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Effects of different corticosteroid therapy on severe COVID-19 patients: a meta-analysis of randomized controlled trials

ABSTRACT Background To assess the efficacy and safety of corticosteroids in COVID-19 patients compared with standard care or placebo. Methods Electronic databases were searched to identify relevant studies. The mortality, adverse events, and other data from studies were pooled for statistical analysis. Results Ten randomized clinical trials were eligible for inclusion. Corticosteroid treatment in COVID-19 patients did not significantly reduce the risk of death (RR: 0.93; CI: 0.82, 1.05) and the need for mechanical ventilation (RR: 0.82; CI: 0.62, 1.08). No mortality reduction was also observed in the subgroup of patients requiring mechanical ventilation (RR: 0.90; CI: 0.79–1.03). The use of corticosteroids increased mortality in the subgroup of patients not requiring oxygen support (RR: 1.24; CI: 1.00–1.55). The survival benefit was observed in a low dosage of corticosteroids (RR: 0.90; CI: 0.84–0.97) and dexamethasone (RR: 0.90; 95% CI: 0.79–1.04). There was no difference in the rates of adverse events (RR: 1.13; CI: 0.58, 2.20) and secondary infections (RR: 0.87; CI: 0.66, 1.15). Conclusion Corticosteroid treatment did not convincingly improve survival in severe COVID-19 patients. Low-dose dexamethasone could be considered as a drug for the treatment of COVID-19 patients. More high-quality trials are needed to further verify this conclusion. Expert Opinion: The effect of corticosteroids on patient survival highly depended on the selection of the right dosage and type and in a specific subgroup of patients. This meta-analysis, which included more RCTs, evaluated the safety and efficacy in severe COVID-19 patients and analyzed the effects of different types of corticosteroid treatments. Corticosteroid treatment did not convincingly improve survival in severe COVID-19 patients. But the low dose dexamethasone appear to have a role in the management of severe COVID-19 patients.


Introduction
Since December 2019, coronavirus disease 2019 (COVID-19), a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), has affected the world [1,2]. Severe pulmonary or extrapulmonary symptoms and even death may present in different populations [3,4]. Up to July 2021, the SARS-COV-2 pandemic had resulted in approximately 4 million deaths worldwide [5], and the number is still rising. Nevertheless, there is currently no definitive and effective antiviral treatment for COVID-19 [6]. Therefore, it is of utmost urgency to determine drug treatment plans to address this severe disease.
Corticosteroids have been confirmed to have an excellent inhibitory effect on the expression of cytokines involved in the inflammatory response and are used as adjuvant drugs to treat viral pneumonia [7,8]. However, the value of corticoids in the treatment of COVID-19 has been widely debated with conflicting results [9][10][11]. Several trials have revealed that COVID-19 patients treated with corticosteroids had lower all-cause mortality than those not treated with corticosteroids [12,13]. Meanwhile, other randomized controlled trials (RCTs) showed no significant difference in allcause mortality between COVID-19 patients treated with corticosteroids and those not treated with corticosteroids [10,14]. Previous meta-analyses mainly focused on the association between corticosteroids and COVID-19, and few of them explored the dose, the type of corticosteroids, and the disease severity of patients. In addition, most of the studies included in previous meta-analyses were retrospective or observational studies, or fewer RCTs, which provide low evidence grades to draw a scientific conclusion on the systemic use of corticosteroids in COVID-19 patients [15]. Our meta-analysis, which included more RCTs, aimed to evaluate the safety and efficacy in severe COVID-19 patients to provide a high level of evidence for clinical decisionmaking in treating severe COVID-19 patients.

Methods
This study-level systematic review and meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16]. The PROSPERO registration ID is CRD42021229507.

Inclusion and exclusion criteria
The inclusion criteria were as follows: (1)age>18 years; (2) hospitalized patients diagnosed with COVID-19; (3) patients treated with corticosteroids; (4) RCTs; (5) patients with SpO 2 ≤ 94% at room air or the use of supplementary oxygen or mechanical ventilation; and (6) all languages available. The exclusion criteria were as follows: (1) lack of placebo or control group; (2) studies with missing data or outliers; (3) lack of dose control group or no fixed-dose strategery; and (4) repeated publication of literature or research using similar data.

Outcomes
The primary outcomes of this study included mortality and adverse events. The secondary outcomes included the need for invasive mechanical ventilation (for patients not intubated at inclusion) and secondary infections.

Data extraction
The two authors (Jiayuan T and Tian X) who screened studies according to the inclusion and exclusion criteria also independently extracted data from the included studies. Any differences were resolved by a third reviewer (Yun Liu) or by consensus. The extracted information included the first author, study design, median age, sex, intervention (including the type and dosage of corticosteroids), control, primary outcomes, and secondary outcomes.

Quality assessment
Two other reviewers independently assessed the quality of the RCTs with the Cochrane risk of bias tool, which contains seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias [17]. A third reviewer arbitrated any disagreements.

