retention, and so on, make the safety and efficacy of their treatment of COVID-19 still controversial.
This network meta-analysis focuses on whether glucocorticoid therapy can improve the prognosis of COVID-19 patients, to find the optimal glucocorticoid regimen, so as to provide evidence for the clinical use of glucocorticoids in COVID-19 patients.

Protocol and search strategy
The study protocol of this network meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42022350407) with basic principles of data extraction and the analysis method, the literature search results are reported according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) for NMA [14] (PRISMA checklist were provided in Additional file 2).
The retrieval languages of this network meta-analysis were Chinese and English, databases including PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure Database (CNKI database), Wanfang Database, China Biology Medicine disc(CBMdisc) were searched for published randomized controlled trials.The retrieval period was from the establishment of the database to November 1, 2022.Medical Subject heading (MeSH) terms were used, including COVID-19, glucocorticoid, steroids, etc., while other keywords were limited to title and abstract (details of search strategies were provided in Additional file 1).

Study selection and data extraction
Only published randomized controlled trials of glucocorticoids for the treatment of COVID-19 were included, excluding studies including case-control studies, cohort studies, etc. Inclusion criteria included: adults(age ≥ 18 years old), confirmed COVID-19 and willingness to provide informed consent.Exclusion criteria included foreseeable and inevitable death, pregnancy, breast-feeding, and use of glucocorticoids for other needs.Full inclusion and exclusion criteria in the appendix (Additional file 1).
Articles included in this network meta-analysis was retrieved and identified by two authors (QH and CW).After full-text review, for articles that met inclusion criteria, patient characteristics, interventions, controls, and outcomes were extracted using Excel, opinions of a third author (MZ) were solicited if necessary.

Quality assessment
The risk of bias was assessed by the Cochrane Handbook for Systematic Reviews of Interventions [17,18], and was assessed independently by two investigators.The evaluation contents including randomization bias, implementation of distribution concealment scheme, blind implementation; integrity of the result data, selective reporting bias and other sources of bias.

Outcome measures and definitions
The primary outcome of this network meta-analysis is all-cause mortality at 28 days, the secondary outcome is hospitalization duration, the utilization and duration of invasive mechanical ventilation, intensive care unit admission and duration and safety outcome.

Data analysis
All statistical analyses of this review were performed in STATA, version 17.0 (Stata Corporation, College Station, TX, USA), using frequentist framework.Relative odds ratio (OR) and 95% credible intervals were used as the effect indicators of binary outcome.For continuous variables, mean difference (MD) and 95% credible intervals were used.The level of significance for all analyses was p < 0.05, the heterogeneity of the included studies was evaluated by heterogeneity parameter tau-square (τ 2 ).When P > 0.05 and τ 2 ≤ 50%, the heterogeneity of the study was small, and the fixed effect model was used.On the contrary, if P < 0.05 and τ 2 > 50%, the random effects model was used.The surface under the cumulative ranking curve (SUCRA) of each intervention was used to reflect the efficacy of different glucocorticoid treatment regimens.The closer it was to 100%, the more likely it was that the treatment regimen had the optimal efficacy.The funnel plot was drawn to determine whether there were publication bias or small sample effect.For studies that only reported the interquartile range and median, we used the methods that were introduced by literature to estimate the mean and standard deviation [19,20].

Study selection
The selection process of included studies selection is shown in Fig. 1.A total of 3877 records were retrieved Fig. 1 Flow diagram of searching processes from PubMed, Embase, Cochrane Library, CNKI fulltext database, Wanfang Database, CBMdisc and other sources.After removing duplicate literatures and further screening by reading their titles and abstracts, 1643 articles were excluded.After screening of the titles and abstracts, 1714 articles were excluded.A total of 271 articles were retrieved and under full-text reading and 74 of them were assessed for eligibility.Finally, 19 articles were included for this network meta-analysis.
To assess publication bias, we performed funnel plot analyses of OR and SE (log [OR]) for 28-day all-cause mortality of 9 glucocorticoid regimens.The distribution on both sides of the funnel plot is basically symmetrical, and most of them are concentrated in the middle and upper part of the funnel plot, indicating that there is less possibility of small sample effect or publication bias (Fig. S2a).