Statistical analysis
The data were analyzed using Review Manager 5.4. We derived risk ratios (RRs) and their 95% confidence intervals (CIs) for dichotomous outcomes. Depending on the presence of statistical heterogeneity, we used either fixed-effect or random-effects models. We quantified inconsistencies in associations among the trials using the I 2 statistic and derived P values for heterogeneity using the Cochran Q statistic. P < 0.05 was considered statistically significant. Sensitivity analysis was conducted to assess the stability of the combined results.

Study selection and characteristics
A total of 1647 articles were identified by searching the electronic databases. After the duplicates were removed, 1058 articles remained. A total of 573 articles were excluded after the title and abstract screening. After assessing the remaining 16 articles, six were excluded because they either did not report corticosteroid treatment or were not RCTs. Finally, 10 articles were included ( Figure 1) [10,11,14,[18][19][20][21][22][23][24].
The main characteristics of the included studies are shown in Table 1. The studies originated from Brazil, Iran, the United Kingdom, China, Spain, and France with international cooperation, with varied sample sizes ranging from 50 to 6425 patients. The median ages of the patients in the enrolled studies ranged from 54 to 73 years, and the patients were predominantly male (46.5% to 72%). Clinical heterogeneity is mainly due to inclusion criteria, mechanical ventilation, type of corticosteroid, dosage and duration of administration, accompanying antiviral or anti-inflammatory drugs.

Discussion
In this study, a meta-analysis of 10 randomized clinical trials with a total of 12,473 severe COVID-19 patients showed corticosteroids treatment did not significantly reduce mortality. However, the subgroup analysis found the survival benefit was observed in both patients treated with a low dosage of corticosteroids and patients treated with dexamethasone. No increased risk of the need for mechanical ventilation, adverse events, or secondary infections were found. However, due to the great heterogeneity between trials, clear conclusions remain a challenge. COVID-19 is an emerging infectious disease, and there is currently no optimal treatment [8]. Based on its in vitro SARS-CoV-2 antiviral activity and data from observational researches that effectively reduce viral load, corticosteroids have been widely used in severe COVID-19 patients [24], Whether the efficacy of this strategy has been controversial. Several metaanalysis studies have evaluated the efficacy of corticosteroids in COVID-19 patients with inconsistent results. In a metaanalysis based on retrospective studies, Pei et al. [25] reported that corticosteroids treatment might increase the risk of death (OR: 2.43; 95% CI: 1.44-4.1; P = 0.0001). Another meta-analysis  of cohort studies shared a similar conclusion that corticosteroids were ineffective in reducing mortality, shortening the duration of symptoms, or virus clearance time [26]. However, both of these meta-analyses include non-RCTs, which may be biased and reduce the quality of conclusions. Conversely, Some recent meta-analyses of RCTs showed a mortality benefit in severe COVID-19 patients treated with corticosteroids [27,28]. Our meta-analysis included more RCTs and reached the different conclusions that 1135 (26.2%) patients died in the corticosteroid treatment group, 2153 (26.5%) patients died in the usual care or placebo group, corticosteroids did not significantly reduce the risk of death. But due to the different inclusion criteria, type of corticosteroid, dosage, this conclusion had great heterogeneity.
The effect of corticosteroids on patient survival highly depended on the selection of the right dosage and type  and in a specific subgroup of patients [27]. Pasin et al. [29] found a reduction in mortality was observed in the subgroup of patients who required mechanical ventilation. It was recommended that severe patients could consider corticosteroids therapy. In our meta-analysis, the survival benefit of corticosteroid therapy was not observed in the subgroup of patients requiring mechanical ventilation. Evidence was mainly obtained from 5 trials, of which four trials showed no survival benefit [14,20,22,24]. One trial indicated that the use of dexamethasone reduced the 28day mortality among those receiving either mechanical ventilation or oxygen alone [11]. Remarkably, our study found patients who have not received oxygen had a trend toward increased mortality when using corticosteroids. Jeronimo et al. [14] proposed a possible explanation that early use of corticosteroids in COVID-19 patients could lead to an increase in viral load, which needs to be confirmed by further studies. Therefore, caution is needed in the use of corticosteroids in mild subjects not receiving oxygen therapy. In addition, Patients over 60 years old receiving corticosteroids therapy had a lower mortality rate, while patients under 60 years old had a higher mortality rate [14]. However, Corral-Gudino et al. [21] found no evidence of interaction between treatment and patient age; corticosteroids have similar beneficial effects in the treatment of young and old patients.
Subgroup analyses of different dosages and types of corticosteroids were performed in our meta-analysis. The survival benefit was observed in a low dosage of corticosteroids but not in high-dose corticosteroids. Similar to Ma et al.'s findings [27]. 8 studies used low-dose corticosteroids (25-150 mg/d, methylprednisolone) and 2 studies used high-dose corticosteroids(>150 mg/d, methylprednisolone) [30]. Edalatifard et al. [19] used a higher dose of   methylprednisolone(250 mg/d), and the results suggest it could be an efficient therapeutic agent for COVID-19 patients. On the contrary, Horby et al. [24] used 1200 mg/ d hydroxychloroquine (equivalent dose was 240 mg/d methylprednisolone), and results suggest it had a longer duration of hospitalization and a higher risk of invasive mechanical ventilation or death. In previous research, the mortality rate was extremely high among COVID-19 patients treated with high-dose corticosteroids [31]. However, due to limited trials and great clinical heterogeneity, more data are required to elucidate the underlying clinical significance.
The survival benefit was also observed in treatment with dexamethasone. In our study, the main types of corticosteroids were hydrocortisone, dexamethasone, and methylprednisolone. No difference in mortality was found in the subgroups of hydrocortisone and methylprednisolone. A retrospective quasi-experimental study showed that dexamethasone is more effective in improving the PO2/FiO2 ratio of COVID-19 patients than methylprednisolone [32]. Another study also provided evidence that dexamethasone and betamethasone are effective for COVID-19 treatment because of their potential to inhibit the proteolytic activity of Mpro (a cysteine protease that plays a vital role in polyprotein processing and virus maturation) by comparing molecular docking studies of six corticosteroids (cortisone, hydrocortisone, prednisolone, methylprednisolone, betamethasone, and dexamethasone) and two repurposed drugs (darunavir and lopinavir) [33][34][35][36]. However, these survival benefits depended largely on the RECOVERY trial [11], which consisted of approximately 83.5% and 94.8%of the total number of patients in the analysis. if the RECOVERY trial excluded [11], these survival benefits were absent, more RCTs are needed in the future to draw definite conclusions.
The safety of corticosteroids in COVID-19 still is debated. Corticosteroid therapy attenuates the immune response, which increased the chance of infection and other adverse events [37]. In our study, seven studies reported the incidence rate of adverse events in COVID-19 patients (corticosteroid:7.0% vs control:5.9%) [10,[18][19][20][21]23,24]. Four studies reported the incidence rate of nosocomial infections (corticosteroid:22.8% vs control:26.7%) [10,[19][20][21]. There was no difference in the rates of adverse events and nosocomial infections between the corticosteroids group and the control group. One of 7 studies (GLUCOCOVID) showed that hyperglycemia (>180 mg/dl) was more frequent in the corticosteroid group in the ICU, with a significant difference [21]. Tomazini et al. [20] also reported unspecified hyperglycemia. Except for hyperglycemia, the incidence of adverse events was similar in either group. Similarly, a systematic review including peer-reviewed studies of any design reported that hyperglycemia was the most common adverse effect [38]. Therefore, when corticosteroids are used in clinical treatment, we need to pay more attention to blood sugar levels.

Limitations
The study has several limitations. First, only ten trials were included, and we were unable to obtain data for the ongoing unfinished studies, which may cause selection bias. Second, the presence of confounding variables (age, severity of disease, corticosteroids type, dosage, treatment duration, and so on) led to significant clinical heterogeneity and weakened the results of this meta-analysis. Therefore, the summary results need to be interpreted carefully. Third, the mortality rates in different periods were reported by multiple studies; 5 trials reported mortality at 28 days, 2 trials reported mortality at 21 days, 1 trial reported mortality at 14 days, and 1 trial did not mention the time of death, potentially leading to inconsistent experimental results. Fourth, Except for the RECOVERY trial and RECOVERY2 trial, most of the included studies have small sample sizes and may be biased. Small studies might have lower quality and a high risk of bias, which might contribute to the exaggerated intervention effects compared with large studies, so further exploration is needed [39,40].

Conclusions
In this meta-analysis of 10 RCTs and 12473 severe COVID-19 patients, pooled results suggested that corticosteroid therapy did not convincingly improve survival and reduce the need for mechanical ventilation in severe patients with COVID-19, and it is not recommended for patients who do not require oxygen support. A low dosage of dexamethasone could be considered as a drug for the treatment of COVID-19 patients. Due to significant clinical heterogeneity, more high-quality clinical trials are needed to further verify this conclusion.

Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Ethics approval and consent to participate
Not applicable. The PROSPERO registration ID is CRD42021229507.

Availability of data and material
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions
JY. Tu and T Xie conducted the literature search and selected studies. XQ. Mo and XD. Zhang assessed the methodologic quality of the studies. J Xie, Y Liu, and XS. Chen extracted data. JY. Tun conceived and planned the review, assessed the methodologic quality of the studies, verified the data, and drafted and revised the manuscript. T Xie provided methodologic advice, content expertise, and revised the manuscript. All authors contributed to writing the protocol. All authors read and approved the final manuscript.

Funding
This paper was not funded.