Other outcomes
We also conducted network meta-analysis of mechanical ventilation duration, ICU admission and ICU duration.Their network plots have shown in Fig. S1.For mechanical ventilation duration, we found that, neither HD-dm (MD = 0.40;95%CI: -0.15, 0.95), nor VHD-dm (MD = 0.40;95%CI: -0.96, -0.16) can shorten the duration of mechanical ventilation in patients with COVID-19.The MD-dm significantly increased the length of mechanical ventilation (MD = 4.63;95%CI: 3.02, 6.23) (Fig. S3a).For ICU admission and length of stay in the ICU, glucocorticoid regimens did not reduce the rate of admission or length of stay in the ICU compared with placebo (Figs.4d and 5d, S3b).SUCRA graph were shown in Fig. S4.

Discussion
Although glucocorticoids are commonly prescribed for SARS [8] and MERS [9], the efficacy of using glucocorticoids to treat COVID-19 patients remains controversial.The largest clinical trial evidence to date has shown that dexamethasone at a medium-dose (6 mg/day) reduces 28-day mortality in patients with COVID-19.However, the merits and disadvantages of other doses and types of glucocorticoids for COVID-19 treatment have not been fully explored.
This network meta-analysis was based on 19 randomized controlled trials, involving 10,544 COVID-19 patients randomly assigned to nine glucocorticoids or to placebo groups.Similar to the previous meta-analysis [38,39], a medium-dose of dexamethasone (6 mg/day) did reduce 28-day all-cause mortality, length of hospitalization, and the need for mechanical ventilation in patients with COVID-19.We further found that very high-dose methylprednisolone (80-200 mg/day) not only reduces the above outcomes, but also has better efficacy than dexamethasone (6 mg/day).
The use of pulse therapy methylprednisolone was only reported in one RCT [34].The analysis showed that pulse therapy methylprednisolone was better than any other dose and type of glucocorticoid, including very high-dose methylprednisolone methylprednisolone, in reducing patient's death within 28 days.However, the duration of mechanical ventilation use and duration of ICU admission were not reported in Edalatifard et al. 's study, therefore it could not be compared with other glucocorticoid protocols.
Due to the following limitations, this network metaanalysis should be interpreted with caution.First, SARS-Cov-2 is a highly variable virus, the time span of RCTs included in our study was 2 years, during which different RCTs may enroll patients with different virus subspecies.Different virus subspecies may have different virulence and different clinical symptoms.However, the RCTs included in this network meta-analysis did not report the subspecies of virus patients were infected with, which may be a potential source of bias [40,41].Second, our study was conducted at the study level and may not reflect variables at the patient level, limited by the quantity and quality of the included article, further studies are needed to determine the optimal type and dosage of glucocorticoids, and to take these results into account with long-term clinical efficacy and safety to provide a basis for clinical use.Third, not all glucocorticoid treatment regimens reported the outcomes we wanted to explore.For example, pulse therapy methylprednisolone did not report the length of hospital stay, invasive ventilation utilization, and ICU admission that we were interested in.
Despite these limitations, our study has two key advantages.We divided glucocorticoid treatment regimens into 9 groups, further revealing the role of glucocorticoid type and dose in the prognosis of COVID-19 patients.Secondly, we only included randomized controlled trials on glucocorticoid therapy for COVID-19, the number of included articles was larger than the previous meta-analysis, therefore, the results were more credible.
In conclusion, all included glucocorticoid regimens were superior to placebo in reducing 28-day mortality, and methylprednisolone and medium or high-dose dexamethasone were significantly superior to other treatments, among which pulse therapy methylprednisolone was the best.In terms of length of hospital stay, glucocorticoids were superior to placebo except for unreported glucocorticoid regimens and high-dose methylprednisolone, and methylprednisolone was the best.In terms of ventilation utilization, methylprednisolone (80-200 mg/day), hydrocortisone (120-400 mg/day), dexamethasone (1.125-6 mg/day) can reduce the probability of mechanical ventilation.The sequence from high to low that glucocorticoids reduced ICU admission was: highdose dexamethasone; medium-dose dexamethasone; very high-dose methylprednisolone; very high-dose dexamethasone; high-dose methylprednisolone, but there was no statistical significance.In terms of adverse effects, glucocorticoid use did not increase the occurrence of adverse reactions.
Different regimens of glucocorticoids have variable pleiotropic effects in the treatment of COVID-19.In order to better interpret our conclusions, we had discussed commonly used clinical dose of the above glucocorticoids in the treatment of COVID-19, the most common dosage of dexamethasone was medium dose, and the common dosage of methylprednisolone and hydrocortisone were both high dose.Their primary and secondary outcomes in the treatment of COVID-19 were: only medium dose dexamethasone can both reduce the 28-day all-cause mortality, hospitalization duration and mechanical ventilation requirement of patients, but could not improve ICU admission rate; high dose methylprednisolone was not reported in terms of mechanical ventilation requirement, there was no significant improvement in the other three outcomes.No RCTs had been reported on hospitalization duration and ICU admission in high dose hydrocortisone, and it didn't improve 28-day all-cause mortality and mechanical ventilation requirement in COVID-19 patients.
To compare the effects of different types of glucocorticoids on the primary and secondary outcomes of the treatment of COVID-19 at the equivalent dose, we took the most commonly used glucocorticoid regimen as an example: medium dose dexamethasone, and other equivalent doses of glucocorticoids were: medium dose methylprednisolone and hydrocortisone, the type of glucocorticoids with the best performance was medium dose dexamethasone, which can significantly reduce the 28-day all-cause mortality and other secondary outcomes, including hospitalization duration and mechanical ventilation requirement of patients.While no RCTs have been conducted on methylprednisolone at this dosage till the literature retrieval was completed in this meta-analysis.As for medium dose hydrocortisone, it was only reported in the 28-day all-cause mortality and had no improvement on it.
From the above point of view, we can conclude that medium dose dexamethasone was the most commonly used glucocorticoid regimen for the treatment of COVID-19, and it has the best effect among the commonly used and equivalent doses of other glucocorticoids.The reason for the different results of the same equivalent dose of glucocorticoids used in the treatment of COVID-19 is still unclear, and we speculate that it may be due to the different types of glucocorticoids have different metabolism and half-life: dexamethasone is a long-acting glucocorticoids, methylprednisolone is a medium-acting glucocorticoids, and hydrocortisone is a short-acting glucocorticoids.

Fig. 2
Fig.2The quality assessment of included randomized controlled trials.a Risk of bias summary (Green circles represent "low risk of bias", yellow circles represent "unclear risk of bias", red circles represent "high risk of bias").b Risk of bias graph Abbreviations: SpO2 Pulse oxygen saturation, PaO2/FiO2 Partial pressure of oxygen/ fraction of inspired oxygen, IV Intravenous injection, BID Bis in die, NIMV Non-invasive mechanical ventilation, QID Quarter in die, IMV Invasive mechanical ventilation, CPAP Continuous positive airway pressure, ARDS Acute respiratory distress syndrome, AHRF Acute hypoxemic respiratory failure, ICU Intensive care unit, TID Ter in die, RT-PCR Reverse transcription-PCR

Fig. 5
Fig. 5 SUCRA ranking charts different regimen of glucocorticoid.A 28-day all-cause mortality; B Hospitalization duration; C Mechanical ventilation requirement; D ICU admission

Table 1
Details of included studies